Hypermobility of Joints

Transcription

Peter Beighton • Rodney Grahame
Howard Bird
Fourth Edition
Peter Beighton, OMB, MD, PhD
FRCP, FRSSA
Department of Human Genetics
University of Cape Town
Cape Town
South Africa
Rodney Grahame, CBE, MD, FRCP, FACP
Department of Rheumatolgy
University College Hospital
London
United Kingdom
Howard Bird, MA, MD, FRCP
Department of Musculo-Skeletal Medicine
University of Leeds
Leeds
United Kingdom
ISBN 978-1-84882-084-5 4th Edition
e-ISBN 978-1-84882-085-2
ISBN 978-1-85233-142-9 3rd Edition
ISBN 978-3-540-19564-1 2nd Edition
ISBN 978-3-540-12113-8 1st Edition
DOI 10.1007/978-1-84882-085-2
Springer London Dordrecht Heidelberg New York
British Library Cataloguing in Publication Data
A catalogue record for this book is available from the British Library
Library of Congress Control Number: 2011939069
© Springer-Verlag London Limited 2012
First published 1983
Second edition 1989
Third edition 1999
Fourth edition 2012
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Foreword to the Fourth Edition
It is an honour and a pleasure to introduce the fourth edition of this remarkable
book on joint hypermobility to the clinical and scientific community.
The authors of this book, Peter Beighton, Rodney Graham and Howard Bird are
distinguished physicians with a long and solid professional expertise in the clinical
and genetic aspects of articular hypermobility. Thanks to this landmark book, the
first edition of which dates from 1983, the ‘joint hypermobility syndrome’ became
gradually recognized as an important and heterogeneous clinical entity that may
bear significant impact on the physical and psychosocial well-being of affected individuals and their families.
A major strength of this work is the comprehensive approach of the subject, whereby
the authors address all medical aspects of the ‘joint hypermobility syndrome’, the clinical term that refers to the symptomatic status of articular hypermobility. Based on their
vast clinical experience and wisdom, they systematically review the diagnostic challenges and management issues and illustrate the important contribution of joint hypermobility to the pathogenesis of rheumatological and orthopaedic manifestations. In
addition, this fourth edition elaborates more extensively on the extra-articular manifestations such as autonomic dysfunction, proprioceptive impairment and chronic pain
which may significantly increase the morbidity of hypermobility conditions.
Not less importantly, the authors highlight the socio-economic and psychological burden that is associated with the chronic pain and physical disabilities that may
arise as consequences of the joint hypermobility syndromes, and draw attention to
the multidisciplinary approach of medical management that should include a combination of medical, technical, physiotherapeutic strategies and – where necessary –
behavioural techniques such as cognitive behavioural therapy.
In addition to addressing the diagnostic, nosological and management issues, the
authors also respond to the rapidly evolving scientific knowledge on the genetic and
molecular basis of joint hypermobility, by including appropriate updates of the
chapters on molecular collagen biology and on the expanding list of known heritable disorders in which joint hypermobility is a major clinical manifestation, such as
the Ehlers–Danlos syndrome.
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Foreword to the Fourth Edition
Last but not least, the final chapter opens a window to future avenues for research
by formulating some speculative but challenging topics for further study that will
certainly keep the next generation of clinicians and scientists busy not only in trying
to resolve unanswered research questions but also in translating their findings to
effective therapies for the patients. And, although the authors claim that this is the
last edition from their own hand, it is obvious that the hypermobility syndromes will
remain a fascinating clinical and scientific field for many decades to come.
A. De Paepe, M.D., Ph.D.
Professor of Human and Medical Genetics
Centre for Medical Genetics, Ghent University
Ghent, Belgium
Preface
It is now 28 years since the publication of the first edition of this book in 1983, and
updated second and third editions appeared in 1989 and 1999 respectively. It seemed
appropriate to once again re-visit this expanding and fascinating area, as urged by
the late Professor Eric Bywaters in his foreword to the third edition. We are most
grateful to Professor Anne de Paepe for gracing this fourth edition with a new
foreword.
The format is similar to that of previous monographs with the chapters on assessment, biomechanics and hypermobility in the performing arts and sports all updated.
The introduction, the chapters on the molecular basis of hypermobility, illustrative
case histories and the heritable hypermobility syndromes have been completely
re-written. The clinical chapters have also been re-written, with specific division
between articular and extra-articular features. With the expectation that this edition
will be the last from our own pens, the innovative Chap. 10 speculates on future
avenues for research that might provoke ideas and provide content for a future edition, probably with different editors, a decade hence.
The last 10 years have seen significant advances in nosology of heritable hypermobility syndromes and, in particular, in our understanding of the molecular basis
of these conditions. The latter informs on the possible pathogenesis of more heterogeneous hypermobility syndromes in the context of our increasing realisation that
joints act as a surrogate for clinical features associated with joint hypermobility in
other parts of the body.
Translational research in the field of hypermobility may lead to real advances in
this interesting group of conditions, perhaps paving the way for medical management through manipulation of cytokines connected with growth and eventually even
with genetic engineering.
Peter Beighton
Rodney Grahame
Howard Bird
vii
Acknowledgements
The authors would like to thank the following for their contribution:
Karl Ernest Kadler, B.Sc. (Hons), Ph.D.
and
Gillian Anne Wallis, B.Sc. (Hons), M.A., Ph.D.
Faculty of Medicine and Human Sciences
and Faculty of Life Sciences
University of Manchester
Michael Smith Building
Manchester M13 9PT, United Kingdom
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Contents
1 Introduction to Hypermobility ..................................................................
1.1 Historical Background ........................................................................
1.2 Rheumatological Manifestations ........................................................
1.3 Extra-Articular Manifestations of Hypermobility ..............................
1.4 Late Effects of Hypermobility ............................................................
1.5 Measurement of Joint Hypermobility .................................................
1.6 Syndromic Associations of Joint Hypermobility ................................
1.7 Nosology of the Hypermobility Syndromes .......................................
References.....................................................................................................
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2 Assessment of Hypermobility ....................................................................
2.1 Simple Scoring Systems for Hypermobility .......................................
2.2 The Brighton Criteria for Hypermobility Syndrome ..........................
2.3 General Principles of More Precise Measurement
at Selected Joints.................................................................................
2.4 Back and Spinal Mobility ...................................................................
2.5 Rotation in the Limbs .........................................................................
2.6 Movement at the Metacarpophalangeal Joint .....................................
2.7 Joint Proprioception ............................................................................
2.8 Correlations Between Scoring Systems Used in Assessing
Joint Laxity .........................................................................................
2.9 Variation of Joint Laxity Within Populations .....................................
2.10 Clinical Applications of Scoring Systems ..........................................
2.11 Joint Hypolaxity..................................................................................
References ....................................................................................................
11
12
14
3 The Molecular Basis of Joint Hypermobility ...........................................
3.1 Introduction.........................................................................................
3.2 The Family of Fibril-Forming Collagens............................................
3.3 Genes Encoding Type I and V Collagens ...........................................
3.4 Biosynthesis of Type I and V Collagens .............................................
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Contents
3.5
3.6
3.7
3.8
3.9
3.10
3.11
3.12
Collagen Fibril Assembly ...................................................................
EDS and Type I Collagen ...................................................................
EDS and ADAMTS2 ..........................................................................
EDS and Lysyl Hydroxylase ...............................................................
EDS and Type V Collagen ..................................................................
EDS and Tenascin-X...........................................................................
EDS and Type VI Collagen ................................................................
Relationship Between Elastic Fibre Abnormalities,
Marfan Syndrome and EDS ................................................................
3.13 Conclusions.........................................................................................
References ....................................................................................................
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4 Biomechanics of Hypermobility: Selected Aspects..................................
4.1 Mechanical Factors in Joint Mobility .................................................
4.1.1 Relative Contributions of Different Factors............................
4.1.2 Bony Surfaces .........................................................................
4.1.3 Collagen ..................................................................................
4.1.4 Neuromuscular Control ..........................................................
4.1.5 Proprioception.........................................................................
4.2 Podiatric Aspects ................................................................................
4.3 Lubrication and Stiffness ....................................................................
4.3.1 Lubrication of the Synovial Membrane ..................................
4.3.2 Measurement of Stiffness .......................................................
4.3.3 Artificial Lubricants ................................................................
4.4 Hypermobility and Osteoarthritis .......................................................
4.5 Prospects for Surgical Intervention.....................................................
References ....................................................................................................
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5 Musculoskeletal Features of Hypermobility
and Their Management..............................................................................
5.1 Hypermobility and Hypermobility Syndrome ....................................
5.1.1 Impaired Healing ....................................................................
5.2 Epidemiology of JHS ..........................................................................
5.3 The Clinical Significance of Hypermobility .......................................
5.4 Musculoskeletal Features....................................................................
5.5 Hypermobility Syndrome in Children ................................................
5.5.1 Epidemiology ..........................................................................
5.5.2 Clinical Presentation in Childhood .........................................
5.6 Hypermobility in Adults .....................................................................
5.6.1 Prevalence ...............................................................................
5.6.2 Role of Lax Ligaments ...........................................................
5.6.3 Clinical Manifestations ...........................................................
5.6.4 Articular Features ...................................................................
5.6.5 Soft Tissue Lesions .................................................................
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Contents
xiii
5.6.6
5.6.7
5.6.8
5.6.9
5.6.10
5.6.11
5.6.12
5.6.13
5.6.14
Chondromalacia Patellae ........................................................
Acute Articular and Peri-articular Traumatic Lesions ............
Chronic Polyarthritis or Monoarticular Arthritis in Adults ....
Dislocation of Joints ...............................................................
Temporomandibular Joint Dysfunction ..................................
Premature Osteoarthritis (Other Than TMJ)...........................
Spinal Complications ..............................................................
Bone Fragility .........................................................................
The Natural History of JHS and the Development
of Chronic Pain ......................................................................
5.7 Management of Articular Complications in the
Hypermobility Syndrome ...................................................................
5.7.1 General Management ..............................................................
5.7.2 Specific Management..............................................................
5.7.3 Rest .........................................................................................
5.7.4 Local Steroid Injections ..........................................................
5.7.5 Physiotherapy..........................................................................
5.7.6 General Principles ...................................................................
5.7.7 Passive Mobilisation ...............................................................
5.7.8 Exercise Therapy ....................................................................
5.7.9 Podiatry ...................................................................................
5.7.10 Surgical Intervention...............................................................
5.7.11 Soft Tissue Lesions .................................................................
5.7.12 Persistent Synovitis .................................................................
5.7.13 Recurrent Dislocation or Joint Instability ...............................
5.7.14 Cervical or Lumbar Discectomy .............................................
5.7.15 Surgery of the Foot .................................................................
5.7.16 Advanced Osteoarthritis .........................................................
5.7.17 Symptomatic Treatment ..........................................................
5.7.18 Analgesic and Non-steroidal Anti-inflammatory Drugs .........
5.7.19 Massage, Mobilisation, Hydrotherapy
and Water Immersion ..............................................................
5.7.20 Behavioural Techniques ..........................................................
5.7.21 Acupuncture and Transcutaneous Neural
Electrical Stimulation .............................................................
5.7.22 Denervation Procedures ..........................................................
5.7.23 Support and Information .........................................................
References ....................................................................................................
6 Extra-articular Manifestations of Hypermobility ...................................
6.1 Introduction.........................................................................................
6.1.1 Weakness of Supporting Structures Including
Pelvic Floor Insufficiency .......................................................
6.1.2 Mitral Valve Prolapse..............................................................
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Contents
6.1.3 Chronic Pain ...........................................................................
6.1.4 Proprioceptive Impairment .....................................................
6.1.5 Lack of Efficacy of Local Anaesthetics ..................................
6.1.6 Autonomic Dysfunction..........................................................
6.1.7 Certain Psychiatric Disorders .................................................
6.1.8 Functional Disorders of the Gastrointestinal Tract .................
6.2 Straws in the Wind ..............................................................................
References ....................................................................................................
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7 Illustrative Case Histories..........................................................................
Case 7.1: A 6-Year-Old Boy with EDS II/III with Grossly
Unstable Hind Feet.......................................................................
Case 7.2: Pelvic Floor Problems After Childbirth in a Patient
with EDS Hypermobility Type.....................................................
Case 7.3: A Labral Tear and Autonomic Dysfunction
Complicating Hypermobility .......................................................
Case 7.4: Complexities in Diagnosis and Management ...............................
Case 7.5: Bony Abnormality and Complications of Subluxation ................
Case 7.6: Arnold–Chiari Malformation
and Specialised Physiotherapy .....................................................
Case 7.7: The Performing Artist...................................................................
References ....................................................................................................
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8 Hypermobility in the Performing Arts and Sport ...................................
8.1 Dancers ...............................................................................................
8.1.1 Are Ballet Dancers Born or Made ..........................................
8.1.2 Is Generalised Joint Laxity an Asset or a Liability
in Ballet Dancing? ..................................................................
8.1.3 The Prevention of Injury .........................................................
8.2 Contortionists ......................................................................................
8.2.1 Historical Background ............................................................
8.2.2 Nosology and Semantics.........................................................
8.2.3 Training ...................................................................................
8.2.4 Socio-medical Implications ....................................................
8.3 Musicians ............................................................................................
8.4 Occupational Ills of Instrumentalists ..................................................
8.4.1 Illustrative Case Histories .......................................................
8.4.2 Repetitive Strain Syndrome ....................................................
8.5 Sport ....................................................................................................
8.5.1 Joint Hypermobility in Selected Sports ..................................
8.5.2 Joint Hypermobility in Cricket ...............................................
8.5.3 Joint Hypermobility in Yoga ...................................................
8.6 Hypermobility and Injury ...................................................................
8.6.1 Training Methods to Improve Joint Flexibility .......................
8.6.2 Hormonal Aspects ..................................................................
References ....................................................................................................
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Contents
xv
9 Heritable Hypermobility Syndromes........................................................
9.1 Ehlers–Danlos Syndrome ...................................................................
9.1.1 General Features .....................................................................
9.1.2 Nosology .................................................................................
9.1.3 Diagnostic Considerations ......................................................
9.1.4 Rare Forms of the EDS ...........................................................
9.1.5 Articular Manifestations .........................................................
9.1.6 Orthopaedic Management of Articular Problems ...................
9.1.7 Non-articular Complications ..................................................
9.1.8 Resources: Patient Support Groups ........................................
9.2 Familial Articular Hypermobility Syndromes ....................................
9.2.1 Nosology .................................................................................
9.2.2 Articular Complications..........................................................
9.2.3 Other Phenotypic Manifestations ...........................................
9.3 Miscellaneous Joint Laxity Syndromes ..............................................
9.3.1 Joint Laxity in Inherited Connective Tissue Disorders...........
9.3.2 Skeletal Dysplasias with Predominant Joint Laxity ...............
9.3.3 Dwarfing Dysplasias with Variable Joint Laxity ....................
9.3.4 Genetic Syndromes in Which Hypermobility
Is Overshadowed by Other Manifestations ............................
References ....................................................................................................
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10 Future Avenues for Research.....................................................................
10.1 Arterial Elasticity ................................................................................
10.2 Cytokine Modulation ..........................................................................
10.3 Candidate Genes .................................................................................
10.4 Disease Association: True or Artefactual? .........................................
10.5 Neurological Aspects ..........................................................................
10.6 Podiatry ...............................................................................................
10.7 Hormonal Aspects ..............................................................................
10.8 Joint Hypermobility as a Model of Accelerated Osteoarthritis ..........
References ....................................................................................................
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Index ................................................................................................................ 199
Chapter 1
Introduction to Hypermobility
1.1
Historical Background
The first clinical description of articular hypermobility is attributed to Hippocrates,
who, in the fourth century B.C., described the Scythians, a race of Iranian horseriding nomads inhabiting the region that now forms the Ukraine, as having humidity, flabbiness and atony such that they were unable to use their weapons. Their
main problem in warfare was that hyperlaxity of the elbow and shoulder joints prevented them from drawing their bows effectively.
Thereafter, the study of joint hypermobility was ignored until the late nineteenth
century, when general physicians were energetically defining medical syndromes,
some of which included joint hypermobility as an important feature. Notable
amongst these were Ehlers–Danlos syndrome (EDS) and Marfan syndrome.
The last 50 years have seen the recognition of joint hypermobility, without obvious widespread connective tissue abnormality, as a cause of orthopaedic and rheumatological symptoms. In investigations on a small number of subjects, Finkelstein1
and Key2 noted a familial predisposition to lax joints. Subsequently, orthopaedic
surgeons recognised the importance of generalised joint laxity in the pathogenesis
of dislocation of a single joint. Congenital dislocation of the hip was investigated by
Massie and Howarth3 and Carter and Wilkinson.4 Carter and Sweetnam studied dislocation of the patella5 and dislocation of the patella and shoulder.6 Thereafter, generalised joint laxity was recognised as being more common than had previously
been realised. This led to the introduction of simple clinical scoring systems for
measuring joint laxity in affected individuals and populations.
The first report of an association between joint laxity and rheumatological
symptoms emanated from Sutro,7 who described 13 young adults with effusions
and pain in hypermobile knees and ankles. Similar clinical observations led Kirk
et al.8 to define the ‘hypermobility syndrome’ in a group of patients with joint laxity and musculoskeletal complaints. In the absence of demonstrable systemic
rheumatological disease, these authors attributed the symptoms to articular
hypermobility.
P. Beighton et al., Hypermobility of Joints,
DOI 10.1007/978-1-84882-085-2_1, © Springer-Verlag London Limited 2012
1
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1
Wood9 argued from the epidemiological viewpoint that joint hypermobility
should be considered as a graded trait rather than as an ‘all or nothing’ syndrome.
This is a simplistic concept, and there is general agreement amongst colleagues with
clinical experience that the category ‘loose-jointed persons’ contains not only those
at the upper end of the normal spectrum but also examples of familial articular
hypermobility syndromes (see Chaps. 5 and 6).
The decade prior to the publication of the third edition of this book in 1999
brought an increased recognition of the importance of inheritance of joint laxity in
the pathogenesis of a variety of rheumatological problems. Biomolecular studies10
were then in their infancy and have advanced considerably since (see Chap. 3). The
last decade has drawn increasing attention to the manifestations of the hypermobility syndrome at sites in the body other than the joints. Features such as compression
neuropathy and involvement of the cardiovascular system have long been recognised. To this has recently been added involvement of the autonomic nervous system
and the bowel.
At the joints, understanding of the different factors that contribute to the observed
range of joint movement has advanced with attention not just to the structure of collagen and shape of the bony articulating surfaces at each individual joint11 but also
to the nuances of neuromuscular control and their links to impairment in joint proprioception, which often occurs.
In the field of translational science, hypermobility syndrome, once relatively
unfashionable, is providing a fertile area for fundamental studies in many different
areas of medicine (see Chap. 10).
1.2
Rheumatological Manifestations
It is apparent that symptoms arising from lax joints may commence at any age.
In their classic paper, Kirk et al.8 described 24 patients with generalised joint hypermobility. Their symptoms started between the ages of 3 and 55 years, and threequarters had problems before the age of 15. Females were more frequently affected
than males. Symptoms were mainly in the lower limbs, the commonest being pain
in the knees and ankles, although joint effusions and muscle cramps also occurred.
Supraspinatus and bicipital tendonitis, tennis elbow and painful Achilles tendons
were also noted.
In a comprehensive review, Ansell12 mentioned that symptoms occur after, rather
than during, unaccustomed exercise and diminish in later life, perhaps as the joints
stiffen. Although the prognosis is good, other arthropathies must be excluded before
making a diagnosis of the ‘hypermobility syndrome’. Thus, in 690 new referrals to
a paediatric rheumatology unit, hypermobility was considered to be the final diagnosis in only 12 referrals. Most clinicians now, however, agree that the condition is
under-diagnosed,13 and some series from general practice have suggested that hypermobility accounts for up to one-fifth of all musculoskeletal referrals in children but
also in adults (J. Dickson 2009, personal communication).
1.4
Late Effects of Hypermobility
3
Some persons consider themselves to be ‘double jointed’ or ‘loose limbed’.
There is often a family history of loose joints, and they may be talented at activities
such as dance (see Chap. 8). By contrast, symptomatic patients are sometimes
labelled as neurotic when medical practitioners who are unaware of the syndrome
are unable to explain their symptoms.
The hypermobile individual may be especially at risk from chronic back pain,
disc prolapse and spondylolisthesis. In addition, the ‘loose back’ syndrome, in
which women with hypermobility develop unexplained back pain in the absence of
demonstrable disc lesions and spondylitis, is now accepted as being more common
than originally supposed.14
The importance of both localised and generalised hypermobility in the pathogenesis of joint pains in children was emphasised by Lewkonia and Ansell.15 In this
context, Gedalia et al.16 reported that 21 (66%) of 32 children with episodic arthritis
had generalised joint laxity. These issues are discussed in Chap. 6.
1.3
Extra-Articular Manifestations of Hypermobility
The paucity of studies on extra-articular manifestations of familial hypermobility
both in children17 and adults11 is being addressed, and this book covers recent developments in areas not previously considered to be relevant to joint hypermobility. To
the strong impression that individuals with loose joints are susceptible to varicose
veins, herniae and rupture of lung tissue leading to pneumothorax, have been added
an increasing interest in mitral valve prolapse (floppy mitral valve syndrome),
asthma, collagen structure in the bowel wall and at the sphincters and involvement
of the autonomic nervous system affecting both the bowel and the vasculature
(see Chap. 6).
Dermal hyperelasticity is sometimes present in individuals with hypermobile
joints, and various methods for measuring the physical properties of skin have been
devised. These techniques have been used in EDS18 and in population studies.19,20
1.4
Late Effects of Hypermobility
Throughout the literature, it is widely held that premature osteoarthritis may be a
direct consequence of hypermobility. However, final proof may only come from large
and prospective long-term studies with adequate controls. In an investigation of EDS,
which exhibits classical hypermobility, 16 out of a group of 22 individuals over the
age of 40 had clinical osteoarthritis. The six persons without osteoarthritis had significantly less joint laxity.21 Premature osteoarthritis was a feature of the hypermobile
patients in the original studies of Kirk et al.8; all affected patients were female with an
age of onset of symptoms of 33–56 years. The trapeziometacarpal joints and the cervical spine were the commonest sites of involvement in this group.
4
1
In a radiological, histological and arthroscopic study, Bird et al.22 drew attention
to the way in which joint hyperlaxity apparently predisposes to a traumatic synovitis
in the third decade and premature osteoarthritis in the fourth or fifth. Pyrophosphate
is subsequently deposited in the unstable joint.
Despite the foregoing, it is still uncertain whether loose-jointed persons have a
significant propensity to develop osteoarthritis in later life.23
We are also increasingly coming to understand the social consequences of hypermobility. Accounts from patients24 eloquently describe the chronic difficulties often
associated with this condition, not least the frequent confusion in definitive diagnosis and the dismissive attitude of the medical profession.
1.5
Measurement of Joint Hypermobility
Clinicians and epidemiologists agree on the need to measure joint laxity. The first
scoring system was devised by Carter and Wilkinson4 and subsequently modified
by successive authors.25,26 The method, which has gained general acceptance, is
that derived by Beighton et al.27 from the earlier scheme of Carter and Wilkinson.
In this technique, a score of 0–9 is allocated to each individual, the highest scores
denoting maximum joint laxity. Although more complex systems have been proposed, they are time-consuming and have not been widely used. Measurement of
joint hypermobility in children is especially complex in view of the greater natural laxity in children compared to adults.28
There is a substantial body of literature concerning the measurement of movements at individual joints. Methods include radiological assessment,29 photographic
techniques30 and a pendulum machine devised by Barnett31 for the calculation of the
coefficient of resistance in the interphalangeal joints.
Complicated or invasive techniques cannot be used in large population
studies, and there has been some return to simple methods. Grahame and
Jenkins25 constructed a device to measure the angle of extension at the little
finger when a standard force is applied. To some extent, this has been superseded by the Leeds Finger Hyperextensometer, which records the range of
movement at the metacarpophalangeal joint of the index finger in response to a
pre-set fixed torque.
Quantitative measurements of joint mobility in adolescents were undertaken
by Fairbank et al.32 More recently, simple clinical techniques for the assessment
of hypermobility have been used by Larsson et al.33 for comparison of normal
males and females, and by Wordsworth et al.34 in a study of English Caucasians
and Asian Indians.
Recently, there has been some interest in measurement of neurological associations with joint hypermobility, particularly proprioception, with sophisticated
devices now available for the accurate quantification of proprioception both at the
knee and at the metacarpophalangeal joint. All methods of assessment are reviewed
in detail in Chap. 2.
1.7
1.6
Nosology of the Hypermobility Syndromes
5
Syndromic Associations of Joint Hypermobility
Although no demonstrable hereditary disorder of connective tissue can be recognised in the majority of individuals with joint hypermobility, a proportion have specific genetic conditions such as EDS, familial articular hypermobility syndrome and
Larsen syndrome (see Chap. 9).
It is sometimes extremely difficult to diagnose minor forms of disorders of connective tissue. The characteristic picture of complete Marfan syndrome, with long
thin limbs, ectopia lentis and dilatation of the ascending aorta, is easily recognised,
but a definitive diagnosis is difficult in persons with mild manifestations.
Similarly, although some varieties of EDS are easy to recognise, the hypermobility type, formerly EDS III, can closely mimic the familial articular hypermobility
syndrome in both clinical presentation and mode of inheritance.21 A survey of
British consultant rheumatologists35 demonstrated considerable confusion in the
minds of these specialists as to the extent to which EDS type III could be teased
apart from the less selective clinical features of ‘benign familial hypermobility syndrome’. A recent initiative from the USA36 has suggested that for clinical purposes
(and certainly for political purposes), the two conditions could be considered as the
same entity, not least because treatment for each is broadly the same.
It is of practical importance that joint hypermobility can occur as a secondary
manifestation of inflammatory disorders such as rheumatoid arthritis. In these circumstances, the clinical picture is sometimes complicated by the presence of a neuropathy, which may accentuate joint hyperlaxity. Muscular hypotonia and drugs
such as prednisolone and D-penicillamine, which alter the structure or physical
properties of collagen, also influence joint laxity. The determination of the relative
contributions of multiple aetiological factors, which influence the range of movements at a given joint, is a fascinating challenge to the clinician.
1.7
Increasing interest in hypermobility has led to the subdivision of established disorders and the recognition of new entities. Problems have arisen, however, concerning
syndromic boundaries, nomenclature and classification. There are considerable differences in the pathogenesis, natural history and prognosis in many of these conditions, and in these circumstances, diagnostic imprecision precludes optimal
management. Similarly, the establishment of correlations between the clinical features (phenotype) and the underlying biomolecular defect is dependent upon the use
of the same nosological system at both the clinical and laboratory levels.
These problems first became apparent in EDS, where 11 types had been delineated
and others proposed. The difficulty was accentuated when syndromes of familial articular hypermobility, without additional involvement of other tissues, were lumped together
with EDS. In an attempt to bring order to this potentially chaotic situation, a Nosology
Workshop was held at the Seventh International Congress of Human Genetics, Berlin,
6
1
Table 1.1 Nosology of the Ehlers–Danlos syndrome
Classic (formerly EDS I and II, gravis and
mitis type)
Hypermobility (formerly EDS III, hypermobile type)
Vascular (formerly EDS IV, arterial or
ecchymotic type)
Kyphoscoliosis (formerly EDS VI, ocular or
scoliosis type)
Arthrochalasia (formerly included in EDS VII)
Dermatosparaxis (formerly included in EDS VII)
Other rare forms of the EDS
EDS V
EDS VIII
EDS X
Entries now removed from the EDS classification
EDS IX
EDS XI
AD
AD
AD
AR
AD
AR
C-linked type, resembles the classic
type, in mild to moderate severity.
Delineated in a single large family
in the UK
Periodontal type, resembles the classic
type with the addition of fragility
of the gums. Very rare. Syndromic
status uncertain. AD
Resembles the classic type, in mild
degree, with the additional feature
of abnormal platelet aggregation.
Syndromic status uncertain. AR?
Now termed ‘occipital horn syndrome’.
C-linked disorder of copper
metabolism which is allelic to the
Menkes syndrome
Now termed ‘familial articular
hypermobility syndrome’.
Resembles the hypermobility form
of the EDS
Source: Revised at the Villefranche Meeting, 1997, adapted
in September 1986. In this meeting, experts involved with genetic connective tissue
conditions reached agreement upon syndromic definition and a unified nomenclature.
The final proposals were published under the names of 22 authors as the ‘International
Nosology of Heritable Disorders of Connective Tissue, Berlin 1986’.37
The continuing accumulation of clinical experience and the elucidation of the
molecular defects in some forms of the EDS generated a need for reappraisal of the
nosology of the disorder. For this purpose, in June 1997, a representative group of
interested colleagues, convened by Petros Tsipouras, met in Villefranche-sur-Mer,
France. A new nosology was formulated and the proposals were presented at the
American Society of Human Genetics Congress later in the year, and subsequently
published.38 A summary is reproduced in Table 1.1, and the various forms of the
EDS are further discussed in Chap. 9. Molecular heterogeneity has been recognised
in the Classic type (formerly EDS I and II) and proposed in the Hypermobility type
(formerly EDS III). It is likely that the nosology will be updated in the future in
order to accommodate these advances.
1.7
7
Table 1.2 Familial articular hypermobility syndrome (147 900)
Excludes
EDS group of disorders, notably the hypermobile and arthrochalasia types
Skeletal dysplasias with joint hypermobility, notably the Larsen syndrome
Cardinal manifestations
Generalised articular hypermobility, with or without subluxation or dislocations
No skin involvement
Familial articular hypermobility, uncomplicated type
Familial articular hypermobility, dislocating type (formerly EDS XI, familial
joint instability syndrome)
(The basic defect in these disorders is unknown)
AD/AR
AD
Table 1.3 Skeletal dysplasias with predominant joint laxity
Larsen syndrome
Mild form: AD(150250)
Severe form: AR(245600)
Joint laxity, especially at the knees
Flattened nasal bridge
Short stature
Broad terminal phalanges
Radiographic characteristics
Supernumerary ossification centres in the carpus and calcaneus
Desbuquois syndrome
AR(251450)
Joint laxity
Short stature
Prominent eyes
Broad terminal phalanges
Supernumerary phalanges
Supernumerary carpal ossification centres
Prominent lesser trochanter of femur
Spondyloepimetaphyseal dysplasia with joint laxity
(SEMDJL)
AR(271640)
AD(603546)
Clinical manifestations
Gross joint laxity with progressive spinal malalignment and multiple dislocations
Dwarfism
Variable cardiac defects and palatal clefts
Skeletal dysplasia with changes in the vertebrae, epiphyses and metaphyses
The sections of the ‘Berlin Nosology’ which relate to the familial articular hypermobility syndrome and the skeletal dysplasias with joint laxity are reproduced in Tables 1.2
and 1.3, and the conditions in these categories are also reviewed in Chap. 9. The numbers allocated to entities in the current online version of McKusick’s ‘Mendelian
Inheritance in Man’ [OMIM]39 have been cited in the titles of these disorders.
8
1
References
1. Finkelstein H. Joint hypotonia. N Y Med J. 1916;104:942-943.
2. Key JA. Hypermobility of joints as a sex linked hereditary characteristic. JAMA. 1927;88:
1710-1712.
3. Massie WK, Howarth MB. Congenital dislocation of the hip. Part II. Results of an open reduction as seen in early adult period. J Bone Joint Surg Am. 1951;33:171-190.
4. Carter C, Wilkinson J. Persistent joint laxity and congenital dislocation of the hip. J Bone Joint
Surg Br. 1964;46-B:40-45.
5. Carter C, Sweetnam R. Familial joint laxity and recurrent dislocation of the patella. J Bone
Joint Surg Br. 1958;40-B:664-667.
6. Carter C, Sweetnam R. Recurrent dislocation of the patella and of the shoulder: their association with familial joint laxity. J Bone Joint Surg Br. 1960;42-B:721-727.
7. Sutro J. Hypermobility of the knee due to over lengthened capsular and ligamentous tissues.
Surgery. 1947;21:67-76.
8. Kirk JA, Ansell BM, Bywaters EG. The hyper mobility syndrome. Musculoskeletal complaints
associated with generalized joint hypermobility. Ann Rheum Dis. 1967;26:419-425.
9. Wood PH. Is hypermobility a discrete entity? Proc R Soc Med. 1971;64:690-692.
10. Child AH. Joint hypermobility syndrome: inherited disorder of collagen synthesis. J Rheumatol.
1986;13:239-243.
11. Bird HA. Heritable collagen disorders. In: Reports on the Rheumatic Diseases (Series 5):
Topical Reviews. Chesterfield: Arthritis Research Campaign; 2005.
12. Ansell BM. Hypermobility of joints. Mod Trends Orthop. 1972;6:419-425.
13. Grahame R. Time to take hypermobility seriously (in adults and children). Rheumatology.
2001;40:485-487.
14. Howes RJ, Isdale IC. The loose back: an unrecognised syndrome. Rheumatol Phys Med.
1971;11:72-77.
15. Lewkonia RM, Ansell BM. Articular hypermobility simulating chronic rheumatic disease.
Arch Dis Child. 1983;58:988-992.
16. Gedalia A, Person DA, Brewer EJ, Giannini EH. Hypermobility of the joints in juvenile
episodic arthritis/arthralgia. J Pediatr. 1985;107:873-876.
17. Adib N, Davies K, Grahame R, Woo P, Murray KJ. Joint hypermobility syndrome in childhood. A not so benign multisystem disorder? Rheumatology. 2005;44:744-750.
18. Grahame R, Beighton P. Physical properties of the skin in the Ehlers-Danlos syndrome. Ann
Rheum Dis. 1969;28:246-252.
19. Grahame R. A method for measuring human skin elasticity in vivo with observations of the
effects of age, sex and pregnancy. Clin Sci. 1970;39:223-229.
20. Silverman S, Constine L, Harvey W, Grahame R. Survey of joint mobility and in vivo skin
elasticity in London schoolchildren. Ann Rheum Dis. 1975;34:177-180.
21. Beighton PH, Price A, Lord J, Dickson E. Variants of the ehlers-danlos syndrome. Clinical,
biochemical, haematological, and chromosomal features of 100 patients. Ann Rheum Dis.
1969;28:228-245.
22. Bird HA, Tribe CR, Bacon PA. Joint hypermobility leading to osteoarthrosis and chondrocalcinosis. Ann Rheum Dis. 1978;37:203-211.
23. Lewkonia RM. Hypermobility of joints. Arch Dis Child. 1987;62:1-2.
24. Gurley-Green S. Living with the hypermobility syndrome. Rheumatology. 2001;40:487-489.
25. Grahame R, Jenkins JM. Joint hypermobility – asset or liability? a study of joint mobility in
ballet dancers. Ann Rheum Dis. 1972;31:109-111.
26. Horan FT, Beighton PH. Recessive inheritance of generalized joint hypermobility. Rheumatol
Rehabil. 1973;12:47-49.
27. Beighton P, Solomon L, Soskolne CL. Articular mobility in an African population. Ann Rheum
Dis. 1973;32:413-418.
28. Bird HA. Joint hypermobility in children. Rheumatology. 2005;44:703-704.
References
9
29. Harris H, Joseph J. Variation in extension of the metacarpo-phalangeal and interphalangeal
joints of the thumb. J Bone Joint Surg Br. 1949;31-B:547-559.
30. Troup JDG, Hood CA, Chapman AE. Measurement of the sagittal mobility of the lumbar spine
and hips. Ann Phys Med. 1968;9:308-321.
31. Barnett CH. The mobility of synovial joints. Rheumatol Phys Med. 1971;11:20-27.
32. Fairbank JC, Pynsent PB, Phillips H. Quantitative measurements of joint mobility in adolescents. Ann Rheum Dis. 1984;43:288-294.
33. Larsson LG, Baum J, Mudholkar GS. Hypermobility: features and differential incidence
between the sexes. Arthritis Rheum. 1987;30:1426-1430.
34. Wordsworth P, Ogilvie D, Smith R, Sykes B. Joint mobility with particular reference to racial
variation and inherited connective tissue disorders. Br J Rheumatol. 1987;26:9-12.
35. Grahame R, Bird H. British consultant rheumatologists’ perceptions about the hypermobility
syndrome: a national survey. Rheumatology (Oxford). 2001;40:559-562.
36. Tinkle BT, Bird HA, Grahame R, Lavallee M, Levy HP, Sillence D. The lack of clinical distinction between the hypermobility type of Ehlers-Danlos syndrome and the joint hypermobility
syndrome (a.k.a. hypermobility syndrome). Am J Med Genet A. 2009;149A(11):2368-2370.
37. Beighton P et al. International nosology of heritable disorders of connective tissue, Berlin,
1986. Am J Med Genet. 1988;29:581-594.
38. Beighton P, De Paepe A, Steinmann B, Tsipouras P, Wenstrup RJ. Ehlers-Danlos syndromes:
revised nosology, Villefranche, 1997. Am J Med Genet. 1998;77:31-37.
39. McKusick VA (2009) Mendelian inheritance in man. Catalogs of autosomal dominant, autosomal recessive and C-linked phenotype. Online www.ncbi.nlm.nih.gov/omim/.
Chapter 2
Assessment of Hypermobility
Adequate methods for measuring the range of movement at joints are essential for
the definition of criteria used in the study of clinical problems associated with
joint hypermobility. Scoring systems for hypermobility that survey a large number of joints in simple fashion are ideal for epidemiological studies in large populations. Latterly, investigators have devised sophisticated mechanical devices for
the precise quantification of movement at a single joint. The greater precision
afforded may be ideal for serial assessments in the same patient but this greater
precision is of limited use in epidemiological work if the joint fails to mirror the
status of laxity at other joints in the body. Moreover, a joint may display acquired
hyperlaxity in compensation for a reduced range of movement at adjacent joints,
for example in the vertebral column.
A recent trend has therefore been to return to scoring systems in which a reasonably large number of joints are assessed in simple fashion. Nevertheless, there still
remains uncertainty about the value of new assessments proposed. The original
scoring system, first devised by Carter and Wilkinson1 and modified by Beighton
et al.,2 even now is re-emerging as the simple method of first choice, particularly for
the screening of large populations.
The definition of ‘generalised joint hypermobility’ still remains arbitrary, and
rationally should reflect both the number of joints involved and the extent to which
they move. Hypermobility may represent one extreme of a Gaussian distribution of
joint laxity throughout the population. Scoring systems devised for measuring joint
hypermobility have proved less satisfactory in the measurement of joint hypomobility. Attention has recently been directed at the factors that contribute to the range
of joint movement, not only the shape of bony articulating surfaces, the inherited
collagen structure and the tone and bulk of the restraining muscle, but also recently
to their neurological control, particularly in respect of proprioception, which may
be impaired. It is likely that future scoring systems will concentrate even more on
aetiological aspects as we attempt to separate groups of patients who may be at
particular risk of osteoarthritis.
11
12
2.1
2 Assessment of Hypermobility
Simple Scoring Systems for Hypermobility
The first scoring system was devised by Carter and Wilkinson1 in conjunction with
their work on congenital dislocation of the hip. They defined generalised joint laxity
as being present when three of the following tests were positive, provided both
upper and lower limbs were involved:
1. Passive apposition of the thumb to the flexor aspect of the forearm
2. Passive hyperextension of the fingers so that they lie parallel with the extensor
aspect of the forearm
3. Ability to hyperextend the elbow more than 10°
4. Ability to hyperextend the knee more than 10°
5. An excess range of passive dorsiflexion of the ankle and eversion of the foot
A more complex assessment was suggested by Kirk et al.,3 but in practice this
proved to be too time-consuming for routine use. The system of Carter and
Wilkinson1 was revised by Beighton and Horan4 for the measurement of joint laxity
in persons with the Ehlers–Danlos syndrome (EDS). Passive dorsiflexion of the
little finger beyond 90°, with the forearm flat on the table, was substituted for
passive hyperextension of the fingers, as the latter test had proved too severe; the
range of ankle movement was replaced by measurement of forward flexion of the
trunk. Patients were given a score between 0 and 5.
Grahame and Jenkins5 modified this system to include passive dorsiflexion of the
ankle beyond 15°. This was partly an adaptation to the particular subjects under
study, half of whom are ballet dancers. Subsequently, Beighton et al.2 amended the
1969 system for use in an epidemiological survey of bone and joint disorders in an
indigenous rural South African community. They employed the same tests, but gave
one point for each side of the body for the paired tests. The range of scoring was
thus between 0 and 9, with high scores denoting greater joint laxity. The manoeuvres used in this scoring system are listed below and depicted in Fig. 2.1:
1. Passive dorsiflexion of the little fingers beyond 90° (one point for each hand) –
two points
2. Passive apposition of the thumbs to the flexor aspects of the forearm (one point
for each thumb) – two points
3. Hyperextension of the elbows beyond 10° (one point for each elbow) – two points
4. Hyperextension of the knee beyond 10° (one point for each knee) – two points
5. Forward flexion of the trunk with knees fully extended so that the palms of the
hands rest flat on the floor – one point
This method has found favour for the following reasons:
1. Scoring systems using hyperextension of the middle rather than the little finger
exclude too many persons.
2. Scoring systems using ankle movements, although perhaps appropriate for
dancers, are unlikely to show much variation between individuals in a normal
population.
3. Scoring systems that include trunk and hip movement (composite joint movement)
are more likely to reflect generalised articular laxity.
2.1
Simple Scoring Systems for Hypermobility
13
Fig. 2.1 Beighton et al.2 modification of the Carter and Wilkinson1 scoring system
In a study on 502 normal adult indigenous South Africans (168 males; 334
females), 94% of the males and 80% of the females achieved scores of 0, 1 or 2.
This range of movement might be regarded as normal for adults in this population.
The majority of clinicians require a minimum score in adults of between 4/9 and 6/9
before accepting the diagnosis. Laxity decreases with age and a lower level may be
more appropriate to an elderly population. At any age, females are more mobile
than males. In both sexes the degree of joint laxity diminishes rapidly throughout
childhood and continues to fall more slowly in adult life.
An alternative scoring system was then developed. Based upon work by JP
Contompasis, an American podiatrist,6 and described in detail by Poul and Fait,7 this
scoring system is more complex than the modification by Beighton et al.2 of the Carter
and Wilkinson1 scale. A multiple-point scoring system based on six manoeuvres, five
of which replicate Beighton, its scores span from the normal to the hypermobile range
with a maximum total of 72. Initial studies had suggested that it was highly correlated
14
with Beighton’s score (r = 0.92; p = 0.0001) in original work by the editors, and it had
been claimed that it was particularly useful in the assessment of ligamentous laxity in
children. The scoring system is described in detail elsewhere,8 but greater experience
produced problems in measurement, particularly in the use of foot flexibility tests, the
major feature on which it differed from the Beighton score. Since the Contompasis
score takes significantly longer and, in spite of the theoretical greater sensitivity,
conveys little more information, the score is now only occasionally used.9
In a seminal paper Bulbena and colleagues10 compared Beighton’s modification with
the original Carter and Wilkinson1 scoring system and the most popular scoring system
used in France,11 to find the Beighton system as effective as any in measurement.
Recent studies have emphasised the difficulty in establishing joint hypermobility
as a causative factor of symptoms in children whose joints in any case display an
unusually large range of movement compared to adults.12 A further study on the
high prevalence of joint laxity in West Africans13 has shown that joint hyperlaxity is
substantially greater in a West African population than in almost any other population group in which it has been studied, yet is not associated with joint pain.
2.2
The Brighton Criteria for Hypermobility Syndrome
Although the measurement systems so far described suit the musculoskeletal system alone (and may be of particular value in measuring serial change), it became
increasingly apparent that wherever abnormal collagen was ubiquitous throughout
the body other organ systems would become involved. Moreover, certain individuals, particularly in different ethnic groups, would demonstrate striking hypermobility according to a scoring system but still remain asymptomatic.
It became clear that there was a need for a new scoring system that recognised all
of these points. The Special Interest Group devoted to inheritable connective tissue
disorders of the British Society for Rheumatology addressed this issue. As a result,
criteria were proposed in Brighton in 1999, which were published the following
year.14 These are shown in Table 2.1. Incorporating the Beighton score, still felt to
be the best rapid assessment of musculoskeletal hypermobility, the presence of arthralgia for more than 3 months in four or more joints was allowed equal importance.
A set of minor criteria was additionally proposed and, on the basis of pilot work, a
number of major or minor criteria that needed to be fulfilled were decided.
The Brighton criteria have subsequently enjoyed extensive use. A study from
Chile15 using the Brighton criteria suggested that true diagnosis in the majority of
patients with joint hypermobility syndrome is often overlooked, a finding replicated
in the UK.16 In the study from Chile it was noted that use of the Beighton criteria
alone would have excluded 61% of patients who were identified by use of the
Brighton criteria. It has been suggested that the criteria may yet benefit from further
analysis and validation17 and even the ‘gold standards’ based on ‘a consensus of
experts’18 may be desirable, a point conceded by the original authors.19
Nevertheless, there seems to be a consensus that the Brighton criteria represent a
significant step forward in the quantification of hypermobility.
2.3
General Principles of More Precise Measurement at Selected Joints
15
Table 2.1 The Brighton criteria for joint hypermobility syndrome
Major criteria
• A Beighton score of 4/9 or greater (either currently or historically)
• Arthralgia for longer than 3 months in 4 or more joints
Minor criteria
• A Beighton score of 1, 2 or 3/9 (0, 1, 2 or 3 if aged 50+)
• Arthralgia (>3 months) in one to three joints or back pain (>3 months), spondylosis,
spondylolysis/spondylolisthesis
• Dislocation/subluxation in more than one joint, or in one joint on more than one occasion
• Soft tissue rheumatism >3 lesions (e.g. epicondylitis, tenosynovitis, bursitis)
• Marfanoid habitus (tall, slim, span/height ratio >1.03, upper:lower segment ratio <0.89,
arachnodactyly [positive Steinberg/wrist signs])
• Abnormal skin: striae, hyperextensibility, thin skin, papyraceous scarring
• Eye signs: drooping eyelids or myopia or antimongoloid slant
• Varicose veins or hernia or uterine/rectal prolapse
The joint hypermobility syndrome is diagnosed in the presence of two major criteria, or one
major and two minor criteria, or four minor criteria. Two minor criteria will suffice where
there is an unequivocally affected first-degree relative.
Joint hypermobility syndrome is excluded by the presence of Marfan or Ehlers–Danlos
syndromes (other than the EDS hypermobility type (formerly EDS III) as defined by the
Ghent (1996) and the Villefranche (1998) criteria respectively). Criteria Major 1 and Minor
1 are mutually exclusive as are Major 2 and Minor 2.
Recently, Hakim and colleagues have also devised and validated a simple fivepoint questionnaire that can be used in general practice to alert suspicion to the
presence of hypermobility.20
2.3
General Principles of More Precise Measurement
at Selected Joints
A complete evaluation of a new technique for the precise measurement of movement a single joint requires the following:
1.
2.
3.
4.
Statements on the inter- and intra-observer error of the method
Consideration of the influence of age on the range of observed movement
A study of sex-determined differences
Indication of whether specialist groups have been included in the survey population (for instance, physiotherapists are often used for such studies but are likely
to form a highly selected group by virtue of their training)
5. Consideration of the influence of the dominant side
A hinge goniometer provides the simplest method for measuring the range of movement at a hinged joint. There are difficulties in positioning such an instrument accurately and a spirit-level device is often more appropriate. The Loebl21 hydrogoniometer
was the first such devised described. The MIE clinical goniometer (Fig. 2.2) is an
example of a similar device that is currently manufactured. Providing the patient is correctly positioned, the instrument can be used to record the arc of movement at any joint.
16
a
b
Fig. 2.2 (a) A clinical goniometer capable of measuring arcs of movement in any direction
(manufactured by MIE Medical Research Ltd, 6 Wortley Moor Road, Leeds LS12 4JF, UK).
(b) The goniometer in use
2.4 Back and Spinal Mobility
17
Recent modifications include instruments such as the Myrin goniometer, which resembles an aircraft gyrocompass; however, this instrument is expensive and lacks the sensitivity and precision of the simpler device.
When surface goniometry is correlated with movement measured radiologically,
goniometry frequently proves to be inadequate. The skin, fat and soft tissues may
distend and cause markers on the skin to move less or more than the underlying
bones. Correlation coefficients between angular bony movement at the joint determined radiologically and movement of the overlying skin are rarely provided.
A comprehensive account of techniques for measuring joint movement throughout the body is described in a booklet published by the American Academy of
Orthopaedic Surgeons.22 Diagrams of suitable methods for using goniometers to
determine the arcs of movement at all joints in the body are given, together with
‘normal’ values, but the coefficients of variation for these measurements, both
between serial assessments and in the same observer and between different observers, are not provided. A volume of Clinics in Rheumatic Disease,23 edited by V.
Wright, devotes one chapter to the measurement of movement at each major joint in
the body. Available methods are compared and the most suitable selected. This is
used to define the normal range of movement at each joint in males and females,
usually in 10-year cohorts. Estimations of inter-observer and intra-observer variation are provided.
Some additional devices have been championed for more sophisticated measurement of the range of movement. For the shoulder, an electromagnetic movement
sensor has been devised and validated.24 At the hip, a plurimeter has been devised
and validated, providing a relatively inexpensive measure for the range of movement at this joint and one that might be of particular use in primary care.25
Regular training undoubtedly affects the range of movement, due either to alteration in muscle control or to stretching of the joint capsule. Atha and Wheatley26
showed the effect of training to be a source of greater variation in passive goniometry at larger joints; investigators therefore need to specify whether an individual is
warmed up or participating in a physical training programme designed to increase
the range of movement. Such changes have been further quantified in studies on
athletes,27 which drew attention to the way in which the range of joint movement
could be altered by ‘warm up’ and this varied according to the experience and skill
of the athlete. Programmes were then introduced to stabilise unstable joints by the
use of regular exercises. These were also shown to be effective.28,29
2.4
Back and Spinal Mobility
The spine is a complex set of joints. Restrictions of movement at one site, either
inherited or acquired by disease, may result in compensatory hyperlaxity at adjacent
vertebrae leaving the overall range of movement, as measured by surface techniques,
unaltered.30 Troup et al.31 used photography to study movement of the lumbar spine
and hips in a sagittal plane, and a full review appears elsewhere.32 One-dimensional
18
measures involve skin distraction techniques such as Schober’s33 method, as modified by Macrae and Wright.34 Plumbline techniques have also been described and
lumbar sagittal mobility may be measured by flexicurves. The latter method has
an intra-observer and inter-observer variation of 9% and 15%, respectively.35
A hydrogoniometer is probably the most satisfactory instrument, though more complex spondylometers36 are available. Three-dimensional techniques include stereoradiography, vector stereography and three-dimensional optical systems. All have
been reviewed recently in comprehensive fashion37 and reference values for normal
regional lumbar sagittal mobility have been published.38
It is of interest that, although most studies at peripheral joints have clearly shown
that hypermobility is more prevalent in females than in males, this does not appear
to be so for the lumbar spine. Thus, Loebl21 and Troup31 have both shown that spinal
movement is approximately equal in both sexes, while a seminal paper by Macrae
and Wright34 showed the male spinal mobility to be greater than that in females. The
reason for this is not clear.
In a study correlating low back symptoms with lumbar sagittal mobility (Burton
and Group, unpublished results), flexicurves were used in 958 individuals aged
from 10 to 84 years. Both hypermobility and hypomobility of the lumbar spine
were identified as risk factors for low back trouble, though, as ascertained by
questionnaire, current sufferers were more likely to be relatively hypomobile.
The Polhemus Navigation Sciences 3Space Isotrak system has been used to measure the range of movement in the lumbar spine.39 This proved valuable in detecting
minor changes in spinal movement throughout the 24-h period that were attributed
to the natural circadian variation. Although expensive, sophisticated, and only available in small numbers of centres, this system may provide insight into diurnal variation of symptoms arising from the spine that are a feature of subjects with hyperlaxity
of the spine and also intrude on clinical practice.
2.5
Rotation in the Limbs
Haskard and Silman40 have devised fixed-torque screwdrivers that measure forearm
and lower limb rotation in epidemiological studies. Inter-observer variation has been
validated and is low. One such device measures forearm rotation and another leg rotation. Fairbank et al.41 devised a goniometric assessment involving six joints. Special
jigs were constructed for the measurement of hip rotation and tibial rotation.
2.6
Movement at the Metacarpophalangeal Joint
The metacarpophalangeal (MCP) joint is easily accessible and also forms a component part of conventional scoring systems. Harris and Joseph42 developed a
radiological technique for measuring the range of extension at the MCP joint and
2.7
Joint Proprioception
19
Loebl43 devised a mechanism for abducting the fingers to investigate movement at
the MCP joints. Grahame and Jenkins5 described a simple spring device that
applied a predetermined force (2 lb (0.91 kg)) to the fifth MCP joint. Applied to the
relaxed patient, this force mimicked the passive range of movement measured in
the clinical scoring system. It had good reproducibility but only quantified movement to the nearest 30°.
The Leeds finger hyperextensometer44 (Fig. 2.3) can be used for either hand. It
allows greater precision in quantification of the range of movement and has good
inter-observer and intra-observer reliability. The hyperextensometer applies a
torque of 2.6 kgcm−1.44 The device can be used in epidemiological surveys as it is
portable, light and inexpensively constructed. It is of particular value in serial
assessments of joint laxity in the same patient and has been used to provide the first
demonstration of enhanced peripheral joint laxity prior to parturition in pregnant
females.45 An increased level of serum relaxin has been noted in pregnant women
who have pelvic ligament pain.46 Since relaxin levels are known to be high at the
end of pregnancy when peripheral joint laxity was demonstrated, it remains a possibility that this hormone may be directly related to the development of rheumatological symptoms arising from hyperlax ligaments. A finger arthrograph47 quantifies
the resistance encountered when the index finger is moved in sinusoidal fashion at
a constant speed through a pre-selected angle of displacement and is of value in
measuring stiffness.
Most recently, an electronic gravity goniometer has been developed for determining the passive range of movement of the four MCP joints by the use of preset fixed torques.48 This may represent an improvement on the hyperextensometer.
The arthrograph has also been revisited and a microprocessor-controlled arthrograph devised. In addition to the greater accuracy provided, a novel feature is the
movement of the MCP joint in a lateral rather than a flexion/extension plane.49
2.7
Joint Proprioception
With increasing realisation that this is relevant to hypermobility, efforts have been
directed to its accurate quantification. Ferrell and colleagues in Glasgow have
designed a sophisticated rig to quantify proprioception at the knee joint and have
shown in a sophisticated series of studies that this is impaired in hypermobility
syndrome,50 that enhanced proprioception ameliorates symptoms51 and that musculoskeletal reflex function is also altered in hypermobility.52 The rig used, however, is not portable. Parallel work has shown that proprioception is impaired both
in inflammatory and degenerative arthritis and intriguingly, improved after joint
replacement, probably because of surgical tightening of the capsule.
A portable proprioceptometer has been devised for use in the hand53 and is currently being used in studies of hypermobile individuals, as well as on musicians and
typists. Proprioception has also recently been demonstrated to be abnormal in
hypermobile children.54
20
Fig. 2.3 A finger hyperextensometer for the quantification of joint laxity. The finger of the subject
is hyperextended at the metacarpophalangeal joint by the application of a pre-set fixed torque.
The resultant angle of the hyperextension is read off on the dial
2.9
2.8
Variation of Joint Laxity Within Populations
21
Correlations Between Scoring Systems Used
in Assessing Joint Laxity
A comparison has been made between the Carter and Wilkinson1 scoring system, as
modified by Beighton et al.,2 the Leeds finger hyperextensometer and a ‘global
index’ constructed by using goniometry to assess the range of movement at almost
all the joints in the body. This comparison follows the guidelines suggested by the
American Academy of Orthopaedic Surgeons22 and sums the measured arcs of
movement.55 Individuals were selected from different sporting groups thought to
reflect more generalised hyperlaxity than that seen in the normal population.
Beighton et al.’s modification of the Carter and Wilkinson system correlated well
with the global index, endorsing the value of a simple scoring system that could be
applied to large populations.56 The hyperextensometer appeared to convey more
applied information in an accurate fashion, emphasising that the range of movement
at a single joint does not necessarily correlate with overall joint laxity.
Silman et al.57 have confirmed the Gaussian distribution in joint mobility that can
be measured with fixed-torque measuring devices. Subsequently, a family study
showed that, although the fixed-torque devices reliably reflected anticipated epidemiological findings in Asian families, the index finger hyperextensometer produced
different results. They concluded that both genetic and constitutional factors affect
mobility independently at certain sites.58 Fairbank et al.,41 using goniometry at
6 different joints in a group of 446 normal adolescents, concluded that there was a
weak but significant correlation between the ranges of movement at each of the
different joints measured, except for elbow hyperextension.
2.9
Variation of Joint Laxity Within Populations
A major development in the epidemiology of hypermobility has been the demonstration that the range of movement at a given joint is observed as a Gaussian distribution throughout the population.59 It is no longer acceptable to consider
hypermobility as an ‘all or nothing’ phenomenon and it becomes logical to define
hypermobile individuals as those who comprise a certain extreme proportion of the
normal population. The cut-off point for hypermobility remains arbitrary, but it is
our impression that the majority of musculoskeletal complaints attributable to
hypermobility occur in the most supple 5% or 10% of the population.
The range of normal joint movements decreases rapidly throughout childhood
and more slowly in adulthood. This observation has been confirmed in children in
Edinburgh,60 in a South African population2 and in London children.61 Joint laxity
continues to diminish throughout adult life.3 The joints of females were found by
several authors to be more lax than those of age-matched males,2,42,60 though this
finding has been disputed by Silverman et al.61 and is not always seen in the spine,
as previously described. Laxity may be localised to a small number of joints or a
22
single joint. The concept of pauci-articular hypermobility has been reviewed in
detail by Larsson et al..62
Although few comparative studies have been carried out, there is a strong clinical
impression of a racial variation in joint mobility. For instance, Indians show more
hyperextension of the thumb than Africans, who in turn have greater hyperextension
than Europeans.42 A similar result has been obtained by comparing the finger joints
of different ethnic groups in Southern Africa.63 The question of inter-ethnic variation could be resolved by large-scale comparative studies employing the techniques
discussed in this chapter.
A study on joint mobility among university students in Iraq has shown a relatively high prevalence of individuals scoring 4/9 on Beighton et al.’s2 modification
of the Carter and Wilkinson1 scale, the right (usually dominant) side being significantly less mobile than the left side, whatever the hypermobility score.64 Comparable
data from an age-matched group of English university students has shown a lower
prevalence of hypermobility using the same scoring system.65 When English
Caucasian subjects were compared with Asian Indians and a group of patients suffering from a variety of inherited disorders, including Ehlers–Danlos Syndrome
(EDS) and osteogenesis imperfecta, Asian Indians were significantly more mobile
than English Caucasians. Males and females with EDS were hypermobile, but only
females with osteogenesis imperfecta (and female relatives of those with severe or
lethal osteogenesis imperfecta) showed excess joint laxity.66
Studies with the hyperextensometer in Europe have defined normal curves for
laxity at the MCP joint in relation to age and sex and then correlated hyperlaxity
with various orthopaedic diseases.67 The frequency of occurrence of generalised
ligamentous laxity has been defined in a Czechoslovakian population (Poul J and
Fait M 1989, personal communication). In 890 healthy children, the Contompasis
criteria6 defined the variability of generalised ligamentous laxity in relation to age
and sex. It was found that pathology was most likely to develop in subjects who
exhibited two standard deviations from the mean. This study failed to show a discrete clinical abnormality of connective tissue – it was felt that rheumatic or orthopaedic symptoms could occur in any individuals, providing their overall hyperlaxity
exceeded a certain degree. This favours mechanical rather than biochemical aetiology for symptoms arising from joint hypermobility. A study from Yugoslavia
(I. Jajic 1988, personal communication), in which 632 schoolchildren were surveyed,
confirmed the greater prevalence of joint hypermobility, as measured by the Beighton
et al.2 scoring system, in schoolgirls compared to age-matched schoolboys.
2.10
Clinical Applications of Scoring Systems
Both the Beighton2 and Contompasis scoring systems have been used to quantify
laxity in a study of 58 consecutive patients presenting to a rheumatology clinic with
putative benign joint hypermobility syndrome (BJHS). There appeared to be no
great prevalence of cardiac, bone, skin or eye abnormalities in this group, helping to
References
23
differentiate it from more serious hereditary disorders of connective tissue.68
An epidemiological study in rheumatology clinics has evaluated 130 consecutive
new patients with joint hypermobility.69 Musculoskeletal problems were the main
reason for referral, and there was a statistically significant association between diffuse joint hypermobility and osteoarthritis, supporting the hypothesis that joint
hypermobility predisposes to musculoskeletal disorders, particularly osteoarthritis.
More contentious is whether joint hypermobility is associated with fibromyalgia
or even a cause of that condition. Criteria for fibromyalgia have recently been proposed by the American College of Rheumatology.70 This has allowed the correlation
of scoring systems for mobility with diagnostic criteria for fibromyalgia in schoolchildren,71 which showed an apparent strong association between the two conditions, certainly in schoolchildren. In a group of adults in Oman, there was less
correlation between widespread musculoskeletal symptoms in any age group and
joint mobility scores72 though specific diagnostic criteria for fibromyalgia were not
sought. Other studies have suggested there may be an association between hypermobility and fibromyalgic type symptoms in adults,73 and if further studies confirm
this, exercise programmes to reduce hyperextension of joint capsules and other soft
tissues may become a recognised part of the treatment of fibromyalgia.74
The new international Nosology of heritable disorders of connective tissue from
Beighton and colleagues75 has replaced the earlier classification, first proposed in
1986, though not published until later.76 This has defined the benign joint hypermobility syndrome as an entity quite discreet from rarer and more serious inherited
abnormalities of connective tissue such as the EDS, some variants of which cause
much greater involvement of body structures other than joints, particularly the
blood vessels.
2.11
Joint Hypolaxity
Restricted movement of the joint has been recognised clinically in association with
certain diseases, particularly diabetes mellitus. Reduced movement has been
reported in the hand, shoulder, wrist, elbow and ankle.77-79 The scoring systems currently used for hyperlaxity have evolved specifically for this need and prove not to
be particularly suited to the detection and measurement of joint hypolaxity.80
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24
4. Beighton P, Horan F. Orthopaedic aspects of the Ehlers Danlos syndrome. J Bone Joint Surg
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5. Grahame R, Jenkins JM. Joint hypermobility – asset or liability? A study of joint mobility in
6. McNerney JE, Johnston WB. Generalized ligamentous laxity, hallux abducto valgus and the
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8. Beighton PH, Grahame R, Bird HA. Hypermobility of Joints. 2nd ed. Berlin/Heidelberg:
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9. Morgan AW, Bird HA. Special interest group for joint hypermobility. Br J Rheumatol.
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10. Bulbena A, Duro J, Porta M, Faus S, Vallescar R, Martin-Santos R. Clinical assessment of
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11. Rotés-Querol J, Argany A. La laxité articulaire considerée comme facteur des altérations de
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13. Birrell FN, Adebajo AO, Hazleman BL, Silman AJ. High prevalence of joint laxity in West
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14. Grahame R, Bird HA, Child A, et al. The revised (Brighton 1998) criteria for the diagnosis of
benign joint hypermobility syndrome (BJHS). J Rheumatol. 2000;27:1777-1779.
15. Bravo JF, Wolff C. Clinical study of hereditary disorders of connective tissues in a Chilean
population: joint hypermobility syndrome and vascular Ehlers-Danlos syndrome. Arthritis
Rheum. 2006;54:515-523.
16. Grahame R, Hakim AJ. High prevalence of joint hypermobility syndrome in clinical
referrals to a North London community hospital. Rheumatology (Oxford). 2004;43(Suppl 2):
90. Abs 198.
17. Remvig L, Jensen DV, Ward RC. Are diagnostic criteria for general joint hypermobility and
benign joint hypermobility syndrome based on reproducible and valid tests? A review of the
literature. J Rheumatol. 2007;34:798-803.
18. Remvig L, Jensen DV, Ward RC. Epidemiology of general joint hypermobility and basis
for the proposed criteria for benign joint hypermobility syndrome: review of the literature.
J Rheumatol. 2007;34:804-809.
19. Grahame R. The need to take a fresh look at criteria for hypermobility. J Rheumatol.
2007;34:664-665.
20. Hakim AJ, Grahame R. A simple questionnaire to detect hypermobility: an adjunct to
the assessment of patients with diffuse musculoskeletal pain. Int J Clin Pract. 2003;57:
163-166.
21. Loebl WY. Measurement of spinal posture and range of spinal movement. Ann Phys Med.
1967;9:103-110.
22. American Academy of Orthopaedic Surgeons. Joint Motion: Method of Measuring and
Recording. Edinburgh: Churchill Livingstone; 1965.
23. Wright V, ed. Measurement of Joint Movement. Clinics in Rheumatic Diseases, vol. 9. London:
WB Saunders Company Ltd; 1982.
24. Johnson GR, Fyfe NC, Heward M. Ranges of movement at the shoulder complex using
an electromagnetic movement sensor. Ann Rheum Dis. 1991;50:824-827.
25. Croft PR, Nahit ES, Macfarlane GJ, Silman AJ. Interobserver reliability in measuring flexion,
internal rotation, and external rotation of the hip using a plurimeter. Ann Rheum Dis.
1996;55:320-323.
26. Atha J, Wheatley DW. The mobilising effects of repeated measurement on hip flexion.
Br J Sports Med. 1976;10:22-25.
27. Barton L, Bird HA, Lindsay M, Newton J, Wright V. The effect of different joint interventions
on the range of movement at a joint. J Orthop Rheumatol. 1995;8:87-92.
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28. Barton L, Bird HA, Lindsay M, Newton J, Wright V. The quantification of joint hyperlaxity in
athletes. J Orthop Rheumatol. 1995;8:79-86.
29. Barton L, Bird HA. Improving pain by stabilisation of hyperlax joints. J Orthop Rheumatol.
1996;9:46-51.
30. Hilton RC, Ball J, Benn RT. In-vitro mobility of the lumbar spine. Ann Rheum Dis. 1979;38:378-383.
31. Troup JDG, Hood CA, Chapman AE. Measurements of the sagittal mobility of the lumbar
spine and hips. Ann Phys Med. 1968;9:308-321.
32. Anderson JAD. The thoraco-lumbar spine. Clin Rheum Dis. 1982;8:631-653.
33. Schober P. Lendenwirbelsäul und kreuzschmerzen. Much Med Wochenschr. 1937;84:336-339.
34. Macrae IF, Wright V. Measurement of back movement. Ann Rheum Dis. 1969;28:584-589.
35. Burton AK. Regional lumbar sagittal mobility; measurement by flexicurves. Clin Biomech.
1986;1:20-26.
36. Sturrock RD, Wojtulewski J, Dudley Hart F. Spondylometry in a normal population and in
ankylosing spondylitis. Rheumatol Rehabil. 1973;12:135-142.
37. Pearcy M. Measurement of back and spinal mobility. Clin Biomech. 1986;1:44-51.
38. Burton AK, Tillotson KM. Reference values for ‘normal’ regional lumbar sagittal mobility.
Clin Biomech. 1988;3:106-113.
39. Russell P, Weld A, Pearcy MJ, Hogg R, Unsworth A. Variation in lumbar spine mobility
measured over a 24-hour period. Br J Rheumatol. 1992;31:329-332.
40. Haskard DO, Silman AJ. Measuring devices for studying joint mobility in the normal population. Eng Med. 1985;14:75-77.
41. Fairbank JC, Pynsent PB, Phillips H. Quantitative measurements of joint mobility in adolescents. Ann Rheum Dis. 1984;43:288-294.
42. Harris H, Joseph J. Variation in extension of the metacarpophalangeal and interphalangeal
joints of the thumb. J Bone Joint Surg Br. 1949;31-B:547-559.
43. Loebl WY. The assessment of mobility in the metacarpophalangeal joints. Rheumatol Phys
Med. 1972;11:365-379.
44. Jobbins B, Bird HA, Wright V. A joint hyperextensometer for the quantification of joint laxity.
Eng Med. 1979;8:103-104.
45. Calguneri M, Bird HA, Wright V. Changes in joint laxity occurring during pregnancy. Ann
Rheum Dis. 1982;41:126-128.
46. Maclennan AH, Green RC, Nicolson R, Bath M. Serum relaxin and pelvic pain of pregnancy.
Lancet. 1986;328:243-245.
47. Jobbins B, Bird HA, Wright V. A finger arthrograph for the quantification of joint stiffness.
Eng Med. 1981;10:85-88.
48. Wagner C, Drescher D. Measuring mobility of the metacarpophalangeal joints II, III, IV and
V in the dorso-volar plane. Eng Med. 1984;13:15-20.
49. Howe A, Thompson D, Wright V. Reference values for metacarpophalangeal joint stiffness in
normals. Ann Rheum Dis. 1985;44:469-476.
50. Hall MG, Ferrell WR, Sturrock RD, Hamblen DL, Baxendale RH. The effect of the hypermobility syndrome on knee joint proprioception. Br J Rheumatol. 1995;34:121-125.
51. Ferrell WR, Tennant N, Sturrock RD, et al. Amelioration of symptoms by enhancement
of proprioception in patients with joint hypermobility syndrome. Arthritis Rheum.
2004;50:3323-3328.
52. Ferrell WR, Tennant N, Baxendale RH, Kusel M, Sturrock RD. Musculoskeletal reflex function in the joint hypermobility syndrome. Arthritis Care Res. 2007;57:1329-1333.
53. Wycherley AS, Helliwell PS, Bird HA. A novel device for the measurement of proprioception
in the hand. Rheumatology (Oxford). 2005;44:638-641.
54. Fatoye F, Palmer S, Macmillan F, Rowe P, van der Linden M. Proprioception and muscle torque
deficits in children with hypermobility syndrome. Rheumatology (Oxford). 2009;48:152-157.
55. Bird HA, Brodie DA, Wright V. Quantification of joint laxity. Rheumatol Rehabil. 1979;18:161-166.
56. Beighton P. Hypermobility scoring. Br J Rheumatol. 1988;27:163.
57. Silman AJ, Haskard D, Day S. Distribution of joint mobility in a normal population: results of
the use of fixed torque measuring devices. Ann Rheum Dis. 1986;45:27-30.
26
58. Silman AJ, Day SJ, Haskard DO. Factors associated with joint mobility in an adolescent
population. Ann Rheum Dis. 1987;46:209-212.
60. Wynne-Davies R. Acetabular dysplasia and familial joint laxity: two etiological factors in
congenital dislocation of the hip. J Bone Joint Surg Br. 1970;52-B:704-716.
63. Schweitzer G. Laxity of metacarpophalangeal joints of fingers and interphalangeal joint of the
thumb: a comparative inter-racial study. S Afr Med J. 1970;44:246-249.
64. Al-Rawi ZS, Al-Aszawi AJ, Al-Chalabi T. Joint mobility among university students in Iraq.
Br J Rheumatol. 1985;24:326-331.
65. Bird HA, Calguneri M. Joint mobility among university students. Br J Rheumatol.
1986;25:314.
66. Wordsworth P, Ogilvie D, Smith R, Sykes B. Joint mobility with particular reference to racial
variation and inherited connective tissue disorders. Br J Rheumatol. 1987;26:9-12.
67. Dubs L, Gschwend N. General joint laxity. Quantification and clinical relevance. Arch Orthop
Trauma Surg. 1988;107:65-72.
68. Mishra MB, Ryan P, Atkinson P, et al. Extra-articular features of benign joint hypermobility
syndrome. Br J Rheumatol. 1996;35:861-866.
69. Bridges AJ, Smith E, Reid J. Joint hypermobility in adults referred to rheumatology clinics.
Ann Rheum Dis. 1992;51:793-796.
70. Wolfe F, Smythe HA, Yunus MB, et al. The American College of Rheumatology 1990 criteria
for the classification of fibromyalgia: report of the multicenter criteria committee. Arthritis
Rheum. 1990;33:160-172.
71. Gedalia A, Press J, Klein M, Buskila D. Joint hypermobility and fibromyalgia in schoolchildren. Ann Rheum Dis. 1993;52:494-496.
72. Pountain G. Musculoskeletal pain in Omanis, and the relationship to joint mobility and body
mass index. Br J Rheumatol. 1992;31:81-85.
73. Hudson N, Starr MR, Esdaile JM, Fitzcharles M-A. Diagnostic associations with hypermobility
in rheumatology patients. Br J Rheumatol. 1995;34:1157-1161.
74. Klemp P. Hypermobility. Ann Rheum Dis. 1997;56:573-575.
76. Beighton P, de Paepe A, Danks D, et al. International nosology of heritable disorders of
connective tissue, Berlin, 1986. Am J Med Genet. 1988;29:581-594.
77. Campbell RR, Hawkins SJ, Maddison PJ, Reckless JP. Limited joint mobility in diabetes
mellitus. Ann Rheum Dis. 1985;44:93-97.
78. Pal B, Anderson J, Dick WC, Griffiths ID. Limitation of joint mobility and shoulder capsulitis
in insulin- and non-insulin-dependent diabetes mellitus. Br J Rheumatol. 1986;25:147-151.
79. Starkman HS, Gleason RE, Rand LI, Miller DE, Soeldner JS. Limited joint mobility (LJM) of
the hand in patients with diabetes mellitus: relation to chronic complications. Ann Rheum Dis.
1986;45:130-135.
80. Bird HA. Joint and tissue laxity. In: Wright V, ed. Topical Reviews in the Rheumatic Disorders,
vol. 2. Bristol: John Wright & Sons Ltd; 1983:133-166.
Chapter 3
The Molecular Basis of Joint Hypermobility
Karl Kadler and Gillian Wallis
3.1
Introduction
The ability of joints to undergo repeated and rapid movements is attributable to the
unique mechanical properties of the extracellular matrix (ECM) of the joint capsule
and surrounding ligaments and tendons. A delicate balance exists between ‘stiffness’
and ‘elasticity’ of these tissues. Stiffness comes from very long collagen fibrils that
are arranged in elaborate architectures such as parallel bundles in tendon (Fig. 3.1),
orthogonal lattices in the cornea and basket-weave in skin, depending on the mechanical requirements of the tissues in which they occur. Elasticity originates from the
crimping of collagen fibrils and from elastic fibres in the ECM (Fig. 3.2). These elastic
fibres have a unique arrangement of macromolecules that permits extension and contraction at a molecular level. An understanding of the molecular and structural basis
of joint hypermobility requires a detailed knowledge of the structure, function and
organisation of the collagenous and elastic polymer systems that comprise the ECM.
Joint hypermobility and joint laxity are features of several heritable disorders of
connective tissue. Studies of the pathway between genotype and phenotype in these
disorders have provided insights into the role and interaction of components of the
ECM in supporting joint function. These studies have shown that: (1) the alteration
of different functional domains of an ECM component can lead to disorders that are
phenotypically distinct, (2) an alteration in either the structure or the biochemical
processing of an ECM component can lead to disorders that are phenotypically similar, and (3) the alteration of distinct ECM components can result in disorders that
have overlapping phenotypic features as a result of the complex interplay between
ECM components in tissues. Studies of the molecular basis of the Ehlers–Danlos
syndrome (EDS) exemplify these points and are the focus of this chapter. Several
excellent reviews on EDS are available, including but not exclusively Refs.1-3 Several
reviews are also available that describe the biosynthesis, structure and organisation
of collagens (e.g. Refs.4-7) and elastic fibres (e.g. Refs.8,9). In this Chapter we provide
an overview of collagen biosynthesis in relation to the Ehlers–Danlos syndrome.
27
28
3 The Molecular Basis of Joint Hypermobility
Fig. 3.1 Transmission
electron microscopy of
tendon from a 6-week-old
mouse. The collagen fibrils
are closely packed in the
ECM and parallel to the long
axis of the tendon. Note the
broad range of diameters of
collagen fibrils, the close
association of the cell with
the fibrils and plasma
membrane protrusions that
increase the surface area
of the cell in contact with
the collagen fibrils.
Scale bar, 2 mm
3.2
The Family of Fibril-Forming Collagens
Collagen is the major structural protein in animals and provides a supporting
framework for the attachment of cells during the formation of specialised tissues.
Collagens are triple helical proteins comprised of three separate polypeptide chains
with a repeating Gly-X-Y motif, where X and Y can be any amino acid but are
frequently the imino acids proline and hydroxyproline, respectively. Glycine, the
smallest amino acid, is required at every third residue position of each chain to
allow the three chains to fold into a triple helix. At least 28 genetically distinct
types of collagen exist in man which, on the basis of gene structure and protein
sequence, can be classified into different families of collagens. The most abundant
are the fibril-forming collagens that occur in the ECM as fibrils having a characteristic 67-nm D-periodicity (see Fig. 3.2). The fibrils are the largest biopolymers in
animal tissues and can range in diameter (10–500 nm) and length (from 10 mm to
several millimetres) depending on tissue and stage of development10,11 (for review
see Kadler et al.12 and references therein). Mammals have 11 fibrillar collagen
genes, which cluster phylogenetically into three distinct subclasses.13 The corresponding polypeptide chains assemble into seven specific ‘types’ that are assigned
the Roman numerals I, II, III, V, XI, XXII and XXVII (for review see Kadler
et al.5). These collagens comprise a single uninterrupted triple helix containing
~330 contiguous Gly-X-Y triplets. Types XXII and XXVII are newly discovered
3.2
The Family of Fibril-Forming Collagens
Fig. 3.2 Transmission
electron microscopy of
tendon from a 6-week-old
mouse showing an elastic
fibre (arrows). The elastic
fibre is in contact with the
cell and is surrounded by
bundles of large-diameter
collagen fibrils. The elastic
fibre comprises an amorphous
(electron lucent) component
that makes up the vast
majority of the fibre and a
microfibrillar component
(see insert) that consists of
10–12-nm microfibrils. Scale
bar, 2 mm
29
30
Fig. 3.3 Schematic
representation of the domain
structure of the chains of type
I and V collagens. The
N-terminal end of each of the
polypeptide chains is located
at the left-hand side of the
diagram. Box, PARP domain.
Triangle, von Willebrand-like
type C module. Oval,
C-propeptides. n,
approximately 330. m, 15 in
type I procollagen chains and
17 in type V procollagen
chains
N-propeptide
(Gly-X-Y)m
C-propeptide
(Gly-X-Y)n
N-telopeptide
C-telopeptide
members of the fibrillar collagens and are unique in having two short interruptions
in the major triple helix. A unique feature of fibril-forming collagens is that they
are synthesised as precursor procollagens containing N- and C-propeptides that
flank the major triple helix of the molecule.
Types I and V are the most relevant collagens in the Ehlers–Danlos syndrome
where hypermobility is a feature and will therefore form a focus of this review. Type
I collagen is the most abundant collagen and is found throughout the body, except
in cartilaginous tissues. It is the predominant component of the collagen fibrils in
tendon, ligament, bone and skin. Type V collagen is a minor component of several
tissues where it occurs as heterotypic fibrils with type I collagen. In particular, type
V collagen is thought to form the inner core of collagen fibrils comprising type I
collagen in cornea, skin and ligaments and that it plays a crucial role in controlling
assembly of type I/V heterotypic fibrils.14
3.3
Genes Encoding Type I and V Collagens
The organisation and intron-exon structure of the genes for type I and V collagen chains are similar. Differences in the size of the gene mostly arise from
differences in the sizes of the introns (reviewed by Byers15). Type I procollagen
protein is comprised of two proa1(I) chains and a proa2(I) chain, which are
encoded by single genes located on human chromosomes 17 (q21.3-22) and
7 (q21.3-22), respectively. The proa1(I) gene (COL1A1) contains 18 kb and 51
exons, and the proa2(I) gene (COL1A2) contains 40 kb and 52 exons. Forty-two
exons encode the main triple helical domains of each proa1(I) and proa2(I)
chain (see Fig. 3.3 for a schematic representation of the modular structure of
procollagens). These exons comprise 45, 54, 99, 108 or 162 base pairs, i.e. multiples of 9 bp corresponding to Gly-X-Y triplets (commonly 54 bp). Flanking
3.4
Biosynthesis of Type I and V Collagens
31
these exons are exons that encode the sites of proteolytic cleavage of the N- and
C-propeptides of procollagen.
Three different polypeptide chains of type V collagen occur, namely proa1(V),
proa2(V) and proa3(V). Different combinations of these chains are possible in
the formation of the trimer. The most abundant form is [proa1(V)2 proa2(V)], but
homotrimers of proa1(V) and heterotrimers of [proa1(V) proa2(V) proa3(V)]
have also been identified. The genes for proa1(V) (COL5A1), proa2(V) (COL5A2)
and proa3(V) (COL3A2) collagen chains are located on human chromosomes
9q34.2-34.3,16 2q24.3-317 and 19p13.2,18 respectively. COL5A1 consists of 66
exons and spans ~150 kb (excluding the first intron, which itself is greater than
600 kb). Fourteen exons encode the signal peptide, the N-propeptide and the
beginning of the triple helical domain. The remainder of triple helix is encoded by
exons 15–62 which comprise mostly of 54- and 45-bp exons. The C-propeptide is
encoded by exons 63–66. The final exon is identical in size (144 bp) to that of the
genes encoding type I collagen. The COL5A2 gene is evolutionarily closely
related to, and syntenic with, the proa1(III) chain of type III collagen.19 The
COL5A3 gene is closely related to the COL5A1 gene but with marked sequence
difference in the N-propeptide domain and collagenous domain.18
3.4
Biosynthesis of Type I and V Collagens
The biosynthesis of type I and V procollagen molecules begins with co-translational
transport of the nascent proa chains into the endoplasmic reticulum (Fig. 3.4).
Intracellular assembly of procollagen occurs by an initial interaction between
C-propeptides followed by zipper-like folding of the triple helical domain in the
C- to N-terminal direction. Recognition signals within the C-propeptides determine the selective association of individual procollagen chains.20 Specific
sequences in the C-propeptides of type I procollagen determine that two proa1(I)
chains and one proa2(I) chain co-assemble to generate a heterotrimeric type I procollagen molecule. The chain selection in the formation of type V collagen is
more complex, and different combinations of type V and type XI collagen chains
can associate in a tissue-specific manner.18
Prior to folding of the triple helical domain, certain prolyl residues are
hydroxylated at the 4 position by proline-4-hydroxylase, and certain lysyl
residues are hydroxylated by lysyl hydroxylase. Both the prolyl-4-hydroxylase
and lysyl hydroxylase enzymes require Fe2+, 2-ketoglutarate, molecular oxygen and ascorbic acid as cofactors. The hydroxylation of proline is needed to
produce a triple helix that is stable at body temperatures. Hydroxylation of
specific lysyl residues is necessary for O -linked glycosylation (a late step in
procollagen biosynthesis) and the formation of lysyl oxidase-derived crosslinks (for review see Eyre et al.21). A late stage in folding involves the assembly
of the trimeric N-propeptide.
32
Gal-O-
-O-Gal-Glc
Hydroxylation of prolyl and hydrolysyl
residues
-OH
-OH
HO-
N-glycosylation of C-propeptides
-OH
-OH
-OH
NH2 NH2 NH2
O-Gal-Glc
OH
NH2
-s-s-
OH
-N-Man
s-s
-s-s-
NH2
NH2
O-glycosylation of hydroxylysyl
residues in the major Gly-X-Y domain
OH
Association of the C-propeptides
Nucleation and propagation of the
triple helix
O-Gal
O-Gal-Glc
OH
-N-Man
Triple helix formation
OH
O-Gal
procollagen
Fig. 3.4 Schematic representation of the intracellular events of collagen biosynthesis. The
scheme is based on type I procollagen as shown by the absence of the PARP domain and
the shortened N-propeptide. Ribosomes are shown on the cytoplasmic side of the endoplasmic
reticulum. –S-S- denotes inter-chain disulphide bonds within the C-propeptides. Intra-chain disulphide bonds occur within the C- and N-propeptides (not shown)
3.5
Collagen Fibril Assembly
Procollagen cannot assemble into fibrils because of steric hindrance from the
bulky C-propeptides. Removal of the C-propeptides by procollagen C-proteinases
reduces the solubility of the procollagen molecule and facilitates self-assembly
of the molecules into fibrils22 (Fig. 3.5). Once thought to be a single enzyme
with unique specificity for procollagen, it is now known that the procollagen
3.5 Collagen Fibril Assembly
33
type I procollagen
procollagen N-proteinases
(ADAMTS-2, 3, 14)
procollagen C-proteinases
(BMP-1/tolloid family)
propeptide cleavage
N-propeptides
collagen
C-propeptides
fibril formation
circular cross section fibril
gap
overlap
67 nm
Fig. 3.5 Schematic representation of procollagen cleavage and collagen fibrillogenesis.
Procollagen is shown being cleaved by procollagen N- and C-proteinases. Triple helical collagen
molecules are shown assembling into fibrils in which the molecules are staggered (in register) by
67 nm. The light and dark banding pattern of the fibril (as seen by negative staining electron
microscopy) arises from the gap-overlap structure of the fibril. Circle, schematic representation of
the typical circular cross-section of collagen fibrils
C-proteinases are the same as the BMP-1/tolloid family of astacin-like metalloproteinases that have a broad substrate specificity (for review see Greenspan4).
The function of the N-propeptides is unclear. They have been proposed to
have a role in feedback regulation of collagen gene expression, biogenesis and
maturation of type I collagen (for review see Bornstein23). The N-propeptides of
the proa1(I) chain of type I procollagen contain a cysteine-rich domain found in
thrombospondins (the von Willebrand type C domain) that is homologous to
the corresponding domain in the N-propeptides of type II procollagen, and
which binds TGFb1 and BMP2 during chondrogenesis.24 It is possible, therefore, that the N-propeptides of type I procollagen have growth factor-binding
abilities. In contrast to the C-propeptide, cleavage of the N-propeptides does not
inhibit fibril formation. However, persistence of the N-propeptide has severe
34
consequences on fibril structure and tissue integrity, especially in some forms of
EDS (see below).
Like procollagen C-proteinase, the procollagen N-proteinase was originally considered to be a single enzyme with unique substrate specificity for procollagen.
However, we now know that the N-propeptides of procollagen are cleaved by
ADAMTS-2, 3 and 14, which are members of the large family of metalloproteinases
that contain A Disintegrin-like And Metalloprotease domain (reprolysin-type) with
ThromboSpondin type I motifs (for review see Apte25 and references therein).
Removal of the N-propeptides from type I procollagen by ADAMTS226,27 contributes to lowering the solubility of procollagen in the formation of collagen fibrils but
has an additional role in influencing the morphology of the fibrils formed28-30
(described in more detail below). The cleavage of the N-propeptides of type V procollagen is very different to that which occurs in type I procollagen. Within the
heterotrimers, proa1(V) N-propeptides and proa2(V) C-propeptides are processed
by BMP-1-like enzymes, and proa1(V) C-propetides are processed by furin-like
proprotein convertases.31 Partial and complete processing occurs at the N-terminal
end of the proa1(V) chain depending on whether it forms heterotrimers or homotrimers. The N-terminal domain of the proa2(V) chain is not processed.32
3.6
EDS and Type I Collagen
Specific mutations in the COL1A1 and COL2A1 genes that encode the chains of
type I collagen are known to cause either the brittle bone disorder, osteogenesis
imperfecta, or forms of EDS characterised by joint hypermobility. These contrasting phenotypic outcomes arise as a result of mutations that alter different functional
domains of the collagen molecule. Further, as type I collagen is a heterotrimer, the
proportion of the constituent proa1(I) and proa2(I) chains can influence either the
level or nature of the trimer produced, again with different phenotypic outcomes.
It is well established that heterozygosity for mutations leading to a non-functional COL1A1 allele lead to the production of half normal amounts of type I collagen and the phenotype of type I OI, which is characterised by mild to moderate
bone fragility, blue sclerae and hearing loss.33 In contrast, more recent findings
have shown that homozygosity or compound heterozygosity for a non-functional
COL1A2 allele leads to the production of trimers comprised only of a1(I) chains
and a variable EDS phenotype characterised by joint hypermobility, skin hyperextensibility and cardiac valvular disease.2,34 The mutations in this cardiac valvular
form of EDS all appear to result in nonsense mediated decay of the COL1A2 transcript that leads to complete absence of proa2(I) synthesis. Interestingly, a total
absence of a2(I) has also been described to cause a phenotype with features of both
OI and EDS but without skin or cardiovascular problems.35 In this instance, it is
surmised that a small amount of normal and abnormal protein resulting from the
mutant COL2A1 allele is synthesised and hence causes the milder but overlapping
OI/EDS phenotype.34
3.6
EDS and Type I Collagen
Fig. 3.6 Arthrochalasia EDS results from
mutations that cause outsplicing of exon 6
in either COL1A1 or COL1A2. Exons are
denoted as open boxes with the number of
the exon indicated. Introns are represented
as lines, connecting exons. (a) Normal
splicing of exon 6. The sequences encoded
by exon 6 contain the site for cleavage of
the N-propeptide by the procollagen
N-proteinase. (b) Outsplicing of exon 6 in
COL1A1 and COL1A2 in arthrochalasia
EDS type A and B, respectively, caused by
mutations at the intron-exon boundaries
35
5
6
5
7
6
7
a
5
6
5
7
7
b
Similarly, it is also well established that mutations in type I collagen genes
that alter the repeating Gly-X-Y structure of the triple helix affect the ability of the
collagen to undergo normal mineralisation during bone formation36 and hence cause
forms of OI that range from mild to lethal.33 Conversely, mutations in COL1A1 or
COL1A2 that cause a structural change in type I procollagen and lead to the deficient processing of the N-propeptide of type I procollagen cause the arthrochalasia
type of EDS (formally EDS VII). The autosomal dominant arthrochalasia EDS is
distinct from other forms of EDS by virtue of severe generalised joint hypermobility, recurrent subluxations and congenital bilateral hip dislocation. The failure to
process completely the N-propeptide of type I procollagen37 results from mutations
that cause the skipping of exon 6 (the exon encoding the cleavage site for ADAMTS2)
during processing of pre-mRNA for either the proa1(I) or the proa2(I) chain of type
I procollagen38,39 (Fig. 3.6). Subsets of the arthrochalasia EDS are defined after
molecular characterisation of the mutation; mutations in the COL1A1 gene cause
subtype A,40,41 and mutations in the COL1A2 cause subtype B.30,42-48 Again, mutations within the triple helical domain of type I collagen that are close to the
N-terminal domain have features of both OI and EDS as processing of the
N-propeptide is delayed as a consequence of the abnormal structure of the procollagen molecule in that region.33
Studies of individuals with arthrochalasia EDS subtype B have shown that the
collagen fibrils in their skin, bone and fascia are irregular in cross-section because
of retention of the N-peptide. Analysis of type I procollagen from the cultured
skin fibroblasts of these individuals showed that half of the type I procollagen
secreted by the cells was cleaved normally by ADAMTS2, and half was resistant
to the enzyme. The abnormally processed procollagen contained normal-sized
a1(I) chains and mutant pNa2(I) chains. Subsequent morphological, chemical
and immunochemical studies showed that the excised a1(I) N-propeptides
remained in non-covalent association with mutant pNa1(I)−ex6 chains in vivo and
36
in vitro.49 In procollagen, the N-propeptide normally has a restricted conformation
and is found bent back (in a hairpin conformation) on the main triple helical
domain of the procollagen.50 Partial cleavage of this domain alters it conformation
and allows it to be in either a hairpin or an extended conformation. As such the
abnormally processed N-propeptides can occupy gap or overlap regions of the
collagen fibril and hence potentially mask binding sights for other ECM components to the fibril surface. Further, the presence of N-propeptides in a hairpin
conformation forces a proportion of pNcollagen molecules to be located at the
fibril surface. This increases the surface area/volume ratio of the fibril and explains
the irregular appearance of the fibrils in cross-section (Fig. 3.7).
3.7
EDS and ADAMTS2
The irregular cross-section of type I collagen fibrils in arthrochalasia EDS is reminiscent of, but not as marked as, the characteristic hieroglyphic or ‘cauliflower-like’
fibrils of the dermatosparaxis type of EDS (formerly EDS type VIIC)3 (Fig. 3.8).
Dermatosparaxis EDS is the human equivalent of a disorder that was originally identified in cattle51 and includes symptoms of severe skin fragility, sagging and redundant
skin as well as progressive generalised joint hypermobility. Dermatosparaxis EDS is
a recessively inherited condition that results from homozygosity or compound
heterozygosity for mutations in ADAMTS2 that result in ablation or a significant
reduction in N-proteinase activity. Hence skin extracts from affected individuals show
an accumulation of pNcollagen as a result of the failure to cleave the N-propeptides
from the proa1(I) and proa2(I) chains in type I procollagen molecules. In this instance,
the vast majority of collagen in the fibril is pNcollagen, and the N-propeptides retain
a hairpin conformation (as opposed to the flexible conformation of the N-propeptides
of the partially processed pNcollagen of the arthrochalasia-type EDS described
above). The surface location of the N-propeptides forces the majority of pNcollagen
molecules to be located at the fibril surface with a dramatic effect on the surface area/
volume ratio of the fibril and hence the hieroglyphic appearance of the fibrils in crosssection. The altered biophysical properties of the collagen fibrils of this altered morphology presumably contribute to the fragility of skin in individuals with
dermatosparaxis. Further, the difference in phenotype between arthrochalasia and
dermatosparaxis EDS might arise because the different conformations of ‘nicked’
and intact N-propeptides at the surface of collagen fibrils might change the way collagen fibrils bind other ECM macromolecules. This opens up the intriguing possibility
that mutations in macromolecules that bind the surfaces of collagen fibrils might predispose individuals to as yet uncharacterised forms of joint hypermobility.2
Studies of mice lacking one or more of the small leucine-rich proteoglycans
(SLRP, e.g. decorin, lumican and fibromodulin) have demonstrated the importance
of these extracellular macromolecules in determining the mechanical properties of
connective tissues. The first SLRP knockout was decorin, which produced a mouse
with fragile skin containing collagen fibrils that were abnormal in cross-section,52
and therefore similar to the abnormal collagen fibrils seen in the tissues of
3.7
EDS and ADAMTS2
37
type I procollagen
N-propeptides
collagen
pNcollagen
N-propeptides in
bent-back
conformation
C-propeptides
cleavage of N-propeptides in
unaffected procollagen molecules
retention of N-propeptides in
procollagen molecules lacking the
ADAMTS2 cleavage site or if
ADAMTS2 is absent
N-propeptides in
extended
conformation
Fig. 3.7 Schematic representation of the abnormal cleavage of the N-propeptides in arthrochalasia EDS or dermatosparactic EDS. The cleavage of the C-propeptides occurs normally, thereby
producing molecules that are competent to assemble into fibrils. The absence of ADAMTS2
N-proteinase activity (in dermatosparactic EDS) or the presence of structurally altered procollagen molecules (in arthrochalasia EDS) leads to accumulation of pNcollagen molecules. The
N-propeptides in structurally normal pNcollagen molecules (i.e. as in dermatosparactic EDS) are
in bent-back conformation. The N-propeptides in molecules in which the proa2(I) chain is ‘nicked’
(as in arthrochalasia EDS subtype B) remain associated with the uncleaved proa1(I) N-propeptides
and can be in either bent-back or extended conformation. The retention of the N-propeptides at the
surface of collagen fibrils causes an increase in the ratio [surface area]/[volume] with concomitant
appearance of fibrils with irregular cross-sections
individuals with EDS. Another example is joint laxity and impaired tendon
development in lumican and fibromodulin-deficient mice.53 Further studies have
shown that disruption of dermatospontin,54 mimecan55 and thrombospondin-255
also results in abnormal collagen fibrillogenesis. Although no human examples
have been reported for disease-causing mutations in these genes, the proteins are
modulators and effectors of collagen fibrillogenesis and therefore might be expected
to be phenotype modifiers.
38
Fig. 3.8 Cauliflower-like fibrils in dermatosparactic animals. Transmission electron microscopy
of skin from a normal calf (a) and a calf with dermatosparaxis (b). Note the circular appearance of
fibrils in a cross-section of fibrils in normal skin, compared to the cauliflower-like (hieroglyphic)
shape of fibrils in cross-section in animals with dermatosparaxis. Fibrils with similar appearance
occur in people with dermatosparactic EDS. Scale bar = 500 nm
3.8
EDS and Lysyl Hydroxylase
The importance of the cross-linking of collagen to connective tissue integrity has
been illustrated by studies of the autosomal recessive kyphoscoliotic type of EDS
(formally EDS VIA) which is allelic to Nevo Syndrome.56,57 This form of EDS is
characterised by severe joint hypermobility and luxations, severe muscular hypotonia, progressive kyphoscoliosis from birth, scleral fragility and rupture of the globe,
and is associated with features of skin fragility with abnormal scarring, a marfanoid
habitus, osteopenia and arterial rupture. This form of EDS is caused by homozygosity or compound heterozygosity for mutations in the gene, PLOD1, which encodes
lysyl hydroxylase-1 (or procollagen-lysine, oxoglutarate 5-dioxygenase). Lysyl
hydroxylase-1 is known to be required for the hydroxylation of specific lysine residues in X-Lys-Gly sequences of collagens I and II and is an essential precursor for
subsequent cross-linking reactions. Multiple tissues are affected in kyphoscoliotic
EDS, and the phenotype overlaps with other connective tissue disorders such as
3.9 EDS and Type V Collagen
39
Bethlem myopathy, the classic form of EDS and the vascular form of EDS that are
caused by mutations in the genes encoding collagen types VI, V and III, respectively. It is yet to be elucidated if altered lysyl hydroxylation is part of the disease
mechanism in these forms of EDS.
Changes in the levels of hydroxylysine (and hydroxyproline) occur in the spondylocheiro dysplastic form of the Ehlers–Danlos syndrome, an autosomal-recessive
form of EDS caused by mutations in the zinc transporter gene SLC39A13.58 Increases
in Zn2+ in the endoplasmic reticulum are thought to compete for Fe2+, a cofactor that
is necessary for hydroxylation of lysyl and prolyl residues in collagen. Individuals
with spondylocheiro dysplastic EDS exhibit a mild skeletal dysplasia with EDS-like
characteristics including hyperelastic, thin and bruisable skin, hypermobility of the
small joints with a tendency to contractures, protuberant eyes, hands with finely
wrinkled palms, atrophy of the thenar muscles and tapering fingers.
3.9
EDS and Type V Collagen
The autosomal dominant classic type of EDS is characterised by joint hypermobility, skin hyperextensibility and abnormal wound healing, with wide atrophic scars.
This form of EDS was originally subdivided and designated EDS type I (‘gravis’)
and EDS type II (‘mitis’) to represent more severe and milder forms of the disorder,
respectively. However clinical evidence pointed towards there being a phenotypic
continuum between EDS type I and II, and hence these two forms of EDS have been
reclassified as the classic type.
It is now well established that heterozygosity for mutations in COL5A1 and
COL5A2 is responsible for about 50% of the cases of classic EDS.59 Mutations in
COL5A3 have not however, as yet, been found to cause EDS. About 50% of the
mutations identified thus far are haploinsufficient for proa1(V) mRNA as a consequence of mutations (including nonsense mutations, splice site mutations and insertions/deletions leading to frame-shifts) that lead to nonsense-mediated mRNA
decay.60 Such mutations result in half normal amounts of type V collagen being
secreted into the matrix. Similarly, mutations in COL5A1 that alter the signal peptide of pre-proa1(V) prevent its translocation to the endoplasmic reticulum and
hence its availability for trimer formation with a consequent decrease in type V
collagen in the matrix.61 In addition, mutations in COL5A1 have been identified that
alter the C-propeptide of proa1(V) and prevent its incorporation into type V procollagen again leading to lower levels of type V collagen in the matrix.62,63 Surprisingly,
however, mutations (splice-site mutations and glycine substitutions) that alter the
structure of the collagenous domain and have an effect on triple helical formation
have also been identified in both COL5A1 and COL5A2.64,65 By analogy with similar
mutations of type I collagen that cause osteogenesis imperfecta, these mutations
would exert a dominant negative effect because of the co-assembly of mutant and
normal chains into procollagen trimers, and consequently abnormal type V collagen
would be deposited in the matrix. There is however no evidence that this class of
40
mutations has a more severe phenotypic outcome than those of type V haploinsufficiency. Indeed, no distinct correlation between genotype and phenotype has been
identified for mutations causing classic EDS. Further, pedigrees have been identified where affected individuals with haploinsufficiency for COL5A1 have phenotypes that range from the severe end of the classic EDS spectrum to mild localised
joint hypermobility that is more consistent with hypermobility EDS.2 It is possible
that variability in the components of the ECM that interact or modify type V collagen can affect the phenotypic outcome of the primary mutation. Identification of
such components may provide clues as to the molecular basis of as yet uncharacterised forms of classic and hypermobility EDS.
3.10
EDS and Tenascin-X
Tenascin-X is a large extracellular matrix non-collagenous glycoprotein of an estimated 4,267 amino acids that has a modular structure including five N-linked glycosylation sites and multiple EGF and fibronectin type III repeats (see Bristow
et al.66 for review). In humans it is encoded by the tenascin-X gene located on chromosome 6p21.3 and comprises at least 39 differentially spliced exons. Tenascin-X
is expressed predominantly in tendon sheaths, ligaments, synovium, muscle, epicardium, blood vessel adventitia, gut, skin and the vasculature.67-69 Fibronectin type III
repeats are capable of reversible unfolding-refolding and might act as micro-elastic
modules.70 Taking into account that tenascin-X associates with collagen fibrils,
tenascin-X might act as an elastic linker between collagen fibrils.71
A landmark study72 of chromosomal deletions encompassing all or part of the
TNX-B locus identified an affected individual with a phenotype that included hyperextensible joints and skin and easy bruising reminiscent of EDS. This led to a largescale screen of 151 patients with EDS that identified five unrelated individuals who
had complete absence of tenascin-X and a phenotype of hypermobile joints, hyperextensible skin, easy bruising and tissue fragility. Mutation screening of the TNX-B
gene identified either compound heterozygosity or homozygosity for truncating
mutations or large deletions in these individuals.73 This provided molecular confirmation for an autosomal recessive form of classic-like EDS that has features of the
classic type but without the presence of atrophic scarring.1
In a subsequent study, members of the families of the individuals with classiclike EDS identified above who were heterozygous for the mutations in TNX-B
were examined for clinical symptoms of EDS. None of the male relatives were
found to have symptoms but 65% of the female heterozygotes were found to have
generalised joint hypermobility often associated with joint subluxations and
chronic musculoskeletal pain.74 This phenotype was consistent with the autosomal
dominant hypermobility form of EDS (formally EDS type III). A further screen of
patients with hypermobility EDS found a significant reduction in tenascin-X levels
in 7.5% (all female) of those screened and the identification of a heterozygous
deletion mutation in one of those individuals. These studies support that
3.11
EDS and Type VI Collagen
41
haploinsufficiency for tenascin-X may cause the phenotype of hypermobility EDS
that is partially penetrant in females whereas absence of TNX-B expression leads
to the phenotype of classic-like EDS that is penetrant in both males and females.
Haploinsufficiency for TNX-B mutations however only accounts for a small subset of patients with joint hypermobility, and other candidate genes are currently
been sought through both linkage and mutation screening.1
Studies of the skin in both individuals lacking tenascin-X and in a mouse knockout model75 show a reduction in the packing density of collagen fibrils as opposed
to fibrils with an altered morphology, as seen in some forms of EDS. This indicates
that tenascin-X has a role in the regulation of fibril deposition independent of collagen synthesis. There is some evidence that tenascin mediates this role through an
interaction with collagen fibrils and the proteoglycan, decorin.76 The reduction in
the number of collagen fibrils and increased fibril-to-fibril spacing are likely to
alter the biomechanical properties of the affected tissues making them less resistant to force.
3.11
EDS and Type VI Collagen
One of the patients originally described by Schalkwijk and co-workers73 (and later
by Voermans et al.77) who had features of EDS also had generalised muscle weakness and distal contractures. Both of these features are also characteristic of forms
of myopathy associated with joint hypermobility, notably Ullrich congenital muscular dystrophy and Bethlem myopathy which both result from defects in type VI
collagen (reviewed in Voermans et al.78). This suggests a functional relationship
between type VI collagen and tenascin.
In fact, studies of tenascin-X null mice have shown that deficiency of the protein
causes a decrease in the level of expression of type VI collagen.79 Here, tenascin-X
null fibroblasts show decreased cell-matrix and cell-cell adhesion, decreased mRNA
expression of COL6A1, COL6A2 and COL6A3 (which encode the polypeptide chains
of type VI collagen), and decreased levels of the a3(VI) chain of type VI collagen.
Interestingly, the levels of type I collagen synthesised by tenascin-X null cells were
also decreased, suggesting the possibility that tenascin-X has a significant role in regulating cell-cell and cell-matrix interactions as well as collagen fibrillogenesis. Such
alterations in the homeostasis of the collagenous matrix are expected to have a knockon effect on the biomechanical properties of tissues such as tendon and skin in which
these components occur. In further studies, Minamitani and co-workers have shown
that tenascin-X binds type I collagen (although, interestingly, not type VI collagen)
and markedly increased the rate of collagen fibril formation in vitro. However, combined addition of tenascin-X and type VI collagen to type I collagen had an additive
effect on the rate of collagen fibril formation. These studies highlight an important
correlation between the interactions of type I collagen, type VI collagen and tenascin
at the genetic and protein levels, which helps to provide a molecular understanding of
the overlapping phenotypes of forms of EDS and muscle myopathies.
42
3.12
Relationship Between Elastic Fibre Abnormalities,
Marfan Syndrome and EDS
Elastic fibres are ECM structures that provide resilience and elastic recoil to deformable connective tissues (e.g. arteries, lungs, skin and ligaments) and thereby complement the tensile properties of collagen fibrils in the same tissues. Although only
a few elastic fibres are present in ligaments and tendons, they are likely to be important in maintaining stability of joints. Therefore mutations that alter elastic fibre
synthesis and function might be expected to generate or modify the phenotypic
aspects of EDS involving skin and joint extensibility.
Elastic fibres consist of elastin and fibrillin microfibrils as well as MAGP1, fibulin-4
and fibulin-5, lysyl oxidase, and latent TGFb binding protein (LTBP)-1 and LTBP-2.
The fibrillin-rich microfibrils have a beaded appearance and a cross-sectional diameter of 10–12 nm.80 In addition to having a scaffolding role in elastic fibre assembly,
fibrillin-1 has a pivotal role in tissue development by regulating the bioactivity of
TGFb. Immunolocalisation studies show co-distribution of fibrillin-1 and fibrillin-2 in
both elastic and non-elastic tissues, but fibrillin-2 appears to be preferentially accumulated in elastin-rich tissues.81 Fibrillin-containing microfibrils also occur in tissue lacking elastin, especially ocular ciliary zonules and periodontal ligament, in which they
can contribute to the elasticity of the tissue. Mutations in genes that encode elastic fibre
components can cause severe, often life-threatening, disorders including the Marfan
syndrome, supravalvular aortic stenosis and cutis laxa (see Kielty9 for review).
Marfan syndrome is a clinically heterogenous autosomal dominant disorder
characterised by myopia and lens dislocation, tall stature, arachnodactyly and cardiovascular complications. It is caused by mutations in FBN1, which is the gene that
encodes fibrillin-1.82 In addition to the characteristic marfanoid habitus (tall and
slender build and arachnodactyly), affected individuals can also have hyperextensibility of the skin and joint hypermobility.83 The skin and joint involvement in the
Marfan syndrome clearly overlaps with the phenotype typical of classic-like EDS
caused by deficiency of tenascin-X. Interestingly, the skin of tenascin-X-deficient
individuals shows abnormal elastic fibres as well as reduced collagen deposition.84
The molecular basis for the involvement of tenascin-X in elastic fibre formation is
poorly understood, but a role in fibre development85 and anchorage to cells via integrins86 has been proposed. An involvement of tenascin-X in elastic fibre development might help explain why some cases of hypermobility EDS have a marfanoid
habitus whereas Marfan syndrome may be associated with moderate joint hypermobility (reviewed by Malfait et al.2).
3.13
Conclusions
EDS is a clinically and genetically heterogenous connective tissue disorder characterised by joint hypermobility, skin hyperextensibility and tissue fragility. The first
disease-causing mutations in EDS were located in the genes encoding collagen
References
43
types I and V, and the collagen-processing enzymes lysyl hydroxylase and procollagen N-proteinase. Consequently, the initial belief was that EDS was a disorder of
fibrillar collagen metabolism but different from osteogenesis imperfecta in which
individuals have brittle bones caused by mutations in the genes for type I collagen.
However, as studies of EDS progressed, it became clear that causative mutations
can reside in genes not normally associated with collagen metabolism. The best
example is tenascin-X. Furthermore, studies of the Marfan syndrome, which is
caused by mutations in fibrillin genes, have shown that defects in elastic fibre synthesis can also lead to joint hypermobility and skin involvement. A picture has
emerged showing that a fine balance exists between normal tissue tension (attributed to the collagens) and elasticity (mostly attributed to elastic fibres) and that
mutations in several genes that encode ECM macromolecules can potentially tilt
this balance towards elasticity resulting in an EDS phenotype.
Studies of genetic disorders have highlighted the critical importance of type I
and V collagens, tenascin-X and the fibrillins in determining the normal mobility of
joints. Future studies are needed to provide a detailed picture, at the atomic level, of
how the different proteins and glycoconjugates in the ECM assemble into tensile
and elastic networks that interact with each other to produce functional tissues. This
new knowledge is a prerequisite for the development of medical strategies in the
treatment of genetic and acquired diseases of joint hypermobility.
Acknowledgements The work in the authors’ laboratories is funded by the Wellcome Trust and
the Arthritis Research Campaign. Special thanks are given to Mrs. Yinhui Lu for electron
microscopy.
References
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Rheumatol. 2008;22(1):165-189.
2. Malfait F et al. The genetic basis of the joint hypermobility syndromes. Rheumatology
(Oxford). 2006;45(5):502-507.
3. Beighton P et al. Ehlers-Danlos syndromes: revised nosology, Villefranche, 1997. EhlersDanlos National Foundation (USA) and Ehlers-Danlos Support Group (UK). Am J Med Genet.
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27. Colige A et al. cDNA cloning and expression of bovine procollagen I N-proteinase: a new
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29. Watson RB et al. Surface located procollagen N-propeptides on dermatosparactic collagen
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30. Watson RB et al. Ehlers Danlos syndrome type VIIB. Incomplete cleavage of abnormal
type I procollagen by N-proteinase in vitro results in the formation of copolymers of collagen
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31. Unsold C et al. Biosynthetic processing of the pro-alpha 1(V)2pro-alpha 2(V) collagen
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32. Gopalakrishnan B, Wang W-M, Greenspan DS. Biosynthetic processing of the Pro-alpha1(V)
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30904-30912.
33. Marini JC et al. Consortium for osteogenesis imperfecta mutations in the helical domain of
type I collagen: regions rich in lethal mutations align with collagen binding sites for integrins
and proteoglycans. Hum Mutat. 2007;28(3):209-221.
34. Schwarze U et al. Rare autosomal recessive cardiac valvular form of Ehlers-Danlos syndrome
results from mutations in the COL1A2 gene that activate the nonsense-mediated RNA decay
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35. Nicholls AC et al. Homozygosity for a splice site mutation of the COL1A2 gene yields a nonfunctional pro(alpha)2(I) chain and an EDS/OI clinical phenotype. J Med Genet. 2001;38(2):
132-136.
36. Culbert AA et al. Substitutions of aspartic acid for glycine-220 and of arginine for glycine-664
in the triple helix of the pro alpha 1(I) chain of type I procollagen produce lethal osteogenesis
imperfecta and disrupt the ability of collagen fibrils to incorporate crystalline hydroxyapatite.
Biochem J. 1995;311(Pt 3):815-820.
37. Lichtenstein JR et al. Defect in conversion of procollagen to collagen in a form of EhlersDanlos syndrome. Science. 1973;182(109):298-300.
38. Eyre DR, Shapiro FD, Aldridge JF. A heterozygous collagen defect in a variant of the EhlersDanlos syndrome type VII. Evidence for a deleted amino-telopeptide domain in the pro-alpha
2(I) chain. J Biol Chem. 1985;260(20):11322-11329.
39. Byers PH et al. Ehlers-Danlos syndrome type VIIA and VIIB result from splice-junction mutations or genomic deletions that involve exon 6 in the COL1A1 and COL1A2 genes of type I
collagen. Am J Med Genet. 1997;72(1):94-105.
40. Cole WG et al. Deletion of 24 amino acids from the pro-alpha 1(I) chain of type I procollagen
in a patient with the Ehlers-Danlos syndrome type VII. J Biol Chem. 1986;261(12):
5496-5503.
41. Chiodo AA, Hockey A, Cole WG. A base substitution at the splice acceptor site of intron 5 of
the COL1A2 gene activates a cryptic splice site within exon 6 and generates abnormal type I
procollagen in a patient with Ehlers-Danlos syndrome type VII. J Biol Chem. 1992;267(9):
6361-6369.
42. Steinmann B et al. Evidence for a structural mutation of procollagen type I in a patient with the
Ehlers-Danlos syndrome type VII. J Biol Chem. 1980;255(18):8887-8893.
43. Weil D et al. Temperature-dependent expression of a collagen splicing defect in the fibroblasts of
a patient with Ehlers-Danlos syndrome type VII. J Biol Chem. 1989;264(28):16804-16809.
44. Weil D et al. Structural and functional characterization of a splicing mutation in the pro-alpha 2(I)
collagen gene of an Ehlers-Danlos type VII patient. J Biol Chem. 1990;265(26):16007-16011.
45. Weil D et al. A base substitution in the exon of a collagen gene causes alternative splicing and
generates a structurally abnormal polypeptide in a patient with Ehlers-Danlos syndrome type
VII. EMBO J. 1989;8(6):1705-1710.
46. Weil D et al. Identification of a mutation that causes exon skipping during collagen pre-mRNA
splicing in an Ehlers-Danlos syndrome variant. J Biol Chem. 1988;263(18):8561-8564.
47. Nicholls AC et al. Ehlers-Danlos syndrome type VII: a single base change that causes exon
skipping in the type I collagen alpha 2(I) chain. Hum Genet. 1991;87(2):193-198.
48. Vasan NS et al. A mutation in the pro alpha 2(I) gene (COL1A2) for type I procollagen
in Ehlers-Danlos syndrome type VII: evidence suggesting that skipping of exon 6 in RNA
splicing may be a common cause of the phenotype. Am J Hum Genet. 1991;48(2):305-317.
49. Wirtz MK et al. In vivo and in vitro noncovalent association of excised alpha 1 (I) aminoterminal propeptides with mutant pN alpha 2(I) collagen chains in native mutant collagen in a
case of Ehlers-Danlos syndrome, type VII. J Biol Chem. 1990;265(11):6312-6317.
50. Holmes DF et al. Ehlers-Danlos syndrome type VIIB. Morphology of type I collagen fibrils
formed in vivo and in vitro is determined by the conformation of the retained N-propeptide.
J Biol Chem. 1993;268(21):15758-15765.
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51. Lenaers A et al. Collagen made of extended -chains, procollagen, in genetically-defective
dermatosparaxic calves. Eur J Biochem. 1971;23(3):533-543.
52. Danielson KG et al. Targeted disruption of decorin leads to abnormal collagen fibril morphology and skin fragility. J Cell Biol. 1997;136(3):729-743.
53. Jepsen KJ et al. A syndrome of joint laxity and impaired tendon integrity in lumican- and
fibromodulin-deficient mice. J Biol Chem. 2002;277(38):35532-35540.
54. Takeda U et al. Targeted disruption of dermatopontin causes abnormal collagen fibrillogenesis.
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55. Tasheva ES et al. Mimecan/osteoglycin-deficient mice have collagen fibril abnormalities.
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56. Giunta C et al. Nevo syndrome is allelic to the kyphoscoliotic type of the Ehlers-Danlos
syndrome (EDS VIA). Am J Med Genet A. 2005;133A(2):158-164.
57. Yeowell HN, Walker LC. Mutations in the lysyl hydroxylase 1 gene that result in enzyme
deficiency and the clinical phenotype of Ehlers-Danlos syndrome type VI. Mol Genet Metab.
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58. Giunta C et al. Spondylocheiro dysplastic form of the Ehlers-Danlos syndrome–an autosomalrecessive entity caused by mutations in the zinc transporter gene SLC39A13. Am J Hum Genet.
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59. Malfait F, De Paepe A. Molecular genetics in classic Ehlers-Danlos syndrome. Am J Med
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60. Mitchell AL et al. Molecular mechanisms of classical Ehlers-Danlos syndrome (EDS). Hum
Mutat. 2009;30(6):995-1002.
61. Symoens S et al. COL5A1 signal peptide mutations interfere with protein secretion and cause
classic Ehlers-Danlos syndrome. Hum Mutat. 2009;30(2):E395-E403.
62. De Paepe A et al. Mutations in the COL5A1 gene are causal in the Ehlers-Danlos syndromes
I and II. Am J Hum Genet. 1997;60(3):547-554.
63. Wenstrup RJ et al. A splice-junction mutation in the region of COL5A1 that codes for the
carboxyl propeptide of pro alpha 1(V) chains results in the gravis form of the Ehlers-Danlos
syndrome (type I). Hum Mol Genet. 1996;5(11):1733-1736.
64. Richards AJ et al. A single base mutation in COL5A2 causes Ehlers-Danlos syndrome type II.
J Med Genet. 1998;35(10):846-848.
65. Giunta C et al. Homozygous Gly530Ser substitution in COL5A1 causes mild classical
Ehlers-Danlos syndrome. Am J Med Genet. 2002;109(4):284-290.
66. Bristow J et al. Tenascin-X, collagen, elastin, and the Ehlers-Danlos syndrome. Am J Med
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67. Burch GH et al. Embryonic expression of tenascin-X suggests a role in limb, muscle, and heart
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68. Geffrotin C et al. Distinct tissue distribution in pigs of tenascin-X and tenascin-C transcripts.
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69. Matsumoto K et al. The distribution of tenascin-X is distinct and often reciprocal to that of
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73. Schalkwijk J et al. A recessive form of the Ehlers-Danlos syndrome caused by tenascin-X
deficiency. N Engl J Med. 2001;345(16):1167-1175.
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75. Mao JR et al. Tenascin-X deficiency mimics Ehlers-Danlos syndrome in mice through alteration of collagen deposition. Nat Genet. 2002;30(4):421-425.
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86. Elefteriou F et al. Cell adhesion to tenascin-X mapping of cell adhesion sites and identification
of integrin receptors. Eur J Biochem. 1999;263(3):840-848.
Chapter 4
Biomechanics of Hypermobility:
Selected Aspects
In an early paper, Sutro1 drew attention to the biomechanical aspects of hypermobility.
In a study of recurrent effusions in the knees and ankles of American army recruits,
he noted an increased range of both active and passive movement in the affected
joints. He argued in favour of an ‘over-length’ of certain articular, capsular and ligamentous tissues, and suggested that there might be disproportion in the relative rate
of growth of the bones and their attached ligaments.
Two decades later, Coomes2 made a detailed analysis of lateral instability of the
knee joint. Movements were measured in 59 normal subjects and 57 patients with
rheumatoid arthritis. Instability was present in rheumatoid patients with severely
affected knee joints but not in those with mild disease. Instability was not present in
normal knees but adolescents up to the age of 20 years displayed more lateral movement than normal adults. No change was seen in patients with ankylosing spondylitis
and only moderate change in patients with psoriatic arthropathy.
A biomechanical study on autopsy specimens of hip joints3 using cryosectioning
and cryodissection has shown that loading of the hips at 45° of flexion with a moderate force for 3 h results in deformation and dislocation similar to changes found at
autopsy in congenital dislocation of the hip. There was no macroscopic damage to the
joint. Loading at 135° of flexion (simulating breech position) also resulted in dislocation, but cartilage deformation was less pronounced than with the load applied at 45°.
After unloading of the dislocated hips with cartilage deformation, ligamentous joint
laxity was observed. This was still present 3 h later. By implication, loads applied at
critical angles can cause cartilage deformation, though ligamentous laxity, which may
be of considerable duration, is a secondary phenomenon.
Practical clinical studies tend to confirm the importance of these hypotheses, which
are based upon detailed laboratory findings. In an investigation of injuries to knee
ligaments in American professional football players,4 139 players were classified as
either ‘loose’ or ‘tight’. When subsequently checked for the incidence of major ligament rupture requiring surgery, an increased likelihood of ligament injury was found
in players with lax joints. It was hypothesised that regular training programmes concentrating on increasing muscle tone, and thereby achieving joint stability, were likely
to be of benefit in protecting players with ‘loose’ ligaments from further injury.
49
50
4.1
4.1.1
4
Biomechanics of Hypermobility: Selected Aspects
Mechanical Factors in Joint Mobility
Relative Contributions of Different Factors
In seminal studies performed by Johns and Wright,5 various tissues were divided in
turn at the wrist joints of anaesthetised cats. An arthrographic technique was used to
determine the relative proportion contributed by each tissue layer to the joint stiffness, measured in mechanical fashion. It was argued that in the intact wrist joint of
the cat, the mechanical properties were similar to those observed at the metacarpophalangeal joint in humans. Non-linear elasticity and plasticity accounted for most
of the stiffness, elasticity being twice as important as plasticity. The joint capsule
contributed 47% of the stiffness, passive action of the muscles 41%, the tendons
10% and the skin 2% to the total torque required to move the joint in its mid-range.
Towards the extremes of joint motion, the restraining effect of tendons became more
important. Clearly, many structures contribute biomechanically to the observed
range of movement at a joint, and the relative proportion of tethering contributed by
each of these may vary according to whether the joint is being moved close to its
normal anatomical range or at an extreme of its range of function.
It has been argued that, for epidemiological and clinical purposes, three main
determinants of joint laxity should be considered.6 These are:
1. The shape of the bony articulating surfaces.
2. The structure of the collagen contributing to the joint capsule, the tendon and the
overlying tissues and its degree of stretch.
3. The neuromuscular tone that will tend to stabilise the joint under physiological
conditions. This is derived both from the nervous system and from the muscle.
4.1.2
Bony Surfaces
The range of movement is extreme for a ball and socket joint (the hip or shoulder)
but non-existent in the joints that contribute to the stability of the skull. Between
these two extremes, various anatomical adaptions are available to provide different
ranges of movement. At the elbow, there is bony locking to prevent hyperextension,
though the increased carrying angle in women allows for a greater amount of hyperextension than in males. The ankle is also a hinge joint at which lateral movement
is restricted more by bony prominences than by tension in the lateral ligaments. The
knee is a hinge joint, depending entirely upon ligaments for its stability (the anterior
and posterior cruciate ligaments and the collateral ligaments); even at the ball and
socket hip joint, some stability is provided by the ligamentum teres.
In general, the shape of the articulating surfaces, determined both by bone and
collagen, is likely to be hereditary. Acetabular dysplasia may lead to a marked
increase in the range of movement, and it is likely that this sort of dysplasia follows
4.1
51
a Gaussian distribution within the population (as described in Chap. 2), rather than
being an ‘all or nothing’ phenomenon. Up to the age of epiphyseal fusion at puberty,
the shape of the bone may be influenced to some extent by external forces.
4.1.3
Collagen
This is described in more detail in Chap. 3. In summary, the tensile strength of the
collagen in the supporting tissues around the joint and in the joint capsule is determined by several factors. These include the chemical structure within the collagen
fibres, the extent to which cross-linking has occurred between adjacent chemical
chains (which increases with age), the coiling, the diameter and the density of packing of the collagen fibres. Defects in collagen formation may result from enzyme
deficiencies and within the different variants of the Ehlers–Danlos Syndrome (EDS),
both deficiencies in collagen production and deficiencies in collagen turnover have
now been recognised.7 Most of these variations are likely to be genetically determined though the total volume of collagen and its weaving may be altered in
response to external forces. Collagen fibres may suffer marked contraction when the
temperature of their surroundings changes.
Elastin is also present in skin and ligaments. The amino acid sequence analysis
of purified elastin, the major protein in the elastic fibres, shows that it differs from
collagen in containing fewer basic acidic amino acid residues. The hydroxyproline
content is only one-fifth of that seen in collagen.8 The cross-links between elastin
fibres are unusual, not only joining two adjacent protein chains but also having the
facility to link three or four nearby chains. With age, elastin changes as well as collagen. Above the age of 45 years, a glycoprotein becomes closely bound to elastin,
producing a more brittle complex that is more readily cleaved chemically.
Most studies on the tensile properties of collagen have been carried out on tendons in the tails of rats, which can be easily freed from secondary tissue. There is
little slack to take up, and the shapes of the load/extension curves of collagen bundles are almost independent on the number of fibres that they contain. After an initial brief alignment of the force/extension curve, there follows an essentially linear
extension, during which Hooke’s law is obeyed. At a certain point, a failure of individual fibres occurs until the tendon as a whole finally ruptures. Some basic biomechanics have been performed by Silverman et al.9 by determining the extensibility
of the fifth right metacarpophalangeal joint in response to increasing loads (Fig. 4.1).
Cases 1 and 2 were normal young subjects; case 3 was clinically hypermobile.
When extensibility of the fifth metacarpophalangeal joint is related to age, a highly
significant inverse correlation becomes apparent (Fig. 4.2).
Elastic fibres, in contrast, undergo appreciable extension under the action of relatively small forces, returning to their original dimension shown when the force is
removed. The properties of elastin are not maintained in older age groups, hence the
change in the texture of normal skin during ageing. The physical properties of skin,
which also contribute to the range of joint movement observed, have been defined
52
4
Fig. 4.1 Extensibility of the fifth
right metacarpophalangeal joint in
response to increasing load in
three subjects (Reproduced from
Silverman et al.,9 with permission
from BMJ Publishing Group Ltd)
Case 1
100
90
Case 2
80
Nm × 10−7
70
Case 3
60
50
40
30
20
10
0
10
30
40
50
Angle (degrees)
20
60
70
Fig. 4.2 Extensibility of the
fifth metacarpophalangeal
joint related to age (in years)
(Reproduced from Silverman
et al.,9 with permission from
BMJ Publishing Group Ltd.)
5
Nm
Extensibility
degrees
10−5
6
4
3
0
Age group
Sample size
5
53
6
58
7
48
8
44
9
50
10
42
4.1
53
Fig. 4.3 Stress (T) versus strain (S) curve
for intact skin from a patient suffering from
Ehlers–Danlos syndrome (Reproduced from
Beighton et al.73)
5
T (Pa × 10−5)
4
3
2
1
0
0.02
0.04
0.06
0.08
0.1
S
Ehlers-Danlos syndrome
Control subject
by Grahame and Harvey10 in terms of thickness and extensibility. The stress–strain
curve for intact skin from a patient suffering from EDS, measured by an in vivo
suction cup method,11,12 is shown in Fig. 4.3.
4.1.4
Neuromuscular Control
In clinical terms, the premature osteoarthritis that can accompany neurological conditions as diverse as subacute combined degeneration of the cord, syringomyelia and tabes
dorsalis attests to the importance of adequate joint protection by the nervous system during normal life. The wide range of movement observed at peripheral joints in patients
with these neurological conditions cannot be explained on the basis of collagen or bony
structure alone. That all these conditions, each involving a different part of the central
nervous system, can cause osteoarthritis attests to the value of the complete integrity of
the afferent proprioceptive arc and the resultant efferent control of the muscle tone. The
importance of neurological ‘servo’ mechanisms in allowing joint stability to be altered
is well recognised by sporting coaches and forms the basis for the methods of proprioceptive neuromuscular facilitation described in more detail in Chap. 8.
It follows that integrity of the Golgi tendon organs and the muscle spindles is
also important in determining the range of joint movement. The quality and nature
of the muscle fibres will therefore contribute both in terms of their physiological
ability to stabilise the joint and in terms of their anatomical bulk, which might act to
impede joint movement by creating a large muscular mass.
54
4
The influence of muscles and tendons is often neglected when the frictional
forces operative at synovial joints are considered. A tensile force is exerted by muscles and tendons in almost all positions of joints, irrespective of muscular contract,
which would exert a further and more powerful force. It has been shown that joints
are more mobile in their mid-positions than at the extremes of their ranges.13 Studies
on the wrist joints of dogs shortly after death show that an ever-increasing force is
required to straighten the joint as the position of full extension is reached.
4.1.5
Proprioception
There has recently been increasing interest in impaired proprioception, both in relation to joint hypermobility and osteoarthritis. Indeed, this may be one of the factors
that bind these two conditions together. Anecdotally, it has been suggested for many
years that ‘joint instability’ is more potent than ‘joint hypermobility’ alone in the
pathogenesis of early premature osteoarthritis.
Proprioception can be assessed clinically (though coarsely) by the estimated
position of the joint when the eyes are closed, or by appropriate biomechanical
devices to quantify this with more precision. Proprioception falls with age,14
paralleling the increasing onset of osteoarthritis. It can also be impaired with
inflammatory arthritis such as rheumatoid disease.15 In animal experiments, low
threshold knee joint mechanoreceptors discharge maximally towards the
extremes of movement.16 These neurones, exerting powerful reflex effects on
limb muscles, act to prevent hyperextension and hyperflexion of the joint.17
Perhaps these receptors protect the joint from potentially damaging movements
at the extreme of range.
Proprioception can be abnormal in knee joints prior to correction of a lesion of
the medial meniscus, whereupon proprioception improves.18 Normal shoulder proprioception alters the range of movement at that joint.19,20 Simple remedies such as
elastic bandages21 and knee braces22 improve proprioception.
Proprioceptive acuity is abnormal in hypermobility syndrome both at the
proximal interphalangeal joint23 and at the knee joint.24 The sophisticated rig
developed in Glasgow by Ferrell and colleagues for the precise quantification of
proprioception at the knee joint24 has provided new insights. There is some evidence that in addition to impairment of proprioception, probably mediated by
the resetting of nerve receptors in the synovium, the reflex arc may also be
altered.25 In addition, physiotherapy studies, in which exercise has been given to
joints with abnormal proprioception to stabilise them, have improved symptoms
of hypermobility.26
Studies are still needed to determine whether non-weight-bearing joints that are
lax with impaired proprioception are less susceptible to osteoarthritis and also
whether the effect is purely mechanical and anatomical or whether reduced proprioception, either on an acquired or inherited basis, is associated with altered cartilage
turnover or even altered cartilage chemistry.
4.3
Lubrication and Stiffness
4.2
55
Podiatric Aspects
The foot is always important in maintaining gait and especially important in the hypermobile subject since balance and walking may be impaired through proprioception
and the hypermobile foot may be of unusual shape and properties. The typical abnormality is flat feet but, sometimes, a high arched foot is found, analogous to the typical
foot shape in the marfanoid deformity. Recent Arthritis Research Campaign funded
research in Leeds has studied this in more detail with gait analysis and the provision
of orthoses, predominantly designed to restore the natural arch of the flat foot. The
results have been somewhat conflicting: the degree of foot abnormality (and therefore
the need for correction) is not always apparent or correlating with conventional scoring systems for hypermobility (see Chap. 2). Preliminary analysis, however, confirms
that reduced health status, greater foot pain and poorer foot health status correlate well
with higher Beighton scores. Greater magnitude of mid-foot joint excursion during
walking is present in the more hypermobile individuals, also correlating with greater
foot pain. Arch instability rather than arch flattening may also be crucial.27
Recent work from Stanmore has drawn attention to dysfunction of the tibialis
posterior tendon as a common and treatable cause of flat foot deformity in the adult,
manifested by pain and swelling in the medial hind foot.28 Clearly, tendons extrinsic
to the foot as well as those within it also play a part.
4.3
4.3.1
Lubrication and Stiffness
Lubrication of the Synovial Membrane
Although this forms a minor determinant in the observed range of joint movement,
it is relevant to consider briefly why joints move so efficiently. There are a number
of theories to account for the remarkably low resistance to movement observed at
synovial joints, and these may also have some bearing upon the biomechanics of
hyperlaxity.
The oldest theory is that of ‘hydrodynamic lubrication’, first proposed by
MacConaill.29 A thick film of synovial fluid separates the articular surfaces. However,
joint movement is too slow and the pressures across the surfaces are too high to
allow the maintenance of a thick film of this nature.
Charnley30 postulated a monomolecular layer of hyaluronic acid protein complex
that provides the so-called ‘boundary lubrication’. In this context, it is noteworthy
that all known bearings depending upon boundary lubrication have a coefficient of
friction 20 times as high as that present in synovial joints. The synovial joint mechanism may be more analogous to ‘elastohydrodynamic lubrication’. Here, films of
viscous fluid separate rubbery surfaces.
It is likely that no single mode of lubrication can fully explain the biochemical
properties of synovial joints.31 There is clear experimental evidence of fluid film
56
4
lubrication, yet mathematical analysis indicates that this mechanism is not the sole
factor. Fluid films require an elastohydrodynamic entraining action supplemented
by squeeze film lubrication, rather than conventional hydrodynamic action alone, in
order to be effective.
Theoretical considerations of hydrodynamic lubrication have a bearing upon the
design of new artificial joint prostheses. The artificial component provided needs to
simulate the original efficient lubricating mechanism as well as provide adequate
strength. If joint laxity follows a Gaussian distribution throughout the population,
an artificial prosthetic joint might offer a theoretical therapeutic option for the treatment of individuals who display pathological hypolaxity, though, in practice, this
procedure is at present restricted to individuals who have severe flexion contracture
or flexion deformity arising from unrelated disease.
4.3.2
Measurement of Stiffness
Stiffness of joints is important clinically. For instance, morning stiffness is a diagnostic criterion of rheumatoid arthritis, while articular gelling, the subjective impression
of increased stiffness after a short period of immobilisation, is well known to arthritic
patients. Grip strength measurements indicate that there is a circadian rhythm both in
muscle strength and in joint stiffness in normal and arthritic persons.32
Arthrographs have been used in the mechanical evaluation of stiffness at the
metacarpophalangeal joint of the index finger. Similar instruments have also been
designed for the evaluation of stiffness at the knee joint, but these are less easy to
operate and patients with severe arthritis find difficulty in co-operating. However,
important information has been gleaned regarding the muscular and skeletal factors
that determine joint stiffness. Physiological variations noted include increased stiffness in the elderly and reduction in stiffness at higher temperatures. The arthrograph
also allows distinction between the pathological stiffness that occurs in some diseases of joints, such as osteoarthritis and rheumatoid arthritis, and the abnormal
‘suppleness’ in disorders of connective tissue, such as EDS.
The principle of an arthrograph is that the joint to be studied is driven through a
proportion of its normal range of movement by a motor, in sinusoidal fashion. The
role of gravity needs to be considered, though this can sometimes be eliminated by
measuring movement in a horizontal, rather than a vertical, plane. The resistance to
movement is then measured electrically and depicted electronically on a computer
screen. This results in a hysteresis loop being plotted out each time the joint is put
through its predetermined range of motion. Voluntary muscular resistance can be a
problem until the subject learns to relax but, in practice, this occurs early and muscular relaxation is confirmed by the reproducibility of the loops, which will assume
a constant shape and position on the recorder once the subject is fully relaxed.
The most recent studies have used a computerised arthrograph in which the metacarpophalangeal joint of the middle finger is moved in a horizontal plane.33 This has
allowed the demonstration of serial change as the patient’s stiffness responds either to
4.4
Hypermobility and Osteoarthritis
57
intra-articular steroid therapy or to the use of non-steroidal anti-inflammatory drugs.
Interestingly, the stiffness, as perceived by the patient and depicted on a 10-cm visual
analogue scale, does not often coincide with the stiffness measured and defined in
biomechanical terms. In rheumatic diseases, many patients find it difficult to distinguish ‘stiffness’ from ‘pain’. We have had similar experiences when attempting to
define ‘suppleness’ as an index of hypermobility by the use of a postal questionnaire.
The patient’s perception of their own ‘suppleness’ is no substitute for the adequate
mechanical monitoring of the range of joint movement. Studies with selected sporting
groups34 have emphasised the importance of training techniques that enhance the
range of movement at joints. This emphasises the need to determine whether ‘suppleness’ is gauged by the subject before or after an appropriate warm-up period.
A study on the resonant frequency at the wrist35 showed abnormal results compared to controls in hypermobile women with damping though with normal thixotropy (the ability of a fluid or material to alter its viscosity with time or shaking). It was
postulated that connective tissue in the muscles and tendons of hypermobile subjects
might display enhanced compliance. A study of grip and pinch strength in the finger
joints using an electronic strain gauge dynamometer (MIE Medical Research, Leeds,
UK) demonstrated that symptoms of joint stiffness generally correlate with mechanical measures, providing a useful and sensitive objective index on changes occurring
when intra-articular steroid injections were used to relieve stiffness.36
4.3.3
Artificial Lubricants
The development of the arthrograph has paved the way for a study of potential lubricants that might be injected into the synovial joints for the relief of osteoarthritis
and for the enhancement of range of efficient movement. Objective arthrography
has allowed the ranking of a large number of artificial chemicals that might be used
in this capacity. These include polyvinyl alcohol, carbopol, manucol, polyacrylamide and polyvinyl oxide.37 All have lubricating properties similar to those of synovial fluid, though a major pharmacological limitation in their use has been the
failure of these compounds to be retained in the joint cavity. Most foreign chemicals
are cleared quickly from the joint cavity and, at present, artificial lubricants do not
offer a therapeutic option in the management of joint hypolaxity. By analogy, it is
unlikely that a fluid selected because of properties of excessive viscosity would be
of value in the management of joint hyperlaxity.
4.4
It is believed that joint hyperlaxity predisposes to premature osteoarthritis.
Previously, there seemed to be two possible explanations for this situation. Firstly,
the particular collagen structure that contributes to hyperlaxity might be identical
58
4
with that which leads to osteoarthritis. In this conceptual framework, the hyperlaxity was nothing more than a phenotypic marker of a certain genotype that predisposed to premature degeneration. Alternatively, biomechanical factors might be
important in the pathogenesis of the degenerative change. In this way, any hyperlaxity, however acquired, would lead to osteoarthritis, providing it fulfilled the basic
biomechanical requirements. Recently, a third suggestion that proprioception may
be a causative link between hypermobility and osteoarthritis has been advocated,
though the current evidence is not yet completely convincing. Thus, in a study that
compared knee joint proprioception in the osteoarthritic knee and the other unaffected knee in unilateral knee joint osteoarthritis, impaired proprioception was
shown not to be exclusively a local result of knee joint osteoarthritis.38 Clearly, longitudinal studies are required to determine the true role of proprioception in osteoarthritis. Perhaps all three mechanisms contribute.
Findings derived from the canine model of Pond and Nuki39 favour the mechanical theory. Only when the cruciate ligaments were severed did sufficient lateral
instability occur to initiate the earliest chemical changes in cartilage. The frequency
with which osteoarthritis occurs in diseases associated with joint instability is striking. The cause of the instability may be the abnormal collagen in the ligaments, as
in acromegaly,40 or mechanical, as in some neurological diseases.
The studies of the University of Leeds group have indicated that individuals
indulging in sporting activity may be spared osteoarthritis.41 It is suggested that the
protective muscle tone acquired by regular training stabilises the joint and lessens
the likelihood of osteoarthritis. Surveys of professional sportsmen show that osteoarthritis tends to develop in those who have had surgery or injuries to a joint, causing
incongruity of the articulating surfaces or stretching of the ligaments. It may be
significant that in a clinical and arthroscopic study of osteoarthritis, chondrocalcinosis and joint hyperlaxity in females, no sportswomen were found to be hyperlax.42
By implication, those who indulged in regular exercise were spared the symptoms,
if not the actual degenerative progression.
Opinions still differ on whether repeated weight-bearing trauma accelerates or causes
osteoarthritis. When the wrist is turned into a weight-bearing joint by the use of a stick,
osteoarthritis is not more frequently found there.43 The literature varies on the extent to
which the weight-bearing joints in the lower limbs of former elite male athletes do or do
not experience more osteoarthritis.44,45 In less selected subjects, the Framingham study
has implied that habitual physical activity may influence the development of osteophytes but not of more severe or symptomatic knee joint osteoarthritis. In general, habitual physical activity was felt not to increase the risk of osteoarthritis at the knee.46
It must also be accepted that what is conventionally termed ‘osteoarthritis’ is
likely to be a collection of many different conditions. On this basis, hyperlaxity
would seem to be more relevant to secondary osteoarthritis at a small number of
joints than to the primary or generalised osteoarthritis described by Kellgren et al.47
The aetiology of osteoarthritis may be analogous to the current concept of seronegative inflammatory polyarthritis where the disease occurs in the context of the appropriate genetic background, such as the HLA antigen and the relevant provocative
4.4
59
factor, possibly infection. By analogy, joint laxity could be involved in the pathogenesis
of osteoarthritis by either of these mechanisms.
Osteoarthritis is not seen with increased frequency in obese individuals, but when
it does occur, it is usually worse in the medial compartment of the knee. This fact is
conventionally explained by bowing of the leg and a transfer of load from the lateral
to the medial compartment.48 The occurrence of this shift implies some ligamentous
laxity, and the situation may therefore be analogous to the instability induced by
cutting the cruciate ligament in the dog.
There is considerable alteration in the biomechanics following internal derangement of the knee.49 Fractures protect joints from excessive strains,50 and osteoarthritis occurs only if the fracture line enters the joint cavity, leading to non-alignment
of the articulating surfaces.
The concept of a mechanical aetiology of osteoarthritis is also supported by a
study, which showed that in meningomyelocele, articular damage occurred only in
patients who retained the power of movement.51 In the same way, there is a low
incidence of osteoarthritis in limbs paralysed by poliomyelitis but used with the aid
of supporting callipers, which eliminate unwanted lateral movement.52
There remains controversy on the extent to which joint hypermobility can predispose to osteoarthritis in biomechanical terms alone. Mild degrees of joint hypermobility have not obviously been associated with premature osteoarthritis53 providing
proprioception remains intact.54 It is also important to determine the severity of
progression of osteoarthritis before attributing damage to hyperlaxity alone.55
Evidence is still accumulating, however, that patella alignment may be crucial,56 and
the Boston osteoarthritis knee study showed site of ligament damage and therefore
joint malalignment as a predisposing factor amongst others in osteoarthritis.57
Recently, varus–valgus motion has been shown to be a potent aggravating factor for
osteoarthritis.58
Biomechanical aspects apart, collagen structure may also be important (see
Chap. 3). An accumulated number of susceptibility genes are being identified in
osteoarthritis, e.g. FRZB59 and ASPN,60 citing specific differences in osteoarthritis
and are now better understood in light of the skeletal dysplasias, which as previously discussed, is a contributing factor to hypermobility.61 Several specific associations have been recognised,62 thus mutations in the type II collagen gene (COL2A1)
cause congenital spondyloepiphyseal dysplasia with hip osteoarthritis severe at
most hyperlax joints. Recently, transforming growth factor-b (TGF-b) has been
implicated in instability-induced osteoarthritis,63 which is of interest given the close
association of this growth promoter with Marfan’s syndrome.
A review by Bora and Miller64 has outlined the many links between joint
pathophysiology and osteoarthritis. One hypothesis points to an excessive stress, as
typified by joint laxity, imposed upon normal tissue. Another hypothesis emphasises the inadequacy of chondrocyte response, implying a basic genetically determined biochemical failure. In addition, ageing, hormones, possibly diet, crystal
deposition, bone microfractures and immunological factors have all been implicated as adjuncts to the initial joint hyperlaxity.
60
4
The contribution, perhaps mild, of osteoporosis should also not be forgotten.65
Osteoporosis, sometimes deemed to be protective for osteoarthritis, is increasingly
accepted as an accompaniment to hypermobility.65 Discussion continues on whether
osteoporosis is of the conventional type with a quantitative defect in normal collagen or an inherited qualitative defect in a normal amount of collagen, which
renders the bone fragile and perhaps susceptible to fracture. Whether, in turn, this
might or might not respond to bisphosphonate therapy is still a matter for discussion. Osteoporosis, arguably, might confer some protection to osteoarthritis, but
this might be offset by an exacerbation of pain adjacent to hypermobile osteoarthritic joints.
4.5
Prospects for Surgical Intervention
Joint fusion, although time honoured, does not provide a serious surgical option for
the management of extreme joint hypermobility. Conventionally, patients are
instructed to stabilise the joints as far as possible by performing regular physiotherapy exercises in the hope of building up neurological control. Future research is
likely to see the patients with joint hypermobility subdivided according to the factors that cause it. Rationally, patients with extreme acetabular dysplasia causing an
unacceptably large range of movement might be offered a conventional replacement
joint, hip arthroplasty being more refined at present than shoulder arthroplasty.
Patients with generalised joint hyperlaxity mediated by inadequate neuromuscular
control may be best served by attention to the nervous system. Unfortunately, pharmacological intervention has concentrated on the development of drugs that relieve
spasticity rather than the development of drugs that enhance it. For those patients
with generalised joint laxity secondary to abnormal inherited collagen structure,
ligament tightening or ligament replacement by a surgical technique remains a theoretical option. Although not used prophylactically (see below) to any great extent,
artificial ligaments have been developed for the treatment of ruptured ligaments that
occur in athletics injuries.
Replacement of the anterior cruciate ligament at the knee joint provides one such
important example. This has practical importance because rupture of the anterior
cruciate ligament is almost ten times as common as rupture of the posterior cruciate
ligament in the knee joint (G.K. Sefton 1988, personal communication). It also has
theoretical interest because artificial rupture of the anterior cruciate ligament in the
dog produces the classic Pond-Nuki model of osteoarthritis from which much of our
understanding of basic biochemistry in this condition is derived.39 Knee injuries are
the topic of increasingly sophisticated research,66 and a link between ligamentous
laxity and cruciate ligament damage has been demonstrated clearly. Loss of the collateral ligament appears to be less important67 and can, to some extent, be compensated for by the remaining structures, especially the anterior cruciate ligament.
A major surgical problem in replacement of the anterior cruciate ligament is that
of fixation. Because of this, artificial ligaments that are stabilised by allowing an
References
61
ingrowth of bone are preferred. Three such devices exist, the carbon fibre ligament,68,69 the Stryker-Medox Dacron ligament70 and the Leeds-Keio,71 which is a
polyester open-weave structure.
The open-weave structure of the last named device was developed as a result of
collaboration between Dr. Bahaa Seedhom, a University of Leeds bioengineer, and
Professor Fujikawa, a Japanese orthopaedic surgeon. It allows the most efficient
growth of new bone between the fibres of the ligament in the first few months after
insertion. This leads to an even more stable bonding of the ligament to the bone than
can be achieved by conventional techniques such as plugging alone.
At present, the use of these ligaments has been restricted to repair of a rupture.
Their use is recent so we do not yet know whether the accidental simulation of the
Pond-Nuki osteoarthritic model in man can be corrected by the use of a ligament,
with the resultant prevention of secondary osteoarthritis. If this proves to be the
case, surgical tightening or replacement of lax ligaments in patients with genetic
abnormalities of collagen such as EDS might be an attractive possibility. It would
have to be shown that replacement of a single ligament, probably the anterior cruciate, produced adequate stabilisation in the presence of laxity of the posterior cruciate and collateral ligaments. In turn, mechanical devices of the sort recently
developed in Leeds to quantify the component of the different knee ligaments in
joint laxity may be of value. An alternative, and perhaps safer choice for such study,
would be the ankle joint. Here, there is a relative bony restriction of the joint, perhaps allowing for more accurate quantification of the value, if any, of replacing the
lateral ligaments of the ankle with polyester open-weave grafts.
The future is likely to see increasing interest in stem cell technology.72
Replacement joint prostheses are of limited longevity. There is a need to attain
implant survival in the range of 20–30 years as the population ages, with quests for
biological material or tissue regeneration therapy that behaves equivalently to an
autograft, a particular challenge. Training the cells to populate a scaffold remains a
matter of ongoing research but, long-term, the prospects for stem cell replacement
of hyperflexible ligaments in hypermobile patients, both to reduce symptoms and
reduce the risk of future osteoarthritis, remains an attractive proposition.
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71. Seedhom BB, Fujikawa K, Atkinson PJ. The Leeds-Keio artificial ligament for replacing the
cruciates. In: Engineering and Clinical Aspects of Endoprosthetic Fixation. London:
Mechanical Engineering Publications; 1984:99-109.
72. Vats A, Bielby RC, Tolley NS, Nerem R, Polak JM. Stem cells. Lancet. 2005;366:592-602.
73. Beighton P, Price A, Lord J, Dickson E. Variants of the Ehlers-Danlos syndrome. Clinical,
biochemical, haematological, and chromosomal features of 100 patients. Ann Rheum Dis.
1969;28(3):228-245.
Chapter 5
Musculoskeletal Features of Hypermobility
and Their Management
5.1
Hypermobility and Hypermobility Syndrome
A common clinical error is to confuse these two terms, which are not synonymous.
Hypermobility is defined as an excessive range of joint motion, taking into consideration the age, gender and ethnic origin in otherwise healthy subjects, being greater
in males than females, in younger people compared with older people and in those
of Asian or African origin compared to those who are Caucasian. It is characterised
by an inherent increase in laxity and fragility of the connective tissues. Hypermobility
is a direct consequence of ligamentous laxity, which, itself, is an expression of a
genetically determined aberration of one or more of the connective tissue fibrous
protein genes such as those encoding for collagen(s), fibrillin(s) or tenascin(s) (see
Chap. 3). As an unexpected bonus, in hypermobility, the added ranges of motion
turn out to favour selection into the performing arts (see Chap. 8). Hypermobility
itself does not necessarily give rise to symptoms, but when it does, Hypermobility
Syndrome is deemed to be present. Thus, hypermobility is not a diagnosis but HMS
(JHS) is, and it is now classified by means of the 1998 Brighton Revised Criteria for
the Benign Joint Hypermobility Syndrome (BJHS) (see below).1
The biological price for this enhanced flexibility is tissue fragility, which underlies the musculoskeletal elements of JHS. Tissues such as tendon, ligament, bone,
cartilage and skin, which rely on the considerable tensile strength of their collagen
component for their physical integrity, are at greater risk of mechanical failure in
hypermobile people in comparison with others. Those who engage in more demanding physical activities, such as dancers, musicians, sportspersons, etc., are at greater
risk (see Chap. 8). Clinicians often identify hypermobility in the course of their
clinical examination, but rarely attempt to make a precise clinical diagnosis, such as
JHS. As a result, the patient is often left wondering what is wrong with them and
why no tailor-made treatment plan has been developed for their management.2
In clinical terms, with a resulting compromised connective tissue infrastructure
comes a tendency to a variety of soft tissue injuries including ankle and other ligament
strains, muscle tears, tendon–bone attachment traction lesions (enthesopathies) such
65
66
5 Musculoskeletal Features of Hypermobility and Their Management
Fig. 5.1 An example of a typical paper-thin
scar as seen in a patient with JHS. It is
typically pale, shiny and thin and can easily
be puckered when compressed between the
examiner’s index finger and thumb. It is
characteristically sunken below the level of
the surrounding skin. Scars arising from
surgical incisions following lacerations, BCG
immunisation and from chicken pox lesions
are all valuable pointers to skin involvement
in JHS
as epicondylitis, meniscus tears, stress fractures and other overuse lesions (including chondromalacia patellae, work- and performance-related upper limb disorders),
non-inflammatory spinal and joint pain and varying degrees of premature degenerative joint and spinal disease, respectively, osteoarthritis and spondylosis.
5.1.1
Impaired Healing
Coupled with a general predisposition to soft tissue injury, there is in all people with
JHS an impairment of the healing process, which is not only slower than normal, but
may also be incomplete. Scar tissue, itself, is also collagen, which explains why
scars in JHS are often of poor quality, being thin, shiny and sunken below the level
of the surrounding skin. Such scars have significant diagnostic value in JHS and
related disorders1 (Fig. 5.1).
5.2
Epidemiology of JHS
Astonishingly, up to 45% of all patients referred to general rheumatology clinics3,4 satisfy the Brighton criteria for JHS1 and may therefore be said to have JHS, indicating that
this is a very common at-risk phenotype in the community at large. In spite of such
evidence, the rheumatological community remains largely unaware of this entity.
5.3
The Clinical Significance of Hypermobility
The majority of people with lax ligaments and loose joints probably suffer no articular
or peri-articular problems. For example, symptoms were not more prevalent amongst a
group of 31 healthy hypermobile blood donors (average age 28 years) than in age- and
sex-matched controls.5 For most hypermobile subjects, the impression is that it is a
5.5
Hypermobility Syndrome in Children
67
positive attribute, which enables enhanced participation in a wide variety of physical
activities (see Chap. 8). However, not all are so fortunate, and many do experience locomotor and other problems as a direct consequence of their hypermobility. Joint hypermobility is a feature common to most of the heritable disorders of connective tissue
(HDCTs), which include the various types of the Ehlers–Danlos (EDS) syndrome, the
Marfan syndrome (MFS) and osteogenesis imperfecta (OI)6 (see Chap. 9). It is seen in
its grossest form in the classic type of EDS (formerly classified as EDS types I/II).
Generally speaking, the likelihood of developing symptoms, notably arthralgia and joint
instability, is directly proportional to the degree of joint laxity and hypermobility,
although exceptions to this rule occur. When symptoms occur in seemingly otherwise
healthy individuals, the term ‘hypermobility syndrome’ (HMS) is applied.7 In recent
years, however, this term has increasingly been replaced by the preferred ‘benign joint
hypermobility syndrome (BJHS)’ because of the favourable prognosis, at least, as far as
threat to longevity is concerned. Emerging evidence of multi-systemic complications
(documented in Chap. 6) renders the retention of the epithet ‘benign’ as of dubious
veracity, and joint hypermobility syndrome (JHS) has become the most widely accepted
term in common usage. Few clinicians still use an earlier term, familial articular hypermobility, which should probably now be declared obsolete. Most authorities currently
acknowledge that JHS is indistinguishable from, if not identical to, the Ehlers–Danlos
syndrome type III (EDS III), although this remains a somewhat contentious issue.8
5.4
Musculoskeletal Features
The remainder of this chapter reviews the published data on the musculoskeletal
features of JHS and its management. JHS is a condition commonly encountered in
clinical practice, provided it is sought, which, sadly, is by no means commonly the
case. A considerable amount of material concerning the clinical and epidemiological
features of JHS has been published in the decade since the third edition of this monograph appeared in 1999. This has had the effect of reinforcing the widely held contention that JHS (at least as viewed from the clinical perspective) is a forme fruste of
an HDCT with clinical features that overlap in large measure with those encountered
in the MFS, EDS and OI. The question as to whether hypermobility as it exists in the
community is a totally separate entity which is truly a physiological variant, merely
depicting the upper range of a spectrum of normal joint movement – a view favoured
in the 1970s for all hypermobility,9 is becoming increasingly untenable.2
5.5
JHS often makes its presence first felt in childhood, where it can manifest in infancy
as motor delay, ankle instability, flat feet, clumsiness, fidgetiness and developmental
coordination disorder (dyspraxia). As in adults (see below), it may also progress to
a chronic pain syndrome in later childhood.10
68
5.5.1
Epidemiology
A recent review of 13 epidemiological studies of hypermobility in children using
the Beighton 9-point scale conducted in North and South America, Europe and
Africa found prevalences that vary widely ranging from 6.7% in the UK to 43% in
Nigeria. Because of the use of differing measurement and age criteria, these studies
are difficult to interpret. In spite of this, certain clear messages emerge. Prevalences
are generally higher in girls than in boys and in children compared to adults.11
There are as yet no population studies of JHS. This may be due to the fact that the
Brighton criteria have as yet not been fully validated for use in children (Hasson N,
Maillard S, Woo P, Grahame R, 2006, Are the 1998 Brighton criteria for the Benign
Joint Hypermobility Syndrome (BJHS) applicable to children? Unpublished Work).
5.5.2
Clinical Presentation in Childhood
5.5.2.1
Early Features
Congenital Dislocation of the Hip/Developmental Dysplasia
A statistical association between hypermobility and congenital dislocation of the hip
(CDH) has been known since the 1970s.12 Its finding may be the first clinical pointer
to JHS in the neonate, and the routine examination of the hip joints in all newly born
infants should always be undertaken for this purpose. The finding of ‘clicky hips’ at
birth is an important clue to dysplasia, and an ultrasound examination should be performed in cases of doubt.13 In a study of 125 children referred to a tertiary hypermobility clinic in London, 12% had clicky hips at birth and 4% had actual CDH.14
Hypermobility and Motor Development
Joint hypermobility is associated with motor developmental delay in infancy.15 In a
study of 59 infants, both gross and fine motor performance were significantly
delayed in a group of children who exhibited joint hypermobility and motor delay
in infancy. The effects of joint hypermobility resolved more frequently in children
who presented normal motor development at the age of 18 months. Infants with
joint hypermobility and motor delay show a less favourable motor outcome, and
careful follow-up is recommended.16
Motor delay was also observed in approximately one-third of children with generalised hypermobility in a recent Dutch series.17 Fortunately, the motor delay
diminishes as the infant develops.15 A recent study of 29 infants from the same
group reveals that this catch-up can be helped by a programme of monthly physical
therapy combined with a home treatment protocol administered by caregivers.
Weekly physical therapy offered no advantage over a monthly regimen.18
5.5
Fig. 5.2 Bilateral pes planus
with pronation of the forefeet
in a patient with JHS.
Typically, the contour of the
foot is normal with respect to
the longitudinal arch while
non-weight-bearing (a), and it
is only on weight-bearing that
the deformity is apparent (b)
69
a
b
As well as delay in the onset of walking independently, omitting to crawl and
the use of bottom shuffling or sometimes a commando crawl is seen as an alternative means of locomotion prior to independent walking. There is often also a
clumsiness of movement (that may persist into adult life), as well as an irrepressible fidgetiness in affected children. This triad of ‘bendiness, clumsiness and fidgetiness’ is strikingly common and may also persist into adult life. When they do
commence to walk, hypermobile toddlers find walking on tiptoe, or with an in-toed
or out-toed gait helpful in splinting the ankle thereby affording better hindfoot
stability and support. This is often the time when parents notice easy bruising,
especially on the shins. Many hypermobile children have been investigated for
bruising which is a common feature in this condition. Test for bleeding diatheses
is almost invariably normal, and the bruising can be explained on the basis of lack
of the normal capillary support proffered by the inherently weak collagen infrastructure. The finding of spontaneous bruising in infants and children resulting
from hypermobility may lead to suspicions of non-accidental injury, which may
be totally unwarranted and require careful clinical evaluation and, in some cases,
genetic testing to resolve.
Once walking, parents often notice that their child has very flat pronated feet
(Fig. 5.2). Reassurance along the lines that all infants are like this is misleading. Flat
70
pronated feet lead to an abnormal gait with features such as squinting of the patella,
tibial torsion, femoral anteversion and hyperlordosis, and the provision of tailormade orthotics is an important aspect of their rehabilitation.19
Children with JHS often have poor ball-catching skills and difficulty with using
scissors due to an associated developmental coordination disorder (dyspraxia).20
Proprioception is often impaired in hypermobility persisting into adulthood. This
leads to frequent falls, and also clumsiness with walking into door frames and furniture, tripping over, and knocking objects over being common complaints. Once
the infant has mastered walking, other milestones such as climbing and running are
difficult due to suppleness and weakness of muscles. The gait is further disrupted as
in pronation the first metatarsophalangeal joint is locked, and thus toeing off may be
difficult, if not impossible, to accomplish.
Much of the locomotor difficulty encountered by children with JHS derives from
impairment of muscle power and proprioceptive acuity which can be detected both clinically and experimentally. In one study of 37 healthy children (mean age ± SD = 11.5 ± 2.6
years) and 29 children with JHS (mean age ± SD = 11.9 ± 1.8 years), the children with
JHS had significantly poorer joint kinaesthesia, joint position sense and muscle torque
than control subjects (both p < 0.001). Knee extensor and flexor muscle torque was also
significantly reduced (both p < 0.001) in children with JHS compared with healthy counterparts. The authors concluded that these findings provided a rationale for the use of
proprioceptive training and muscle strengthening in treatment,21 as has been advocated
clinically.22 A recent study demonstrated in 41 hypermobile children (mean age 9 years)
that only muscle strength correlated with motor performance,23 adding yet further weight
to the primacy of muscle strength and stamina in children with JHS.
Arthralgia and Muscle Pain
In a recent study of 125 young JHS patients attending a tertiary paediatric rheumatology referral centre, the major presenting symptoms were: joint pain, 92 (74%);
back pain, 7 (6%); problems with gait, falls and coordination, 13 (10%); reduced
joint movement, 12 (10%); problems with handwriting, 4 (3%); and clicky hips, 3
(2%). The most commonly affected joints (in descending order of frequency) were
the knees, ankles, spine, hips, elbows, shoulders and feet. A family history of hypermobility was present in two-thirds of cases. The same study drew attention to hitherto unacknowledged degrees of morbidity and disability that can complicate JHS
in children, with 14% experiencing diffuse musculoskeletal pain, 21% pain amplification, 40% handwriting problems, 48% missing physical education, 24% missing
schooling and 25% using wheelchair or crutches.14
Hypermobility in children may present as juvenile episodic arthritis/arthralgia
(defined as non-specific, short-duration arthritis or arthralgia in the absence of
defined rheumatic disease and with normal laboratory findings). Indeed, no less
than 66% of children with this diagnosis were found to be hypermobile.24 Following
53 hypermobile children over the course of 1 year, 40% suffered from recurrent
arthralgia compared with 17% in a non-hypermobile control group.25
Out of step with most evidence, a large Finnish study involving 1,637 schoolchildren in grades III and V (mean ages 9.8 and 11.8 years, respectively) did not
5.5
71
Fig. 5.3 The Bunnell scoliometer manufactured by Orthopedic Systems Inc. (U.S. Patent No.
5,181,325) and supplied by the National Scoliosis Foundation (NSF@scoliosis.org)
confirm an association between widespread HM and joint pain. 29.9% of the hypermobile (³ 6/9) and 32.3% of non-hypermobile children had musculoskeletal pain
at least once a week. Hypermobile children did not have more injury pain, and disability caused by musculoskeletal pain did not correlate with the Beighton score.26
It is of interest that this large series confirms in children that the prevalence of
pauci-articular hypermobility was much higher than the polyarticular form, as previously demonstrated in adults by Larsson et al.27
JHS can also mimic juvenile chronic arthritis, in particular the pauci-articular28
or the polyarticular variety.29
Spinal Complications
No correlation was seen between back pain and peripheral joint laxity in a group of
115 back-pain sufferers aged 13–17 years.30 A significant association has been
established recently between joint laxity and idiopathic adolescent scoliosis in a
population of Chinese girls in Hong Kong. In this study, the sole measure of hypermobility was the distance between the thumb tip and the volar aspect of the forearm
on forced apposition.31 Scoliosis is a frequently encountered finding in children and
adults with JHS. A recent study of joint laxity using the Bunnell scoliometer32
(Fig. 5.3) (which is, effectively, a modified spirit level) during scoliosis screening of
1,273 children (males 598; females 675; mean age 10.4 years) showed a correlation
between the Beighton score and trunk rotation of ³7 degrees.33
72
‘Growing Pains’ (GP)
A common experience in childhood is joint pains for which no obvious explanation
is forthcoming. Because they often occur at night, the designation Nocturnal
Idiopathic Musculoskeletal Syndrome (NIMS) is widely used. This is preferable to
the more conventional ‘growing pains’, which, though popular, is a misnomer.
Typically, the child is disturbed at night by pain in the legs, especially in the knees.
The symptoms may be quite distressing, but are often relieved by simple measures
such as local heat, gentle massage, simple analgesics and comforting.
Peterson defined growing pains as bilateral, intermittent non-articular pains involving the lower limbs, typically occurring during late afternoons or evenings, with a
normal physical examination and normal laboratory parameters whenever performed.34
There is a growing impression amongst clinicians that JHS provides the key to GP.
This assertion is now beginning to acquire an evidence base. In a study of 433 children
(219 boys and 214 girls; age range 3–9 years), 177 (41%) had JHM (Beighton ³ 5/9),
and 122 (28%) satisfied Peterson’s criteria for GP. Of the 177 with JHM, 75 (42%)
had GP. Of the 122 with GP, 75 (62%) had JHM. Using chi-square statistical analysis,
the authors found that JHM and GP were strongly associated. They also showed a
particularly strong association between knee hypermobility and GP.35
There is now increasing evidence that much of the pain experienced by patients, in
particular, children with JHM, is associated with the increased muscle fatigue due to
deconditioning and the increased demands falling on to muscles attempting to control
joints into the hypermobile range. Ergometric testing on 32 children (mean age
12 years) revealed a significantly reduced absolute peak oxygen consumption and relative peak oxygen consumption in patients with JHS compared to control subjects.36
5.5.2.2
Joint Instability
Joint laxity predisposes a child to joint instability, leading to the possibility of joint
dislocation or subluxation. Dislocation usually occurs following a traumatic episode
but occasionally may be spontaneous. Shoulder and patello-femoral joints are the
most frequently involved joints but the fingers, toes and ankles may also be affected.
Subluxation of the first metacarpophalangeal joint, often asymmetrical (with greater
instability in the non-dominant hand), is a frequent finding both in hypermobile
children and adults. An unusually severe degree of this is shown in Fig. 5.4.
Gross instability of the hindfoot may cause difficulty in walking (see Case 7.1,
Chap. 7).
5.5.2.3
Soft Tissue Lesions
Sprained ankle is the most common of a range of traumatic soft tissue lesions to which
hypermobile children are prone. Other examples include traumatic synovitis (especially
of the fingers, wrists, knees and ankles, often provoked by overuse or by a fall), tendonitis, tenosynovitis, torn knee ligaments, torn muscles, partial or complete tendon rupture
5.6 Hypermobility in Adults
73
Fig. 5.4 Gross instability
of the first metacarpophalangeal
joint in a child with JHS
(EDSHM); the joint can be
dislocated (and reduced)
at will
or avulsion of tendon insertions and joint capsular tears. Such events are particularly
likely to happen in response to vigorous sporting activities or from injuries sustained in
dance or gymnastic activities (see Chap. 8). However, a recently published controlled
study of ‘pulled elbow’ in 106 girls and 94 boys aged 3–84 (mean 24) months failed to
demonstrate a significant association with hypermobility.37
5.5.2.4
Temporomandibular Dysfunction in Children and Adolescents
with Hypermobility
TMJ dysfunction was present in 75% of 20 children aged 14–19 years with generalised joint hypermobility compared with 50% of controls.38 Symptoms and signs of
internal derangement of the temporomandibular joint were also significantly more
common amongst a group of hypermobile adolescents (score ³ 5/9) than amongst
controls.39
5.6
5.6.1
Hypermobility in Adults
Prevalence
The true prevalence of JHS in the community is unknown. Generalised ligamentous
laxity, the prerequisite of joint hypermobility, is seen in a substantial proportion
(perhaps 10–30%) of healthy individuals (varying according to methodology and to
the age, sex and ethnic origin of the population studied).40,41 Individuals with asymptomatic joint laxity certainly outnumber those who experience clinical problems.
Pauci-articular hypermobility is even more highly prevalent in otherwise healthy
subjects than is the generalised variety. Amongst 660 North American music faculty
and students of all ages in Rochester NY, USA, 47% of males and 78% of females
showed at least one hypermobile joint.25
74
Fig. 5.5 A positive Gorlin
sign with the ability to touch
the nose with the tip of the
tongue. It is said that 10% of
normal subjects are able to
perform this manoeuvre and
that in EDS, the incidence is
increased fivefold
It is possible to estimate the importance of hypermobility as a cause of articular
morbidity by surveying the diagnoses of patients attending rheumatology clinics.
Applying the Brighton criteria to consecutive routine general rheumatology hospital
referrals, surprisingly high values for clinic prevalences have been recorded, up to
45% of total referrals in a London clinic.4 A similarly high prevalence was observed
in a specialist hypermobility practice in Santiago, Chile.3
5.6.2
Role of Lax Ligaments
Normal ‘tight’ ligaments protect joints both by limiting the range of movement and by
imposing stability. The lax joint is deprived of such safeguards and is, therefore, more
vulnerable to the effects of injury from trauma and overuse. Many of the features of
JHS are commonly seen in everyday rheumatological, orthopaedic and physiotherapy
practice but occur with far greater frequency in hypermobile individuals.
5.6.3
Clinical Manifestations
The spectrum of clinical manifestations in the hypermobility syndrome is wide.
In most cases, the pathogenesis of the presenting lesion can be ascribed to the effects
of tissue laxity and/or fragility of the collagen-rich structures – ligament, skin,
cartilage, bone, vascular tissues and myofascial supporting structures (pelvic floor,
abdominal wall, etc.). Because of the ubiquitous nature of the connective tissue
fibrous proteins throughout the body, all soft tissues may share the prevailing
laxity – even the tongue, giving rise to a positive Gorlin sign, the ability to touch the
nose with the tip of the tongue (Fig. 5.5)!
75
Fig. 5.6 The absence of the
lingual frenulum is seen.
Based on the results of a
single published study, this
has been proffered as a new
physical sign for EDS.
The finding is yet to be
confirmed in other studies
Another newly discovered clinical sign in EDS is the absence of the lingual and
inferior labial frenula (Fig. 5.6). Absence of the inferior labial frenulum is reported
to have 100% sensitivity and 99.4% specificity. For the inferior labial frenulum, the
equivalent results were 71.4% and 100%, respectively.42 Considering that this study
was based on a sample size of only 12 patients with classical and hypermobility
types of EDS, this study is in urgent need of confirmation in other centres.
5.6.4
Articular Features
5.6.4.1
Arthralgia and Myalgia
Non-inflammatory joint and muscle pain, in the absence of any detectable clinical
abnormality, is a frequent presentation in patients with generalised or pauci-articular
joint laxity. In a population survey, the presence of arthralgia correlated significantly
with the joint hypermobility score.43 The pathogenetic mechanism is obscure, but
unaccustomed physical exertion is a common pre-disposing factor. One postulated
cause is the over-stimulation of sensory nerve endings, which are poorly supported
by defective collagen fibrils.44 A histochemical and electromyographic study has
suggested that a primary muscle defect may be operative in such cases.45 Many
patients are able to describe aggravating and relieving factors. Changes in the
climate, notably the onset of damp or cold weather, may be heralded by an exacerbation of arthralgia. A majority of female patients recognise a temporal relationship to
menstruation, and although many are aware of an improvement during pregnancy, a
few have noted the contrary. The most consistent precipitating factor is physical
activity, which is almost invariably followed by an exacerbation of joint pain. Because
patients’ symptoms occur in the absence of any recognisable articular abnormality,
the true nature of the problem is often overlooked; they may be erroneously labelled
76
psychogenic. This merely adds to the frustration, which stems from the failure of the
medical attendants to explain or relieve their symptoms. Not surprisingly, these patients
become depressed and angry, the anger often directed to their health providers.
5.6.5
Soft Tissue Lesions
A variety of soft tissue lesions which occur in everyday rheumatological practice
seem to present with greater frequency amongst hypermobile individuals. Such
abnormalities include tendon insertion lesions induced by overuse. Common examples are lateral and medial epicondylitis (tennis and golfer’s elbow, respectively),
supraspinatus and bicipital tendonitis of the shoulder and adhesive capsulitis (‘frozen
shoulder’). Entrapment neuropathies may also occur in relation to hypermobile
joints. Examples include the carpal and tarsal tunnel syndromes, common peroneal
and sciatic nerve compression.46,47 Soft tissue rheumatism (including fibromyalgia
syndrome and bursitis/tendonitis) is figured as the most common clinical diagnosis
in 50 newly referred hypermobile rheumatology patients.48
In a study of 675 17-year-old Spanish recruits undergoing military training, the
occurrence of traumatic musculoskeletal lesions (notably ankle sprains) was significantly higher among the 223 hypermobile subjects (³2/5) than in the remainder. It
would appear that their inherent joint laxity acted as a trauma vulnerability factor.49
The odds ratio was calculated by March and Silman to be 3.4 (95% CI 1.7–6.6).50
There are clear implications here for military medicine.
5.6.6
Chondromalacia Patellae
A statistically validated association between joint hypermobility and chondromalacia
patellae (CMP) was recently established in a prospective study. The authors concluded that hypermobility of the knee joint may be a contributory factor in the
pathogenesis of CMP.51
Genu recurvatum (hyperextensibility of the knee), itself, may be an important
pathogenetic factor for chondromalacia patellae. There is evidence that restriction
of hyperextension may reduce symptoms of this disabling condition, which predominantly affects physically active adolescents and young adults.52
5.6.7
Acute Articular and Peri-articular Traumatic Lesions
Acute lesions include traumatic synovitis, especially of the fingers, wrists, knees
and ankles, often provoked by overuse or by a fall. Tenosynovitis of long flexor
tendon sheaths of fingers, torn ligaments, torn muscles, partial or complete avulsion
of tendon insertions and joint capsule tears may result from overstretching. There is
77
abundant evidence that joint laxity plays an important role in the pathogenesis of
such lesions in sport and the performing arts (see Chap. 9).
5.6.8
Chronic Polyarthritis or Monoarticular Arthritis in Adults
Chronic arthritis is a common presentation of hypermobility in the rheumatology
clinic and can give rise to diagnostic difficulties. Typically, there is soft tissue swelling with an effusion. This may be recurrent or persistent without the radiographic or
laboratory features of inflammatory joint disease. The presence of a persistent knee
effusion may lead to the formation of a Baker’s cyst in the popliteal fossa.53 These
patients are often mistakenly diagnosed as suffering from rheumatoid arthritis and
are needlessly worried by this, as well as being exposed to the possible adverse
effects of anti-rheumatoid drugs.
5.6.9
Dislocation of Joints
The loss of stability due to ligamentous laxity may result in recurrent dislocation
after comparatively minor trauma. This is seen particularly in the patella and shoulder. A statistically significant association has been demonstrated between joint
laxity and patellar dislocation.54 Out of 104 subjects (37 men and 67 women aged
12–47 years) with patellar dislocation, 67 showed generalised hypermobility using
the Carter and Wilkinson55 criteria, compared with 12 out of 110 of the controls.
Some loose-jointed people are able to dislocate or sublux and reduce joints at will
(a feat of dubious value!). Similarly, the ability to ‘crack’ finger or other joints is
almost a pathognomonic finding among hypermobile subjects. The cracking results
from the sudden induction of a vacuum within the cavity of the distracted lax joints.
5.6.10
Temporomandibular Joint Dysfunction
Clicking of the temporomandibular joint (TMJ) is a common symptom in hypermobile subjects. The TMJ dysfunction syndrome, which is characterised by ‘clicking’
and pain in the TMJ, is associated with anteromedial displacement of the disc. Of a
series of 40 patients with TMJ dysfunction syndrome,56 no less than 21 (52.5%)
showed a hypermobility score of >3, and 15 (37%) a score of >5 using the Beighton
(1973) criteria. Similarly, a study using magnetic resonance imaging of the TMJs of
62 symptomatic patients and 38 asymptomatic controls revealed a significant association between the occurrence of TMJ symptoms and generalised joint laxity (>4/9)
(odds ratio = 4.0 [95% CI 1.38–10.95; p = 0.01]).57 Westling, using a multiple stepwise regression analysis, established that hypermobility was a more important factor
78
in the pathogenesis of TMJ dysfunction than bruxism.58 Thirty-eight out of 70 (58%)
patients with TMJ osteoarthritis (TMJOA) satisfied the criteria for hypermobility.59
A 30-year follow-up study of 13 hypermobile patients showed an increased radiological tendency to TMJOA compared with controls. Functionally, there was no
difference between the groups.56 Several of the authors concluded that TMJ hypermobility is a subsidiary factor in the development of TMJOA.
5.6.11
Premature Osteoarthritis (Other Than TMJ)
There was for many years a strong clinical impression that hypermobility may predispose to the development of premature osteoarthritis, particularly in weight-bearing
joints. Positive proof of this hypothesis awaits controlled prospective studies.
Studies with dancers suggest that dancers with JHS develop premature hip OA as
compared to their non-hypermobile peers (see Chap. 8).
Scott et al.60 compared joint mobility in a group of 50 consecutive persons aged
50 years and over with symptomatic osteoarthritis with age- and sex-matched controls. These workers demonstrated a significantly higher frequency of hypermobility
amongst the patients with osteoarthritis. They conceded that hypermobility is these
individuals might have been the result of the osteoarthritis rather than vice versa, but
they considered this unlikely.
A statistically significant association between joint hypermobility and osteoarthritis has been established amongst adults attending a general rheumatology clinic.
OA was found in 12/20 (60%) hypermobile patients compared with 33/110 (30%)
patients without hypermobility (chi-sq = 6.73; p < 0.01).61
From Iceland come two studies linking hypermobility with the occurrence and severity
of generalised osteoarthritis of the hand (GOA).62 Comparing 100 GOA patients with
matched controls, it was found that thumb base OA was more common, more advanced
and more disabling in hypermobile patients (³2/9). Disability also correlated with the
hypermobility score. The authors proposed that ‘hypermobility-associated OA’ be designated as a subset of GOA of the hands. In a second study63 by the same group, 50
consecutive female patients with clinical OA hand and thumb base symptoms were
examined for hypermobility according to the Beighton score. Thirty-one out of the 50
patients had a score of >2/9 and 17 patients ³4/9. Corresponding numbers for the 94
matched controls were 30 (p < 0.05) and 9, respectively (p < 0.001). Hypermobile patients
were characterised as with more severe thumb base OA and less severe OA of the interphalangeal joints, whereas in non-hypermobile patients, the converse was true.
5.6.12
Spinal Complications
The spine, notably the lower cervical and lower lumbar region, is commonly affected
by degenerative diseases in later life, as a result of the stresses to which it is submitted.
This process is manifested by a combination of osteoarthritis of the facet joints and
79
changes in the intervertebral discs. The onset may be acute, with herniation of the
nucleus pulposus through the annulus fibrosus, leading to nerve root compression,
or chronic, with osteophyte formation causing nerve root irritation.
It is likely that the interspinous ligaments provide an important restraining force
and prevent an excessive range of movement, which might otherwise lead to additional damage to the vertebrae, intervertebral discs or facet joints. It follows that a
spine devoid of the protection provided by normal ‘tight’ ligaments will be particularly vulnerable to the insults to which the back is constantly subjected in daily life.
Thus, it is reasonable to assume that traumatic lesions including intervertebral disc
lesions, be they in the cervical, dorsal or lumbar region, might occur with greater
frequency amongst hypermobile persons.
Fatigue fractures of the partes interarticularis (spondylolysis) with or without isthmic
spondylolisthesis are also frequent in loose-jointed individuals.64 Notwithstanding
these recognisable structural abnormalities, low back pain does seem to occur in the
absence of such identifiable lesions in otherwise healthy, hypermobile subjects. This
has been termed the ‘loose-back syndrome’.65 As with arthralgia, the mechanism for
the pain in this condition is unknown. The range of spinal motion in this series was not
recorded. Morgan and her colleagues found that JHS and EDS patients had a highly
significantly greater incidence of history of mechanical low back pain, more painful
episodes lasting more than 3 months and more radicular pain than controls. Past ability
to place hands flat on the floor with knees straight or current hyperextensibility of the
lumbar spine were both strongly correlated with these three outcomes.64
Radiological anomalies of the spine, including scoliosis, transitional vertebrae at
the lumbosacral junction and pars interarticularis defects, with or without spondylolisthesis, were more common amongst patients with widespread joint hypermobility. Eleven (73%) of a series of 15 patients with a hypermobility score ³5/9
showed such anomalies. The control groups (scores 3–4/9 and 0–2/9) revealed a
lower incidence of anomalies of 3/9 (33%) and 3/13 (23%), respectively. The differences were statistically significant.66
An attempt to correlate the advent of spondylolisthesis with joint laxity amongst
364 female teachers of physical education failed to produce a significant result.63
However, this negative finding may have been due to the fact that the information
was elicited by means of a postal questionnaire. Nevertheless, a higher prevalence
of concomitants of joint laxity, such as flat feet, was recorded amongst the hypermobile subjects. It is of interest that the spondylolisthesis that occurred in this group
was, with a single exception, of the degenerative (pseudo-spondylolisthesis) rather
than the isthmic variety.
5.6.13
Bone Fragility
Some hypermobile people may have a bone defect, which predisposes to fracture.
Thus, in a series of 33 patients with a hypermobility score of 5–9/9, 17 (52%)
gave a past history of fracture. In two age- and sex-matched control groups with
80
hypermobility scores of 3–4 and 0–2, the incidences of fracture were 3 (14%) and
4 (15%), respectively.60 These findings suggest that there may be a collagen defect
common to ligament and bone in JHS patients. By contrast, there was no excess
of fractures in an early series of 100 patients with EDS.67 This discrepancy might
reflect differences in the nature and distribution of the fundamental abnormalities
of connective tissue in these disorders. More recent studies have strengthened the
link between EDS and osteoporosis68 and between BJHS and osteopenia.69 In the
latter study, bone mineral density was measured in 40 patients compared with
age-matched control subjects. On balance, although BMD was marginally reduced,
the difference did not achieve statistical significance.
Further light is shone on this topic in new study in 25 women said to be diagnosed with BJHS who were compared with matched controls. Total femoral and
trochanteric bone mineral density and t and z scores were significantly lower in
hypermobile patients compared to the control group. Ward’s triangle and femoral
neck z scores were also found to be significantly lower in hypermobile patients
(p < 0.05). Significant inverse correlations were found between Beighton scores and
trochanteric BMD, t and z scores (r = −0.29, r = −0.30, and r = −0.32 respectively) in
hypermobility patients. Low bone mass was more frequently found among subjects
with hypermobility (p = 0.03). Hypermobility was found to increase the risk for
low bone mass by 1.8 times (95% confidence interval 1.01–3.38). The authors suggest that pre-menopausal women with joint hypermobility have lower bone mineral
density when compared to the controls and furthermore, that hypermobility increases
the risk for low bone density.70 Unfortunately, as with many such studies, the authors
confuse hypermobility (as judged by the Beighton scale) with JHS (classified using
the Brighton Criteria) and purport to have studied JHS when, clearly, they report
‘women with hypermobility’. A similar study using patients satisfying the Brighton
Criteria would possibly have produced an even more significant result.
5.6.14
The Natural History of JHS and the Development
of Chronic Pain
The onset of symptoms almost invariably occurs during the childhood years. In one
series, out of 45 adult patients with EDS, symptoms had commenced in childhood
in 40 (89%).71 Their early years are marked by episodic soft tissue injuries, dislocations or non-inflammatory joint or spinal pain. The same seminal study established
that chronic pain in EDS affecting multiple sites is progressive and unrelenting and
is associated with sleep disturbance, impaired physical activity and sexual function.
Abdominal pain and headaches were found to be commonplace (1 in 2 and 1 in 3,
respectively). The authors refer to a ‘severe and lifetime pain’, and they also pointed
out that (at that time) it was unrecognised in the medical literature. They considered
that EDS should always be considered in the differential diagnosis of chronic musculoskeletal pain.66 Chronic pain in EDS is now seen to be its greatest therapeutic
challenge72 (see Treatment Section 5.7).
5.7
Management of Articular Complications in the Hypermobility Syndrome
81
UNACCUSTOMED
PHYSICAL
EXERCISE
INEFFECITIVE
ANALGESICS;
PHYSICAL THERAPY
INADEQUATE OR
INAPPROPRIATE
NON-INFLAMMATORY
JOINT/SPINAL PAIN; RECURRENT
DISLOCATIONS; TRAUMATIC
SOFT TISSUE LESIONS
SLOW/INCOMLETE HEALING
INJURY RTA
WHIPLASH
‘KINESIOPHOBIA’
MUSCLE DECONDITIONING
FUNCTIONAL IMPAIRMENT
PHYSICAL DISABILITY
DEPENDENCY
CHAIR/BED-BOUND
REDUCED QUALITY OF LIFE
LACK OF SELF-EFFICACY
WORK INCAPACITY
SOCIAL ISOLATION
DESPAIR
CHRONIC PAIN SYNDROME
Fig. 5.7 Chronic pain is a frequent occurrence in the national history of JHS. Its pathogenesis is
complex and incompletely understood. The early years of the syndrome are characterised by selflimited episodes of soft tissue injury, which recover, albeit slowly, but become increasingly frequent and incomplete healing may occur. Pain, in general, tends to become amplified over time,
and this may be triggered by the use of ineffective physical therapy and/or analgesic medication.
Other triggers to chronic pain include injury including road traffic accidents, work- or performancerelated upper limb disorder. Pain amplification invokes movement avoidance (kinesiophobia), leading to deconditioning and later weakness of muscle and progressive loss of function and
diminution of quality of life
Its pathogenesis is multi-factorial, and this is shown diagrammatically in
Fig. 5.7.
5.7
Management of Articular Complications
in the Hypermobility Syndrome
Hypermobile patients can be spared much unnecessary suffering by the establishment of the correct diagnosis. Many hapless individuals are misdiagnosed as suffering from rheumatoid arthritis (either adult or juvenile). Needlessly, they are forced
to suffer the anguish of living with that diagnosis and are exposed to the dangers of
the widening selection of anti-rheumatoid drugs and other potentially hazardous
treatments used in its treatment. Others, in the absence of observed physical signs to
82
explain their symptoms (joint hypermobility is often overlooked), are labelled as
neurotic. They either accept this and become resigned to a life of misery and disability, or reject it and go from one doctor to another in their quest for relief. Not
surprisingly, many seek help from purveyors of complementary medicine. From the
foregoing, it is self-evident that establishing a definitive diagnosis can have a profoundly beneficial effect on morale! It is, however, only just the start.
5.7.1
General Management
Although the precise cause of pain in hypermobility syndrome (JHS) may be unclear,
most patients can discover some key exacerbating and relieving factors. The majority
recognises the adverse effects of excessive physical activity, and an individual is often
able to restrict exercise to within their reasonable level of tolerance. This may entail
an avoidance of strenuous sporting pursuits, a change of occupation or a modification
of the manner, speed or frequency of performance of a particular job or activity. The
journey to and from their place of employment may provoke more symptoms than the
actual work itself. Most children with JHS can relate their symptoms to performance
of specific activities or sports. Such information can form the basis for helpful advice,
which may well be of therapeutic benefit. It follows that in this respect, time spent on
taking a detailed history will pay dividends.
There is sound epidemiological evidence that body mass may influence the
development of symptoms in the hypermobility syndrome.73 Anecdotal evidence
suggests that sudden and substantial weight gain may precipitate the onset of symptoms, notably arthralgia, in previously asymptomatic hypermobile individuals.
Despite the fact that no study has as yet demonstrated an improvement in symptoms
following weight loss, it would seem advisable to recommend such a measure to
obese adults or children with the syndrome.
5.7.2
Specific Management
The reader is recommended to consult the standard texts on rheumatology, orthopaedics, physiotherapy and podiatry for a full account of the management of
the wide variety of complications that may be associated with joint hypermobility.
A summary of the principal methods of management is given below.
5.7.3
Rest
After acute soft tissue injury, immobilisation, i.e. resting the affected part, is beneficial in the short term. Care is needed to avoid excessive rest as this may lead to loss
of function. Local rest in the form of splinting combines pain relief and avoidance
5.7
83
of contracture formation, whilst dynamic splinting permits simultaneous restoration
of function. In milder cases, rest and activity avoidance should be prescribed judiciously, and patients whether adult or child should only be denied pleasurable and
healthy physical activities, be they for leisure or work, if it is strictly necessary.
Much distress and needless inactivity can result from such inappropriate advice.
5.7.4
Local Steroid Injections
The treatment of choice in many of the soft tissue lesions associated with hypermobility is a carefully applied topical infiltration with hydrocortisone acetate or methylprednisolone with lidocaine. These entities include tennis and golfer’s elbow
(lateral and medial epicondylitis, respectively), bicipital and supraspinatus tendonitis, adhesive capsulitis, tenosynovitis, bursitis and ligamentous and capsular tears.
The longer-acting corticosteroid preparations should be used with caution in extraarticular conditions, as they may lead to severe connective tissue atrophy with consequent weakening of collagenous tissues.74 The injection of steroid directly into a
tendon should be always avoided, as this can result in tendon damage, atrophy,
weakness and even rupture. Local steroid injections are also effective in stenosing
tenosynovitis – the cause of ‘trigger finger’.
A small volume of a potent steroid preparation, such as hydrocortisone or methylprednisolone, gives excellent results in the treatment of persistent synovitis of
joints and of the carpal tunnel syndrome. In the treatment of discogenic sciatica or
cruralgia, epidural corticosteroid injections given to inpatients bring relief in over
two-thirds of cases, whether or not hypermobility is a predisposing factor. As outpatients, 17 (90%) of 19 patients responded to the active injection in the short term
compared with 3 (19%) of 16 control patients. Two-thirds of responders retained
their benefit up to the time of the 6-month assessment.75
5.7.5
Physiotherapy
For the bulk of patients suffering from the JHS, physiotherapy is the mainstay of
treatment, both in the management of identifiable local traumatic, overuse or degenerative sequelae, but also for the less well-understood symptoms of arthralgia and
myalgia (see Symptomatic Treatment, below). A wide variety of techniques are
practised, ranging from ultrasound, pulsed short-wave diathermy and laser to exercise therapy and passive (Maitland’s) mobilisations. As yet, although most of these
treatments derive their popularity from empirical use, a number of relevant controlled trials have been published. At therapeutic levels, ultrasound has been shown
experimentally to promote in vitro collagen synthesis by human fibroblasts.76 The
clinical application of this technique in JHS lies in the treatment of traumatic lesions
of ligament and muscle. It is also effective in disorders of attachment of tendon to
84
bone, such as tennis and golfer’s elbow, but is generally not as effective as a local
corticosteroid injection in these conditions.
5.7.6
General Principles
Physiotherapists undertaking treatment on hypermobility patients will find that they
will take longer to treat the hypermobility patient than the average patient, because
they often pose quite complex problems – having pain at several sites. In one study,
the average number of painful sites was 8.0.67 Patients’ attitudes may be coloured by
resentment directed towards their former therapists and doctors, whom they perceive to have failed to understand the nature of their problems or to have treated
them inappropriately. For many of these patients, severe pain may have been a common everyday occurrence.67
Their complaint is often as much stiffness as pain, and this is particularly true of
the cervical and thoracic spines, which gradually become hypomobile from failure
to take advantage of the hypermobile range. A full history should be taken, followed
by a thorough examination. It is important to establish whether the presenting problem is an acute one, a series of chronic symptoms or an acute problem complicating
a chronic one. Most acute lesions can then be treated with the usual physiotherapy
modalities, taking care to progress the treatment slowly and to be content with small
gains as recovery tends to take longer. The goal is to ensure that the joints can reach
their natural range, no matter how excessive that may appear to be. Having attained
the end of range of movement, the patient is advised to avoid sustained postures in
this position.
Passive mobilisations can be used to restore range both in peripheral and spinal
joints.77 If the restriction is due to pain with the joint range limited by an increase in
muscle tone, then manual techniques should be very smooth, large amplitude movements in mid-range. During the performance of the technique, the muscle will suddenly relax, allowing a greater range of movement. It is important to stop treatment
at this point, or the patient may experience an increase in pain following treatment
or a feeling of soreness as if they have been engaging in unaccustomed exercise. If
the restriction of movement is due to tightness of the ligaments and capsule around
the joint, this can also give rise to pain. The amplitude of the technique is smaller
but used at end of range. The range will then not be restored so dramatically. It is
important to ensure that patients have muscular control throughout their range of
movement, and that their natural range is restored. The latter can often be assisted
and maintained by the patients themselves.
If postural muscles have become elongated so that they no longer support the
underlying joint range, muscle balance exercises will train the functional length
and recruitment patterns of the local and global stabilisers so that they can control the movement throughout its excessive range. It is thought that the exercises
facilitate slow motor recruitment to retrain the tonic-holding capacity of these
muscles.
5.7
85
These patients lack end-of-range proprioception, which could be one of the
pathogenetic factors in the causation of their joint and muscle pain [see below]. It is
important to teach postural awareness so that patients do not sustain or use their
joints at end of range during static postures. For example, during sitting, all joints
should be in a neutral position. Standing with the knees hyperextended should be
avoided. Patients should, wherever possible, be taught to apply treatment themselves, e.g. rest, ice, heat, TENS machine and auto-mobilisations. They should be
encouraged to work out their own problem-solving strategies such as pacing their
activities and interspersing their activity periods with rest periods. Patients should
also learn to understand the difference between pain and harm, so that excessive rest
induced by fear does not lead to loss of joint range through inactivity, leading to
atrophy, contracture and capsular fibrosis.
Aids and appliances should be reserved for acute episodes of flares in a chronic
one. The exception is where strapping is used as part of the retraining of good joint
function.
5.7.7
Passive Mobilisation
Passive mobilisation is a specialised physiotherapeutic technique requiring rigorous
training. It is widely used in the treatment of a variety of conditions where restricted
joint movement occurs, such as adhesive capsulitis (‘frozen shoulder’) and ‘stuck
neck’ when cervical spine facet joints become impacted. This may happen in hypermobile subjects from partial subluxation following overstretching or later on when
cervical spondylosis develops. In the latter situation, it is important to ensure that
neither cord compression nor basilar insufficiency (both contra-indications to
manipulative therapy of any kind) is present. In the presence of radicular symptoms
and/or signs, extra care is needed to avoid damaging neural structures. Passive
mobilisation is also employed for low back pain, which is not due to bony pathology
or disc prolapse with nerve compression. A word of caution is needed as regards the
use of forceful manipulation in hypermobile patients, as joint subluxation may
result from excessive enthusiasm! Gentle mobilisation procedures, however, are
very useful, particularly in those individuals in whom degenerative changes in the
facet joints cause troublesome locking.
5.7.8
Exercise Therapy
There is a growing evidence base verifying the value of physiotherapy in the JHS.
A recent retrospective study involving 51 hypermobile children (mean age 8 years)
confirmed the experience of many physiotherapists, namely that specific stabilising
exercises can help to reduce symptoms in hypermobile children.77 Exercises specifically designed to improve the stability of hypermobile joints have been shown to
86
reduce significantly pain emanating from the treated joint.78 Some functions also
improved, and in respect of the knee, it was possible to confirm a reduction in
hyperlaxity of joints treated in this way.
A clinical trial of an 8-week home-based exercise programme of closed-chain
exercises aimed at improving proprioception was found to alleviate symptoms in
18 patients with JHS. Not only was proprioceptive acuity significantly improved
(p < 0.001), but there was also improvement in balance board performance and in
quadriceps and hamstring strength. Symptomatic improvement also occurred in
terms of both pain (p = 0.003) and quality-of-life (p = 0.029 for physical functioning,
p = 0.008 for mental health) scores.79
A recently published randomised clinical trial (RCT) in 57 children aged
7–16 years compares a targeted programme, aimed at providing symptomatic joints
with stability by means of enhancing muscle retraining to achieve improved control,
with a generalised one aimed at providing muscle strength and fitness.80 Statistically
significant improvement was seen in terms of parental and patient pain scores
between baseline and 3-month follow-up assessments, but differences in improvement between the two groups were not significant. This is perhaps the first RCT of
physiotherapy in hypermobility in children. Logistic reasons precluded the authors
from acceding to their target numbers which explains why the yield in terms of finding significant differences is perhaps disappointing. Nevertheless, this is an important study which points the way for others to follow.
A problem that commonly confronts hypermobile subjects is peripheral articular
instability, especially of the weight-bearing joints. This is usually the result of ligamentous tears that have occurred as a consequence of pre-existing laxity. The ankle
joint is especially vulnerable, and the sprained ankle is a particularly common problem in hypermobile subjects. Fortunately, the majority of these are of mild or moderate severity (grades I or II), responding to treatment with an Aircast boot for
3 weeks, which reduces swelling but at the same time allows weight-bearing. Its
easy removal permits the early institution of swimming and general rehabilitation.
Severe ankle sprains (grade III) in which instability occurs may require 6 weeks of
immobilisation in a cast, followed by intensive rehabilitation. The most common
cause of pain and swelling after treatment is residual peroneal weakness due to
inadequate rehabilitation.
In other situations, for example the knee, it is possible to improve the stability of
a lax joint by appropriate muscle-strengthening exercises. However, care must be
taken to avoid hyperextension of a lax knee with strenuous and uncontrolled quadriceps exercises, as this merely aggravates the condition. Exercise therapy, perhaps
combined with electrical stimulation, can be useful after knee surgery, e.g. after
anterior cruciate ligament repair. An anti-rotational brace has been found to be helpful
in treating patients with anterolateral rotational instability. Also, shoulder joint
instability may be relieved with the aid of a programme of muscle-strengthening
exercises. In the study referred to above, specific exercises over 6 weeks reduced
knee hyperextensibility as well as relieving pain in hypermobile subjects.
Patients with JHS often report that their experience tells them that physiotherapy is either counterproductive or ineffective, presumably because it is either too
5.7
87
aggressive or perhaps, in some cases, not aggressive enough. A new school of
physiotherapy (still in its infancy) adapting physical therapy to the specific needs
of patients with lax and fragile tissues is emerging based on sound scientific principles and with an evidence base.81,82 In summary, rehabilitation/physiotherapy
aims to improve function and enable individuals to more effectively self-manage
the condition. A comprehensive assessment identifies postural abnormalities,
movement faults, muscle imbalances and weakness and balance deficits present.
A specific, individualized exercise programme is developed with the patient based
on the examination findings. The programme will usually be focused on functional restoration through improvement of movement control, joint stability,
stretching, muscle strength and general fitness (see Hakim, Keer & Grahame
2010).114
5.7.9
Podiatry
Laxity of the ankle and foot region invariably leads to flattening of the longitudinal
arch (pes planus/flat foot). This is usually accompanied by pronation of the forefoot and, in severe cases, calcaneal eversion of the hindfoot. Secondary ligamentous damage, tenosynovitis of the tibialis posterior or peroneal tendon sheaths,
and eventually subluxation of the ankle subtalar and adjacent joint may supervene.
A podiatric assessment is advisable in all such instances, particularly when symptoms develop.
A lax-jointed foot naturally adopts a flat foot shape when weight-bearing, particularly in children. When the weight is taken off the limb, the normal shape is
restored (see Fig. 5.2a, b). Such cases are mostly, but not invariably, painless and no
treatment is required, and child or adult can be reassured appropriately. Where the
foot is symptomatic, podiatric intervention is indicated. A podiatrist has a variety of
orthotics available to help to correct the biomechanical abnormality, and thereby
contain or reverse deformity, improve stability and relieve pain. Thus, the podiatrist
can make an important contribution to the patient’s overall treatment and improve
the quality of life of hypermobile subjects.19
5.7.10
Surgical Intervention
Certain complications of hypermobility may require surgical measures. These are
usually undertaken only after conservative treatment has failed to relieve the problem. Reconstructive procedures should be performed only after careful consideration of the risks of possible failure from recurrent stretching or tearing of the
intrinsically weak tissues. For this reason, certain conditions that in patients with
normal tissues would appropriately be treated surgically may, in the presence of
extreme tissue laxity (as in, for example, in the EDS), be best managed conservatively.
88
In EDS, the skin is thinner and less robust,83 and hence sutures are more likely to
tear through. The fragility and friability of blood vessels can cause technical problems with wound closure and haemostasis, respectively, during operations. The
greatest surgical hazard is in patients with EDS of vascular type (formerly EDS type
IV), where the risk of serious vascular or visceral rupture is present, where the risk
of wound dehiscence is greatest and where surgical mortality is high.84 In the JHS,
the skin and other tissues are also lax, hyperextensible and relatively fragile. Extra
caution is advisable in order to avoid unnecessary damage to soft tissues, which are
less robust. Additional sutures and their longer retention may be advisable to reduce
the risk of wound dehiscence.
The following categories of surgical intervention are encountered.
5.7.11
Soft Tissue Lesions
Tennis and golfer’s elbow, tendonitis of the shoulder and the carpal tunnel syndrome, for example, may occasionally need operation. Tenosynovitis that has failed
to respond to repeated treatment with local corticosteroid injections and other measures will very occasionally require surgical management. In severe chronic tendonitis, as occurs in the flexor hallucis longus tendon in dancers, debridement of calcific
nodules may be required as well as excision of the tendon sheath. Severe (grade III)
ankle sprains with rupture of the lateral ligament are probably best treated by open
repair.
Occasionally, a chronic bursitis unresponsive to non-surgical therapy requires
surgical attention. One example is refractory trochanteric bursitis (which may be
associated with a ‘snapping hip’), which responds to partial excision of the iliotibial band. Similarly, semimembranous tenosynovitis unresponsive to corticosteroid
injections has been successfully treated surgically by excision of the fibrous sheath
surrounding the tendon.
5.7.12
Persistent Synovitis
When this occurs in a joint which has failed to respond to local steroid injections,
surgical synovectomy may be required. Alternatively, if the patient is over 45 years
of age, a radiation synovectomy by means of intra-articular injection of yttrium-90
or other suitable isotope may be considered. Radiation synovectomy carries a
risk of causing leakage of radioactive material from the joint, with consequent
exposure of the regional lymph nodes to ionising radiation. The last decades have
seen the gradual decline in the use of synovectomy, both by surgery and by radiation, following the introduction of more effective topical corticosteroid preparations
for intra- and peri-articular use.
5.7
5.7.13
89
Recurrent Dislocation or Joint Instability
The patella, shoulder or other joint which is subject to recurrent dislocation may
require surgical stabilisation to prevent further dislocation.
The importance of recognising the multi-directional nature of shoulder joint instability in recurrent dislocation has been emphasised by Neer et al.85 The Trillat procedure
for recurrent anterior shoulder dislocation, introduced in 1965, in which the coracoid
process is subjected to osteotomy and tilted downward so that it serves as a bone
block, has given excellent results in 38 (73%), good in 5 (10%), fair in 4 (7%) and
poor in only 5 (10%) of 52 cases after a mean follow-up period of 69 months.86
Recent research has demonstrated that the application of laser energy can affect
the mechanical properties of joint capsular tissues in an experimental model.
Clinical results of laser-assisted thermal capsulorrhaphy in 60 patients (27 men, 32
women) with glenohumeral instability (anterior, 30; posterior, 7; anteroposterior, 4; and
multi-directional (MDI), 19 were analyzed). Patients were evaluated on the basis of pain,
recurrent instability, function and satisfaction. The authors conclude that laser-assisted
thermal capsulorrhaphy is an effective adjunct in the treatment of anterior and posterior
instability. Patients with MDI treated with this technique have high failure rates. The
authors recommend caution when approaching MDI patients with this technique.87
For an up-to-date review of the management of the unstable shoulder in JHS, the
reader is referred to Jaggi and Lambert.88
Recurrent painful dislocation of the distal interphalangeal joint of the finger can
be successfully treated by arthrodesis. Chronic subluxation of a dislocating inferior
radio-ulnar joint may be treated with a surgical reconstruction using the tendon of
flexor carpi ulnaris.
The Krogius tenoplasty – introduced in 1901, for the treatment of recurrent dislocation of the patella, in which a flap of medial retinaculum is moved over the patella
and attached to the lateral retinaculum – is not recommended for use in patients with
joint laxity in view of the high failure rate in such subjects.89 For the same reason, pes
anserinus transfer is not recommended in knee instability from rupture of the anterior
cruciate ligament of the knee. Recurrent subluxation of the patella that fails to respond
to conservative treatment (strengthening the quadriceps and vastus medialis, stretching the tight lateral structures) is best treated by translocating the entire quadriceps
and patellar mechanism medially using the Install procedure. A report from Canada
found that semitendinosus transfer to the patella with tightening of the medial retinaculum and a lateral retinacular release results in a predictable, stable patello-femoral
joint. There were 26 knees (8 hypermobile); 3 boys and 19 girls; mean age at surgery,
14 years and 4 months, range 8.9–17.9 years; mean follow-up, 3.2 years. On longterm follow-up, 23 of the 26 knees (88%) were asymptomatic, and the child had
returned to regular activities. One child experienced recurrence of the patellar dislocation, and one child developed medial patellar subluxation.90
Surgical repair is the treatment of choice for severe (grade III) tears of the medial
collateral ligament of the knee joint in preference to conservative management.
A recent review of the knee in JHS is shortly to be published.91
90
Chrisman-Snook reconstruction is a surgical method for treating chronic lateral
ankle instability and involves rerouting half the peroneus brevis tendon, based distally, through the lateral malleolus and anchoring it to the calcaneum. This study
aims to examine the outcome and possible average follow-up period of 35.3 months,
ranging from 26 to 51 months. The patients were young, and the average age was
24 years. Functional results were assessed using the Kaikkonen ankle stability score.
Joint hypermobility was assessed by the Beighton score. The lateral ligaments were
reconstructed. Excellent results were achieved in ten cases, good in four, and fair in
one. None had poor results. Best outcomes tended to occur in patients with joint
hypermobility.92
Contrary to earlier reports, there is now good evidence to establish an association
between occipito-atlantal and atlanto-axial hypermobility, Chiari malformation type
I (CM-I) and HDCT, predominantly EDS, resulting in lower brain-stem symptoms.93
CM-1 may also be associated with a further complication, namely the tethered cord
syndrome with additional features which include elongation and downward displacement of the hindbrain, normal position of the CMD, tight filum terminale (FT)
and reduced CSF flow in the lumbar theca. The authors present preliminary evidence that section of the FT can reverse moderate degrees of tonsillar ectopia and is
appropriate treatment for cerebellar ptosis after Chiari surgery in this cohort.94
5.7.14
Cervical or Lumbar Discectomy
These may be indicated to remove a prolapsed or sequestered intervertebral disc.
The recent trend has been away from extensive laminectomy towards the smaller
minimally invasive procedures using microsurgical techniques.95,96 A similar
approach has also been applied to decompression for spinal stenosis.97
A recently updated Cochrane Reviews addressed the question of the efficacy of
surgery in the treatment of lumbar disc prolapse. All 40 randomised controlled trials
published up to January 2007 were identified. Many of the early trials were of some
form of chemonucleolysis, while later studies compared either different techniques of
discectomy or the use of some form of membrane to reduce epidural scarring.
Discectomy produces better clinical outcomes than chemonucleolysis, which were
better than placebo. Microdiscectomy gives broadly comparable results to standard
discectomy. Recent trials of an interposition gel covering the dura and of fat show that
they can reduce scar formation, although there is limited evidence about the effect on
clinical outcomes. The evidence for other minimally invasive techniques remains
unclear except for chemonucleolysis using chymopapain, which is no longer widely
available.98 Much interest now rest on the development of intervertebral disc replacement, which has the potential to retain flexibility and, at same time, obviate the additional strain posed by fusion on adjacent intervertebral discs. Basic scientific research
has now developed apace,99 and early results are encouraging.100 However, it will some
time before this intriguing new approach is suggested.
5.7
5.7.15
91
Surgery of the Foot
Instability of the talus has been successfully treated with a brace or by reconstructing the inter-osseous talocalcaneal ligament both in patients with a history of trauma
and in those with generalised joint laxity.101 Hypermobility of the first ray results in
insufficient weight-bearing behind the first metatarsal head. Recent research suggests that there is a direct association between hypermobility or the first metatarsophalangeal joint in extension and painful hallux valgus deformity.102 Treatment is
directed towards re-establishing stable sagittal alignment in addition to reposition of
the metatarsal head over the sesamoid complex. First MTP realignment arthrodesis
by regulating the elasticity of the multi-articular first ray within the sagittal plane
may be the treatment of choice.
Podiatric personnel undertaking surgical procedures have also been urged to
undertake a thorough preoperative medical (including genetic) evaluation followed
by a detailed appraisal of such aspects as anaesthetic risk, tourniquet use, tissue
handling, suture techniques, post operative bandaging, etc.103
5.7.16
Advanced Osteoarthritis
When there is advanced osteoarthritis of the hip or knee complicating JHS or EDS,
total joint replacement may be required, as in patients without hypermobility. In a
Mayo Clinic study, a series of 10 patients with the EDS underwent 12 primary knee
arthroplasty procedures (mean age 43.3 years, mean follow-up 65 months). The
primary indications for surgery were tibio-femoral or patellar instability (n = 8) and
osteoarthritis (n = 4). Knee Society Functional scores averaged 29.6 before surgery
and 51.3 at time of interview (p < 0.005). Knee Society Knee scores at time of follow-up evaluation averaged 70. Tibio-femoral and patello-femoral stability were
significantly improved. The authors concluded that arthroplasty appears to be an
effective option for knee arthritis and instability in EDS patients, although results
and satisfaction were inferior to those reported for conventional arthroplasty
indications.104
5.7.17
Symptomatic Treatment
Many of the locomotor complications of JHS can be attributed to clearly defined
local lesions. Specific treatment, if appropriately applied, usually provides a satisfactory remedy. Many patients, however, suffer from arthralgia, myalgia, stiffness
and/or back pain for which no overt identifiable cause is discernible. Trigger mechanisms may be recognised and, where possible, removed. For many patients, however,
the only solution lies in symptomatic relief, as described below.
92
5.7.18
Analgesic and Non-steroidal Anti-inflammatory Drugs
Pure analgesic drugs, such as paracetamol, dihydrocodeine or nefopam (or mixtures,
such as co-dydramol), are helpful in relieving mild musculoskeletal pain. However,
many patients prefer the non-steroidal anti-inflammatory drugs (NSAIDs), which
seem to have a propensity for relieving locomotor-system pain whether in joint, bone
tendon, ligament or muscle. A wide variety of drugs are available.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
Salicylates – aspirin in various forms
Pyrazoles – azapropazone
Indene derivative – indometacin, sulindac
Propionic acid derivatives – naproxen, ketoprofen, fenoprofen, ibuprofen
Aryl-acetic acid derivatives – diclofenac
Oxicam derivatives – piroxicam, tenoxicam
Miscellaneous NSAIDs – tiaprofenic acid, etodolac, nabumetone
Low-dose tricyclic anti-depressants – amitryptiline
Selective serotonin reuptake inhibitors – fluoxetine, sertraline, paroxetine
Muscle relaxants – carisoprodol
Opioid analgesics – tramadol, buprenorphine, codeine, dihydrocodeine, oxycodone, pentazocine
12. Anti-epileptic drugs – gabapentin, pregabalin.
Despite the large number of such drugs currently available, their usefulness in controlling pain in JHS is limited. All these drugs are capable of causing adverse reactions
including skin rashes, gastrointestinal bleeding and, particularly in elderly subjects,
renal impairment. The possible risk of side effects should be weighed against the need
for analgesia. It is important to re-emphasise that drug therapy is not indicated for a
lesion that requires primarily local treatment. Medicinal agents, however, can provide
a limited level of analgesia for hypermobile patients with intractable arthralgia and/or
neck or back pain. The development of chronic widespread pain poses further therapeutic challenges as analgesics (including the most potent drugs listed above), even in
combination, not infrequently prove to be of little benefit. The most frequently used
description of their efficacy is that at best, ‘they merely take the edge off the pain’.
5.7.19
Massage, Mobilisation, Hydrotherapy
and Water Immersion
Arthralgia and stiffness for no apparent reason are helped by a wide range of accessory and physiological mobilisations77 either within the pain- and resistance-free
range or just beyond it, depending on the severity of the symptoms.
Myalgia – sore, stiff muscles, tender on palpation and aggravated by sustained postures, e.g. holding a hair dryer – often responds to sustained muscle stretch which the
patient can learn and perform when required. A willing relative or friend can also be
taught simple passive mobilising techniques. In this way, the need for a professional
5.7
93
physiotherapist may be reduced to an acute exacerbation only. It is important for the
patients to regain their normal hypermobile range (without exceeding it) in order to
become pain-free. Extreme care is necessary in cases of recurrent dislocation.
Some patients also derive symptomatic pain relief from hydrotherapy, in which
exercises are performed under the supervision of a physiotherapist in a pool warmed to
a temperature of 35°C. Indeed, some appear to gain more benefit from immersion in the
pool than from the exercises. This apparent benefit may have a rational basis and, moreover, may go some way towards explaining the popularity of spa therapy.105 If a hydrotherapy pool is not available, patients can be advised to soak at leisure in a warm bath.
5.7.20
Behavioural Techniques
Progressive relaxation techniques or biofeedback aimed at reducing muscular tension and anxiety have become increasingly widely used in recent years in combating chronic pain. A study in 1984 showed that applied relaxation can significantly
reduce chronic back and/or joint pain.106
Cognitive behavioural therapy (CBT) for chronic pain management aims to
improve physical performance and coping skills and, at the same time, transfers the
control of pain and its management of its related problems back to the patient.107
A meta-analysis of 65 studies of treatment of low back pain has shown that multidisciplinary treatments are more effective than no treatment, waiting list or singledisciplinary medical or physical treatments.108 Not only did pain and mood improve,
but behavioural variables such as return to work and use of health service facilities
did so too. A randomised controlled clinical trial compared the effects of an inpatient
CBT programme administered by a multi-disciplinary team to mixed chronic pain
patients in comparison with a similarly constructed outpatient regimen and with a
waiting list control group. While the control group did not improve, both treatment
groups improved in regard to physical performance, psychological function and
reduced medication use.109 However, the inpatient group made greater gains, which
they had better maintained at 1 year. They also utilised less health care. A recent
review on the use of pain management programmes in the treatment of chronic pain
in EDS gives an authoritative account of the state of current progress.110
5.7.21
Acupuncture and Transcutaneous
Neural Electrical Stimulation
The use of electrical stimulation to relieve pain dates back to Ancient Greece, where
the electric torpedo fish was prescribed for headaches and arthritis. Perhaps the modern equivalent is the transcutaneous nerve stimulator (TENS). A related technique,
subcutaneous nerve stimulation, unfortunately has recently been shown to be no
more effective in relieving pain in osteoarthritis of the hip than a placebo.111
94
Acupuncture was superior to placebo in the form of detuned TENS in a small
series of 13 neck pain cases.112 Further studies are needed to assess the role of these
techniques in the treatment of intractable pain.
5.7.22
Denervation Procedures
When persistent low back pain originates from the facet joints, it may be reduced or
abolished by means of so-called facet joint denervation. After a successful preliminary injection of local anaesthetic into the facet joint under X-ray control, the joint
is ‘denervated’ by radio-frequency ablation of the afferent nerves.113
5.7.23
Support and Information
Patient self-help and support groups now play an important role in providing information and support for their members. Their activities include the publication of
leaflets, books and newsletters, holding study days and maintaining Web sites. In
the UK, there are now three such groups: the Ehlers-Danlos Support Group, the
Hypermobility Syndrome Association and the Marfan Association. All three are
affiliated to the Coalition of the Heritable Disorders of Connective Tissue, an
umbrella organisation. All three maintain contact with their sister organisations in
Europe and in other parts of the world.
Addresses:
Ehlers-Danlos Support UK
P.O. Box 748, Borehamwood
WD6 9HU
Tel: +44 208 736 5604
http://www.ehlers-danlos.org
Hypermobility Syndrome Association
49 Orchard Crescent
Oreston
Plymouth
PL9 7NF
http://www.hypermobility.org/alert.htm
Marfan Association UK
Rochester House
5 Aldershot Road
Fleet, Hants GU13 9NG
Tel: +44 1252 810472
Fax: +44 1252 810473
References
95
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Grahame R, eds. Hypermobility, Fibromyalgia and Chronic Pain. Oxford: Elsevier Limited;
2010.
111. Cottingham B, Phillips PD, Davies GE, Getty CJM. Effect of subcutaneous nerve stimulation
(SCNS) on pain associated with osteoarthritis of the hip. Pain. 1985;22:243-248.
112. Petrie JP, Langley GB. Acupuncture in the treatment of chronic cervical pain. A pilot study.
Clin Exp Rheumatol. 1983;1:333-336.
113. Gallagher J, de Petriccione de Vadi PL, Wedley J, Hamann W, Ryan P, Chikanza I.
Radiofrequency facet joint denervation in the treatment of low back pain: a prospective
controlled double-blind study to assess its efficacy. Pain Clin. 1994;7(3):193-198.
114. Hakim A, Keer R, Grahame R. Hypermobility, Fibromyalgia and Chronic Pain. 1st ed.
Edinburgh, London, New York, Philadelphia, St Louis, Sydney, Toronto: Churchill
Livingstone Elsevier; 2010.
Chapter 6
Extra-articular Manifestations of Hypermobility
6.1
Introduction
Arguably, the most surprising development of the past decade has been the realisation
that the effects of JHS do not lie exclusively within the confines of the musculoskeletal system. Nowadays, it is no exaggeration to state that JHS is seen as a multifacetted multi-system disorder which effectively touches virtually all medical
specialties in one way or another.
The original concept dates back to the original descriptions of the syndrome in
the 1960s1 when JHS was considered to be purely a mechanical problem of lax
joints presenting with pain after exercise, a tendency to instability, leading ultimately to premature osteoarthritis. The affected person was seen as essentially
healthy, merely lax jointed and placed at the upper end of a physiological spectrum
of joint mobility.2 Since few doctors (rheumatologists included), then as now, were
trained to look routinely for hypermobility, the diagnosis was rarely sought and,
thus, even more rarely found. Consequently, it was (and still is) considered to be a
rare condition, which is not the case.3
The great conceptual leap occurred in three stages. Firstly, there was the recognition in the 1970s and 1980s that JHS was itself a forme fruste of a heritable disorder
on connective tissue (HDCT) with overlap features that it shared with other HDCTs
such as Marfan syndrome (MFS), Ehlers–Danlos syndrome (EDS) and osteogenesis
imperfecta (OI)4,5 (Fig. 6.1). Secondly, the notion that what rheumatologists call
JHS is indistinguishable from, if not truly identical to, what clinical geneticists term
the Hypermobility type of EDS (formerly classified as EDS type III6) has become
more widely accepted.7
Then, finally and slowly, over the past three decades came the realisation that
patients with JHS seeking help from doctors and therapists were complaining of
many symptoms that bore no obvious direct relation to joint mobility, pointing,
unequivocally, to a multi-system disorder. Sadly, more often than not, their pleas
initially fell on deaf ears!8,9 Published reports pointed (roughly in the chronological
order of their appearance in the literature) to:
101
102
6
MARFAN
EHLERS-DANLOS
AORTIC DILATATION
ECTOPIA LENTIS
MARFANOID
HABITUS
CLASSICAL,
VASCULAR, ETC
TYPES
STRETCHY SKIN:
PAPYACEOUS SCARS:
STRIAE ATROPHICAE
JOINT HYPERMOBILITY
SYNDROME (=EDS III?)
OSTEOPENIA
OSTEOPOROSIS;
FRACTURES
OSTEOGENESIS
IMPERFECTA
Fig. 6.1 Overlap between the principal heritable disorders of connective tissue – Marfan syndrome, Ehlers–Danlos Syndrome (EDS) and osteogenesis imperfecta and the probable relations
hip between them and the joint hypermobility syndrome (indistinguishable from the hypermobile
type of EDS (EDS III))
1. Weakness of supporting structures, in particular, the pelvic floor, diaphragm and
anterior abdominal wall
2. Mitral valve prolapse
3. Chronic pain
4. Joint proprioceptive impairment
5. Lack of efficacy of local anaesthetics
6. Autonomic dysfunction
7. Certain psychiatric disorders and (most recently of all)
8. Functional disorders of the gastrointestinal tract.
6.1.1
Weakness of Supporting Structures Including
Pelvic Floor Insufficiency
Abdominal, thoracic and pelvic viscera may be affected as a result of weakness
of supporting structures such as the anterior abdominal wall (abdominal hernia), the
pelvic floor (rectal and uterine prolapse), the diaphragm (hiatus hernia) or the
parietal pleura (pneumothorax).
6.1
Introduction
6.1.1.1
103
Hernia
A sevenfold increase in the prevalence of hernia was seen in children with congenital
dislocation of the hip and a fivefold increase in hernia in their fathers and brothers.10
A recent postal survey undertaken among member of the Dutch Ehlers–Danlos
Society found that the popular concept that hernia is more common among EDS
patients was upheld.11 A recent study from neighbouring Belgium failed to detect
differences between the Beighton scores in 60 adult male inguinal hernia subjects
compared to controls.12 Clearly, more research using modern methodologies and
concepts is needed.
6.1.1.2
Rectal Prolapse
The first report of rectal prolapse occurring in EDS was published by Beighton in
1969 in four children, all of whom had experienced complete remission of the
symptom by the age of 5.13
In a study of 21 male and 4 female patients of mean age 69.3 years with rectal
prolapse, the angle of extension of the fifth metacarpophalangeal joint was significantly greater (81° ± 2.2 (S.E.M.)) than in age- and sex-matched controls (68° ± 1.7)14
suggesting that rectal prolapse should be considered part of JHS. Further studies are
needed to substantiate or refute this assertion.
6.1.1.3
Uterine Prolapse
Amongst a group of 76 Iraqi women suffering from various degrees of uterine prolapse, 50 (66%) showed generalised joint laxity (Beighton score >3/9), compared
with 14 (18%) (p < 0.005) in age- and parity-matched female controls.15 This initial
observation has been confirmed in subsequent studies. Norton et al. (1995) found an
incidence of hypermobility of 36% amongst 107 stress incontinence patients examined. Subjects with hypermobility showed a highly significantly increased incidence
of rectocele, cystocele and uterine or vault prolapse than controls (p < 0.001,
p < 0.002, p < 0.002, respectively).16 It is now widely accepted in the gynaecological
literature that tissue laxity is an important factor in the pathogenesis of pelvic floor
problems. In a study of 41 adult women with the EDS (mean age 41 years), genital
prolapse was present in 29.3%, incontinence in 59%, endometriosis in 27%, dyspareunia in 57%, previous hysterectomy in 44% – a higher incidence than expected
for women in this age bracket.17
In a recent Turkish study, 65 women who had been recommended for surgery for
pelvic organ prolapse were compared with 52 age-matched healthy controls. Patients
with prolapse had a significantly higher prevalence of JHM when compared with
controls (53.8% vs. 9.6%). No significant correlation was demonstrated between
Beighton scores and incontinence. Unfortunately, the presence or absence of JHS
according to the Brighton criteria was not recorded.18
104
6
Although pelvic floor problems are occasionally encountered in nulliparous
women, they are usually considered to affect mostly multipara. In one study, 100
pairs of nulliparous and parous postmenopausal sisters were assessed for pelvic
organ prolapse. High concordance of pelvic organ prolapse between nulliparous and
parous sister pairs suggests a familial (possibly, even a genetic) predisposition
toward developing this condition. Vaginal delivery did not appear to confer increased
risk for more severe pelvic organ prolapse in later years.19
Using the International Consultation on Incontinence Questionnaire-Short
Form (ICIQ-SF) and the Manchester Health Questionnaire, Jha et al. (2007) compared 30 JHS patients with 30 controls. They found that incontinence in the JHS
group was present in 18/30 compared to 9/30 (60% vs. 30%; p = 0.037) in the
control group. Twenty-three per cent (7/30) of the women with JHS had in additional anal incontinence compared to none of the controls (23% vs. 0%; p = 0.01).
Thus, the prevalence of both urinary and anal incontinence appears to be significantly higher in women with JHS compared to women controls.20 The same group
also conducted a survey among 148 members of the HMSA (Hypermobility
Syndrome Association), the UK-based patients’ self-help group (40% response
rate). The survey revealed a prevalence of urinary and faecal incontinence of
68.9% and 14.9%, respectively, compared to 30% and 2.2%, respectively, as
reported in the general population.21 Self-reported data of this kind clearly need to
be interpreted with caution, but admittedly, the figures are striking and further
studies are necessary.
6.1.2
Mitral Valve Prolapse
Mitral valve prolapse (MVP) during systole has been reported in patients suffering
from hereditary disorders of connective tissue, such as MFS,22 EDS23 and OI.24
Reports in the 1980s described an increased prevalence of mitral valve prolapse in
persons with hypermobility.4,25 Using the echocardiographic technology and stricter
criteria of the 1990s, Mishra et al.5 were unable to find an increased incidence of
MVP among 58 JHS patients (10%) as compared with 30 age- and sex-matched
controls (7%). The MVP was minimal, and only one patient had associated mitral
regurgitation. Furthermore, not a single patient showed aortic root dilatation, thereby
helping to differentiate patients with JHS from those with MFS and confirming the
distinct and benign nature of JHS. A recent paper from Turkey sheds a little more
light on this subject. Forty-six MVP patients (with or without hypermobility) were
compared with 25 healthy controls. The incidence of H/M as judged by the Beighton
scale was found to be significantly higher in patients than that in the controls. Those
with MVP + H/M had significantly increased anterior mitral leaflet thickness
(AMLT), maximal leaflet displacement (MLD) and degree of mitral regurgitation
(DMR) compared to those without hypermobility. However, the index of aortic stiffness (IAOS) was found to be lower and the aortic distensibility higher. There was a
significant correlation between AMLT, MLD and DMR, and hypermobility. Had the
6.1
Introduction
105
authors used the Brighton criteria for JHS (rather than solely relying on the Beighton
score an index of JHM), these important new data could have clarified the situation
with regard to MVP in JHS rather than in the more nebulous grouping of
hypermobility.26
6.1.3
Chronic Pain
Chronic pain is a frequent symptom in patients attending outpatient clinics with JHS.
Twenty-six per cent of 700 JHS patients attending the author’s specialist hypermobility clinic at University College Hospital, London, admitted that their pain was ‘lifedominating’ at the time of their first attendance (unpublished data). Surprisingly, it is
only in the last decade or so that the link between JHS and chronic pain has become
apparent.27 The onset of chronic pain is usually insidious, superimposing itself on the
pattern of often long-standing widespread joint and spinal pain that preceded it.
Chronic pain is very different from acute pain. Unlike its acute counterpart, chronic
pain cannot usually be directly traced to a specific injury; its distribution is diffuse
without conforming to anatomical patterns; it may cover the whole body, half the
body (top or bottom or left or right) or just a quadrant; it may be accompanied by
dysaesthesiae, hyperesthesia or allodynia (seen in the tender points of fibromyalgia);
and it is generally resistant to the most potent combinations of oral analgesics up to
and including morphine. Most patients describe their efficacy at best, ‘as taking the
edge of it’. In JHS, chronic pain is often aggravated by any body movement. Intuitively,
the affected individual resorts to a strategy of movement avoidance as a means of pain
avoidance, a process termed kinesiophobia.28 This has the effect of aggravating and
compounding muscle deconditioning, indeed, the very opposite effect of what is
needed by a hypermobile person whose joints are inherently unstable through joint
laxity. Not surprisingly, it often plunges them into a vicious downward spiral of declining function, loss of independence, self-esteem and self-efficacy.
This downturn in the patient’s fortune rarely occurs out of the blue and can usually
be traced to either a change in lifestyle, such as a new job or leisure activity involving
greater physical demands on the person’s already compromised locomotor system, or
a sudden traumatic event like an unaccustomed physical challenge, e.g. running in a
race without appropriate prior training, undertaking over-ambitious home improvements schemes or an injury such as a whiplash injury following a road traffic accident
(RTA). The intensity of all their pains is amplified. This includes not only the superimposed diffuse chronic pain, but also the pre-existing pains, be they joint, spinal or
soft tissue in origin, which also increase progressively in parallel over time. The level
of distress is heightened further by associated chronic fatigue (which may be just as
debilitating as the pain itself and may incur an erroneous diagnosis of chronic fatigue
syndrome) and depression. Sadly, for many people in this situation, their medical
attendants, appear unaware of the link between JHS and this level of pain, and they are
either not believed or told that ‘it is ‘all in the mind’.9 There is also a suggestion of an
association between EDS and chronic regional pain syndrome (CRPS).29
106
6
New interest has been added to the established association between hypermobility
and fibromyalgia known to exist both in children and adults30,31 by the finding on
dynamic MRI of the cervical spine of positional cervical cord compression in extension of the cervical spine in patients with widespread chronic pain of the fibromyalgia
type and dysautonomia.32
6.1.4
Proprioceptive Impairment
It has been established that JHS as defined by the Brighton criteria is associated with
impairment of joint proprioceptive acuity both in the finger and knee joints.33,34 Although
it is not yet certain whether this is innate or acquired, it has been shown to be capable
of being improved (even normalised) by appropriate exercise therapy35 where it now
forms part of the evidence-based rehabilitation programme (see Chap. 5).
6.1.5
Lack of Efficacy of Local Anaesthetics
JHS patients can often recall experiences when local anaesthetics have proved to be
ineffective. In one study, the following standardised question was put to groups of JHS
patients and control subjects. They were asked ‘If you have ever had a local anesthetic
injection (e.g. at the dentist, for minor surgery or epidural (spinal) anaesthesia), do
you think that it was as effective as it should have been?’ Some 58% of the 172 JHS
patients answered ‘No’ as compared with 18% of the 53 controls (OR 2.85).36,37 It is
nearly 20 years since Arendt-Nielsen and co-workers confirmed in elegant experiments that there was a true and measurable difference in responses comparing EDS
patients with controls. EDS patients were not totally resistant to local anaesthetics;
they merely showed a shorter duration and a reduced effect.38 Their explanation at the
time for this curious symptom, that the local anaesthetic solution diffuses away more
rapidly from the micro-environment of the site of the injection because of the lax
nature of the connective tissues, has not been bettered over the intervening period.
6.1.6
Autonomic Dysfunction
Patients with JHS frequently complain of symptoms compatible with autonomic
dysfunction. These include palpitation, dizziness, pre-syncope and syncope, and
there is often an orthostatic element, similar to that seen in patients suffering from
chronic fatigue syndrome (CFS) or fibromyalgia (FM).39 Such symptoms may have
in times gone by have previously been misinterpreted as stemming from mitral
valve prolapse.5 The first association between EDS and autonomic dysfunction was
established in children with chronic fatigue.40
6.1
Introduction
107
Gazit et al. (2003) confirmed the occurrence of autonomic symptoms in JHS,
studying 48 patients and 20 controls. Symptoms including syncope, palpitations,
chest discomfort, fatigue and heat intolerance were significantly more frequent
among the JHS patients as compared with the controls. Furthermore, 27 patients
and 21 controls underwent autonomic evaluation: including orthostatic testing of
cardiovascular vagal and sympathetic function. Orthostatic hypotension (OI), postural orthostatic tachycardia syndrome (PoTS) or uncategorized orthostatic intolerance (OI) was found in 78% (21/27) of JHS patients. The authors concluded that
dysautonomia is a part of the extra-articular manifestation of JHS.41 In a study of
170 JHS patients from a specialist hypermobility clinic, Hakim and Grahame identified 41% of patients with light-headedness and other presyncopal symptoms, 26%
with palpitations and shortness of breath and 37% with gastrointestinal symptoms,
compared to 15%, 12% and 16% in controls, respectively.42 Bravo and Wolfe, in a
study of 1,226 JHS patients, found the prevalence of OH and OI to be especially
high in adolescent girls and in adult JHS patients younger than 30 years old.
Autonomic dysfunction was present in 72% of females and 44% of males in this
series.43 In a more recent study, the presence of cardiovascular autonomic dysfunction (CAD) was identified by detailed autonomic testing in symptomatic cases of
JHS. Some 63% of patients had identifiable pathology (43% PoTS, 14% vasovagal
syncope (VVS) and 6% both).44 None were identified as having other pathologies
such as anaemia or epilepsy that might explain their symptoms. One in three of the
symptomatic cases had no identifiable autonomic pathology; a similar finding to
that seen in patients with fibromyalgia and chronic fatigue syndrome.45
A recent paper from Belgium draws attention to the overlapping relationship
between chronic fatigue syndrome (CFS), chronic musculoskeletal pain and JHS
and emphasises the significance of pain catastrophising as an indicator of poor
exercise performance in CFS.46
The well-established correlation between fibromyalgia (FMS) and hypermobility both in adults30 and in children31 has recently received further confirmation in a
study of 118 FMS adult women and 118 healthy controls. Unfortunately, the investigators only measured the Beighton joint score for hypermobility (rather than the
Brighton criteria for JHS), so that the true incidence of JHS in the two groups is not
recorded. Using a cut-off point for hypermobility of ³4/9 on the Beighton scale,
46.6% of the FMS group and 28.8% of the control group were deemed to be H/M.
The mean Beighton score of FM group was higher than in the controls (3.68 vs.
2.55, p < 0.001). More severe clinical findings were seen in hypermobile FMS
patients compared with those who were not hypermobile, but this did not achieve
statistical significance.47
6.1.7
Certain Psychiatric Disorders
A group of psychiatric colleagues working in Barcelona, Spain, have discovered a
perplexing series of links between certain anxiety and phobic states on the one hand
108
6
and hypermobility on the other. Firstly, panic disorder, agoraphobia and simple
phobias were four times more common in hypermobile patients than in controls.48
Then, from the opposite direction, it was apparent that joint laxity was sixteen times
more common in patients with panic attacks or agoraphobia than in controls.49
Finally, a community-based study established beyond question the association
between anxiety disorders and joint laxity.50 The finding by Gratacòs et al. (2001) of
an interstitial duplication on human chromosome 15 (15q24-26) (Dup 25) significantly associated with panic, agoraphobia, social phobia, joint laxity in families and
with panic disorder in non-familial cases led the authors to propose that Dup 25 is a
susceptibility factor for a clinical phenotype that includes both panic and phobic
disorders on the one hand and joint laxity on the other.51 In an attempt to confirm
these interesting findings, a group led by Zhu et al. at NIH used two different methods to detect DUP25: high-throughput molecular gene dosage analysis and fluorescence in situ hybridization (FISH). They evaluated 56 lymphoblastoid cell lines
derived from 26 unrelated patients with panic disorder obtained from several
European and American populations and 30 normal controls, but could not find any
cell line showing a result consistent with DUP25.52 A similar British study attempting to replicate the experimental conditions described by Gratacòs and colleagues in
which fluorescence in situ hybridization was used to examine metaphase chromosomes of patients with panic disorder/social phobia and of control individuals from
a southern region of the UK, the primary aim being to determine the prevalence of
this chromosomal rearrangement in a geographically and ethnically distinct population. DUP25 was not observed in any of the 16 patients, nor in 40 control samples
nor in 3 previously reported DUP25-positive control (Centre d’Etude du
Polymorphisme Humain) cell lines, indicating a highly significant difference in the
frequency of DUP25 between the study by Gratacòs51 and colleagues and the subsequent investigations in two other centres.53
6.1.8
Functional Disorders of the Gastrointestinal Tract
It has long been appreciated that in up to 50% of patients who present to gastroenterologists with GI symptoms, no structural or biochemical abnormality can be
identified. Such patients whose symptoms are unexplained are said to be suffering
from functional gastrointestinal disorders (FGIDs) (this includes so-called irritable
bowel syndrome (IBS)). Because of their high prevalence, FGIDs have enormous
economic consequences. There is increasing evidence to suggest that joint hypermobility is strongly implicated in the pathogenesis of the FGIDs.
A recent Australian study has demonstrated an association between constipation and hypermobility defined as a Beighton score of ³4/9 (but not JHS) in 39
children (aged 7–17 years) with slow transit constipation (STC), a form of chronic
constipation characterised with delayed colonic passage of stool, when compared
with 41 controls without constipation. JHM was sought. The relationship was only
statistically significant in boys.54 In a study of 129 patients with FGIDs, no less
6.2
Straws in the Wind
109
than 63 (49%) were found to have either JHM or JHS.55 Abdominal pain, bloating
and constipation and/or diarrhoea, nausea and an unpleasant taste in the mouth
were the commonest symptoms, and physiological studies showed features of a
pan-intestinal dysmotility including gastroparesis, small bowel dysmotility and
slowed colonic transit.
The first evidence pointing to JHS as a factor in the pathogenesis of obstructive
defecation (OD) came from a study from Australia which observed that OD, chronic
constipation, JHS, chronic heavy lifting and a history of uterovaginal prolapse were
significantly associated with patients with lower urinary tract (LUT) dysfunction
and obstructive defecation compared to those with LUT dysfunction alone. Overall,
symptoms of obstructed defecation were not more prevalent in any one urodynamic
diagnostic group than in others. However, childhood constipation and current constipation were significantly more prevalent in women with voiding dysfunction than
in those with other urodynamic diagnoses (16.7% vs. 5.5%, p = 0.0030 and 13.0%
vs. 5.7%, p = 0.017). The authors concluded that women with LUT dysfunction are
more likely to have symptoms of obstructive defecation than are community controls. Connective tissue disorders such as JHS were considered to be an important
factor in this association.56
A further study of rectal physiology has revealed in hypermobile subjects rectal
evacuatory disorder (RED) with features of functional rectocele, occluding intussusception, megarectum and features suggestive of enterocele on proctography. Of
200 patients satisfying the criteria for JHM using a self-reported validated 5-point
questionnaire,35 56 (86%) were found to have significant morphological abnormalities, compared to only 64% of the non-JHM group (p = 0.001).57 Thus, one-third of
constipated patients presenting to a tertiary centre with symptoms of RED had evidence of JHM compared to reported prevalences of JHM in the general population
of only ~5–20%.57 The notion that the cause of the intestinal dysmotility revealed in
these studies could be due to a common underlying connective defect manifesting
as joint hypermobility is an intriguing one that gastroenterologists have yet to
contemplate.
6.2
Straws in the Wind
If fragility of connective tissue underlies such a wide variety of pathological
processes, it is very likely that links between hypermobility and other diseases
will come to light in years to come. A foretaste of the kind of future ramifications
of hypermobility that may emerge is to be seen in orthostatic (low-pressure)
headache caused by spontaneous intracranial hypotension associated with leakage of cerebrospinal fluid from the sub-arachnoid space through a rent in the
dura. Of 18 patients thus presenting in one series, no less than 7 (38%) showed
evidence of a connective tissue disorder including types of EDS. The authors
postulate at that leakage from the dural membranes may have resulted from their
inherent fragility.58
110
6
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assessment of patients with diffuse musculoskeletal pain. Int J Clin Pract. 2003;57(3):
163-166.
37. Hakim AJ, Grahame R, Norris P, Hopper C. Local anaesthetic failure in joint hypermobility
syndrome. J Roy Soc Med. 2005;98(2):84-85.
38. Arendt-Nielsen L, Kaalund S, Bjerring P, Hogsaa B. Insufficient effect of local analgesics in
Ehlers Danlos type III patients (connective tissue disorder). Acta Anaesth Scand. 1990;34(5):
358-361.
39. Hoad A, Spickett G, Ellio J, Newton J. Postural orthostatic tachycardia syndrome is an underrecognized condition in chronic fatigue syndrome. Q J Med. 2008;101(12):961-965.
40. Rowe PC, Barron DF, Calkins H, Maumenee IH, Tong PY, Geraghty MT. Orthostatic intolerance and chronic fatigue syndrome associated with Ehlers-Danlos syndrome. J Pediatr.
1999;135(4):494-499.
41. Gazit Y, Nahir AM, Grahame R, Jacob G. Dysautonomia in the joint hypermobility syndrome.
Am J Med. 2003;115(1):33-40.
42. Hakim AJ, Grahame R. Non-musculoskeletal symptoms in joint hypermobility syndrome.
Indirect evidence for autonomic dysfunction? Rheumatology (Oxford). 2004;43(9):
1194-1195.
Rheum. 2006;54(2):515-523.
44. Hakim AJ, Mathian C, Grahame R. Outcome of cardiovascular autonomic testing in symptomatic patients with benign joint hypermobility syndrome. Rheumatology. 2009;48(4):216.
45. Raj RR, Brouillard D, Simpson C. Dysautonomia among patients with fibromyalgia:
a non-invasive assessment [Abstract]. J Rheumatol. 2000;27:2660-2665.
46. Nijs J, Meeus M, De Meirleir K. Chronic musculoskeletal pain in chronic fatigue syndrome: recent
developments and therapeutic implications [Review] [54 refs]. Man Ther. 2006;11(3):187-191.
47. Sendur OF, Gurer G, Bozbas GT. The frequency of hypermobility and its relationship with
clinical findings of fibromyalgia patients. Clin Rheumatol. 2007;26(4):485-487.
48. Bulbena A, Duro JC, Mateo A, Porta M, Vallejo J. Joint hypermobility syndrome and anxiety
disorders. Lancet. 1988;2(8612):694.
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49. Bulbena A, Duro JC, Porta M, et al. Anxiety disorders in the joint hypermobility syndrome.
Psychiat Res. 1993;46(1):59-68.
50. Martin-Santos R, Bulbena A, Porta M, Gago J, Molina L, Duro JC. Association between joint
hypermobility syndrome and panic disorder. Am J Psychiat. 1998;155(11):1578-1583.
51. Gratacòs M, Nadal M, M-Santos R, et al. A polymorphic genomic duplication on human chromosome 15 is a susceptibility factor for panic and phobic disorders. Cell. 2001;106(3):367-379.
52. Zhu G, Bartsch O, Skrypnyk C, et al. Failure to detect DUP25 in lymphoblastoid cells derived
from patients with panic disorder and control individuals representing European and American
populations. Eur J Hum Genet. 2004;12(6):505-508.
53. Tabiner M, Youngs S, Dennis N, et al. Failure to find DUP25 in patients with anxiety disorders,
in control individuals, or in previously reported positive control cell lines. Am J Hum Genet.
2003;72(3):535-538.
54. Reilly DJ, Chase JW, Hutson JM, et al. Connective tissue disorder–a new subgroup of boys
with slow transit constipation? J Pediatr Surg. 2008;43(6):1111-1114.
55. Zarate-Lopez N, Farmer AD, Grahame R, et al. Unexplained gastrointestinal symptoms and
joint hypermobility: is connective tissue the missing link? Neurogastroenterol Motil.
2010;22(3):252-e78. Epub Oct 15, 2009.
56. Manning J, Korda A, Benness C, Solomon M. The association of obstructive defecation, lower
urinary tract dysfunction and the benign joint hypermobility syndrome: a case-control study.
Int Urogynecol J Pel. 2003;14(2):128-132.
57. Mohammed SD, Lunniss PJ, Zarate N, et al. Joint hypermobility and rectal evacuatory
dysfunction: an aetiological link in abnormal connective tissue? Neurogastroenterol Motil.
2010;22(10):1085-e283. Epub Jul 5, 2010.
58. Schievink WI, Gordon OK, Tourje J. Connective tissue disorders with spontaneous spinal
cerebrospinal fluid leaks and intracranial hypotension: a prospective study. Neurosurgery.
2004;54(1):65-70.
Chapter 7
Illustrative Case Histories
In all the three earlier editions of this book, published between 1983 and 1999, a
chapter of ‘Illustrative Case Histories’ numbering between 22 and 32 cases was
included. Almost without exception they documented the variegated modes of presentation of JHS as it affected the musculoskeletal system. They illustrated how
until the very end of the twentieth century, despite the evidence that was emerging
over the preceding decades to the contrary, JHS was perceived exclusively as a musculoskeletal problem. With the arrival of the new millennium came the realisation
that JHS is truly a multi-systemic disorder as has been recounted in Chaps. 5 and 6.
To mark the occasion of this radical change of emphasis was the publication in 2000
of the ‘Revised 1998 Brighton Criteria for the BJHS’, which for the first time
provided a reliable and reproducible means of classifying joint hypermobility for
research purposes and clinical purposes.1 It is as a consequence of these two developments that readers will find the current chapter on Illustrative Case Histories,
whilst retaining the same name, is very different in content from its predecessors.
It will attempt to demonstrate the complexity of JHS as it now manifests, as well as
the often unrecognised major disabling effect that it can have on the musculoskeletal
system.
Case 7.1:
A 6-Year-Old Boy with EDS II/III with Grossly
Unstable Hind Feet
M.A. did not walk until after his third birthday, prior to which he bottom-shuffled
rather than crawled as a prelude to walking and thereafter had a marked tendency
to fall. His very stretchy skin and joint hypermobility (Fig. 7.1) was first noted at
the age of 2 when he was admitted to hospital for another illness. He was seen to
walk on the medial aspects of his feet with marked pes planus and calcaneal eversion. His joints, especially his hands and knees, were very lax and his skin soft,
velvety and very stretchy. Another relevant point in the history was the fact that
he bruised easily.
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Fig. 7.1 The hands of a
6-year-old boy with EDS II/
III who had grossly unstable
hind feet
Fig. 7.2 Same patient with
feet showing marked
flattening and pronation on
weight bearing and, in
particular, pronounced
calcaneal eversion
He was the eldest of three siblings, all of whom showed evidence of
hypermobility. There was little doubt that the condition had been inherited from
their father who had been diagnosed as suffering from EDS type II by Professor
Michael Pope in 1993 on the basis of scarring on the forehead, elbows and knees
and the finding of cauliflower fibrils on electron microscopy of his skin collagen.
M.A. was considered to manifest the EDS II/III overlap. He appeared a lively
boy and extremely flexible. He walked with a hyperlordotic posture and borderline scoliosis (5° on the Bunnell scoliometer). His feet showed marked flattening
and pronation on weight bearing and, in particular, pronounced calcaneal eversion (Fig. 7.2). Walking with the current orthotics only partially corrected the
deformity. He scored 6/8 on the modified Beighton scale (only the elbows were
not positive), and outside the scale, many of his other joints including shoulders,
spine, small finger and toe joints, and hips were all markedly hypermobile. His
Case 7.2:
Pelvic Floor Problems After Childbirth
115
Fig. 7.3 Same patient. His skin was very
extensible (3/3)
skin was very extensible (3/3) (Fig. 7.3). There were no scars or striae. His hands
and feet appeared normal in length, but the palate was somewhat high arched and
he had an obvious pectus excavatum.
Initially he had been supplied with Piedro boots and later ankle/foot orthotics,
which he was unable to tolerate. He walked with considerable difficulty because of
the severe ankle deformities. He was referred to a podiatrist for tailor-made
orthotics to good effect.
Comment: This case illustrates the importance of orthotic correction of severe
hind foot deformity in young children with EDS. In this instance, the child was suffering from the EDS type II/III overlap, so the deformity was unusually severe as
was the walking impediment.
Case 7.2:
Pelvic Floor Problems After Childbirth in a Patient
with EDS Hypermobility Type
G.E., a 35-year-old mother of a 6-month-old daughter, presented with severe locomotor problems and widespread joint pain in the presence of hypermobility. As a
child, she had been bendy, clumsy and fidgety, performing contortionist tricks, ballet and gymnastics, going on to experience so-called growing pains in her legs in her
early teens. She subsequently developed pains in her wrists, knees, hips and shoulders, neck, thoracic and, during pregnancy, the low back region. Her father, paternal
uncle and two first cousins on her father’s side were also hypermobile. She had had
a series of orthopaedic procedures mainly directed towards her knees with indifferent results. In the course of a forceps delivery of her daughter, she sustained a fourth
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degree perineal tear. Post-delivery, she suffered from vaginal prolapse and lack of
sensation as well as urinary urgency, frequency and leakage. She was treated with
supervised intensive pelvic floor exercises supplemented with long courses of biofeedback and neuromuscular stimulation. After the birth of her daughter, she found
it difficult to care for her, and this gave rise to considerable concern. Compatible
with a hypermobility syndrome was the recurrent dislocation of her patellae and left
shoulder, widespread joint clicking, stress incontinence since childbirth and orthostatic intolerance with syncope.
Examination confirmed the presence of widespread joint laxity with a hypermobility score of 4 [historically 7/9] on the Beighton scale. By contrast, her cervical
and thoracic spine movements were significantly reduced in all directions, the cervical spine particularly so and the restriction was painful. Her skin was characteristically soft and silky and showed increased stretchiness in the phase of taking up
slack. A number of her operative scars were paper thin, and although she had no
striae atrophicae, the absence of striae gravidarum was characteristic of the condition. The lingual frenulum was absent, another inconsistent sign of the EDS. There
were no features of a marfanoid habitus. She conformed to the 1998 Brighton criteria for the joint hypermobility syndrome equivalent to the EDS hypermobility type,
formerly EDS III. The nature of the condition was explained to her, in particular its
genetic basis and the vulnerability it confers on soft tissue to the effects of injury
and overuse. In her case, it had resulted in longstanding spinal pain and instability.
Comment: Unfortunately, the emphasis in her management thus far had been
along the orthopaedic route, and the results had been disappointing. She needed
urgent attention to the rest of her locomotor system, in particular the axial skeleton,
including a programme combining core and joint stabilising and proprioception
enhancing exercises coupled with a general fitness programme to restore function
and reverse the changes resulting from deconditioning, together with the use of
mobilising techniques to restore areas of the spine or peripheral joints to their natural hypermobile state. She was referred to the physiotherapy department for assessment. She already attended other hospitals for her complaints and a Women’s
Health physiotherapist for the pelvic floor problem. A community physiotherapist
visited her at home, and she also attended pain clinics at two hospitals. She found
analgesics generally unhelpful, and this is a feature of the pain amplification that
accompanies JHS.
Case 7.3:
A Labral Tear and Autonomic Dysfunction
Complicating Hypermobility
G.V. was a 29-year-old former mental health support worker who had not worked
since her hip problem started in 2006. She was considered to have joint hypermobility
syndrome.
Like many hypermobile people, she walked late, experienced the so-called growing pains in her limbs, performed contortionist tricks and gymnastics in childhood,
Case 7.3: A Labral Tear and Autonomic Dysfunction Complicating Hypermobility
117
and went on to suffer from recurrent ankle sprains from the age of 10 years, which
had persisted to the present time. She was clumsy with a tendency to trip and bump
into furniture, which is also characteristic of the condition. From the age of 10 years,
she complained of pain in her knees, hips and ankles, which has persisted. One day
after sitting cross-legged for 3 h (as she is wont to do), she suddenly jumped up and
developed an instantaneous severe left hip pain, which was excruciating and subsequently caused great difficulty in walking. From then on she managed to get about
on crutches but needed a wheelchair for outdoor use. An MRI with contrast revealed
a large tear of the acetabular labrum on the left. Compatible with a hypermobility
syndrome were her disc prolapse at the age of 20 with left-sided sciatica and a dislocation of the left shoulder at the age of 23 when she fell downstairs, recurrent
dislocations of the patellae and left 1st MCP joint. Widespread joint clicking, easy
bruising, poor skin healing, history of capsulitis of the shoulder following a dislocation and right-sided costal chondritis, TMJ problems and resistance to lidocaine at
the dentist and during minor surgery were other syndromic complaints. She also had
osteopenia and was receiving calcium and vitamin D. She had experienced orthostatic intolerance from the age of 13 and had a history of panic attacks and claustrophobia, both of which have been linked to hypermobility.
The examination revealed evidence of marked and widespread joint laxity with a
Beighton score of 9/9 on the hypermobility scale. Outside the scale, her shoulders
and cervical spine were also hypermobile. However, her dorsal spine showed restriction due to pain on rotation to the right. There is a 2° scoliosis on the Bunnell scoliometer but no other features of a marfanoid habitus. Her feet flattened on weight
bearing. Her skin was soft and silky and showed increased stretchiness in the phase
of taking up slack. There were a few small paper thin scars on her knees from childhood scrapes and striae atrophicae which had been present since the age of 14 years.
The lingual frenulum was present, a normal finding. She scored relatively high
(15/30) on the checklist of symptoms consistent with autonomic dysfunction commonly seen in JHS. It was not possible to confirm the presence of orthostatic hypertension or postural orthostatic tachycardia in clinic, although a rise in her pulse rate
of 19 bpm on standing from lying was somewhat suggestive of the latter. She conformed to the 1998 Brighton Criteria for the Joint Hypermobility Syndrome1 (equivalent to the EDS hypermobility type, formerly EDS III). The nature of the condition
was explained to her, in particular its genetic basis and the vulnerability it confers
on soft tissues to the effects of injury and overuse. In her case, it had resulted in
longstanding joint pain, probably early thoracic spinal spondylosis, a past lumbosacral disc prolapse and what was, almost certainly, a labral tear associated with
a dysplastic hip, and the beginnings of a chronic pain syndrome.
Comment: The first priority was the need for further investigation and treatment
of her autonomic symptoms and to seek orthopaedic guidance for management of
the hip problem. Once this was obtained, there was the need for a programme of
appropriate rehabilitation to deal with the other aspects of her condition.
Physiotherapy being the mainstay of treatment, we recommended a physiotherapy
programme combining core- and joint-stabilising and proprioception-enhancing
exercises together with a general fitness programme to offset or reverse the tendency
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to deconditioning. Where appropriate, the use of mobilising techniques to restore
mobility in stiffened joints/spinal segments to their previously natural hypermobile
state was also initiated.2 She had previously found painkilling drugs ineffective and
had entered a pain management programme in which a cognitive behavioural
approach was used.
Case 7.4:
Complexities in Diagnosis and Management
C.C. was first referred at the age of 24 years by a consultant rheumatologist following a succession of referrals to the clinicians. She was then a graduate in psychology, aspiring to a second degree to allow a career as a solicitor. At 5 ft 10 in., she
was the tallest member of the family, the mother being much shorter and not obviously hypermobile though there was an implication that the separated father might
have been hypermobile, and he was able to bite his toenails. Her paternal grandfather had a horseshoe kidney.
The Beighton score was 9/9 though this only gave a modest assessment of
extreme hyperlaxity which was present at certain sites, especially the fingers.
She had avoided sports because of ‘poor co-ordination’ and easily fulfilled
the criteria for hypermobility syndrome.1 Her scars were well healed and were
not typical of EDS, the ocular lenses were not subluxed and, although her
fingers and toes were long and thin, these latter features were not classical
for arachnodactyly. The changes in the spine were those of a simple thoracic
scoliosis rather than any of typical marfanoid deformities. Echocardiogram had
shown mild prolapse of the mitral valve and no concerns in the aortic area or the
aortic ring.
There were concerns with vision, and an ophthalmologist had previously
diagnosed ‘swollen optic nerves’; optic neuritis had been excluded on appropriate investigation as had the Stickler syndrome. She did, however, display variation between extreme short-sightedness and extreme long-sightedness and, more
recently, had developed astigmatism. There was also a family history of psoriasis
(though her own skin lesions were thought to represent acne) and of possible
psoriatic arthritis, though at no stage was she considered to have developed an
anterior uveitis and HLA-B27 testing was negative.
The gynaecological history was complex. Her periods started at 14 years, but
prior to this, she was given Co-cyprindiol for skin lesions, and found that this preparation made the hyperlax joints more painful. At one point, polycystic ovary syndrome was suspected, and this has remained under review.
Whilst symptoms had been present at all joints, the main practical problem was
the management of the extreme hyperlaxity in the long fingers and the extreme laxity at the shoulders, both combining to cause considerable difficulties in the large
amount of writing required in her second university course. Orthopaedic review in
respect of the shoulders had so far avoided plication or laser capsular shrinkage and
Case 7.5: Bony Abnormality and Complications of Subluxation
119
it was possible the slight thoracic scoliosis was contributing to an asymmetry of
symptoms at the shoulders.
Management to date has been with intensive physiotherapy and guidance on
thoraco-scapular tracking. Standard measures had been offered for the hands including chunky pens, three-fingered grip, elasticated gloves, spica splints by day (even
when writing), and firm night rest splints ensuring the hands and wrists remained in
a physiological position overnight prior to writing the next day. Both universities
had been supportive with the provision of an ergonomic computer keyboard, voice
recognition software and even the use of a scribe in examinations.
Urinary tract symptoms including mild stress incontinence and a succession of
infections were initially attributed to bladder and pelvic floor dysfunction often
found in hypermobility syndrome. More recent investigation, however, has confirmed the presence of bilateral duplex kidneys.
Comment: Although ‘benign joint hypermobility syndrome’ provides broad
cover for the many symptoms experienced by hypermobile patients, careful exclusion of alternative diagnoses is still required. Inflammatory arthritis mimicking
hypermobility is unlikely to be missed, but overlap with other inherited abnormalities such as a mild variant of Marfan syndrome or even osteogenesis imperfecta
needs to be kept in mind. In this case, it seemed prudent to continue with intermittent monitoring of the diameter of the aortic ring. Many patients also demonstrate
clustering with other heritable disorders, in this case a condition at the eye, not fully
diagnosed but thought not to be Stickler syndrome, and bilateral duplex kidney.
Against this background, completion of two university courses has been challenging, but the subject is a determined optimist who has vowed to use her legal skills in
the support of claimants with inherited abnormalities, hoping ultimately to specialise
in this area.
Case 7.5: Bony Abnormality and Complications
of Subluxation
J.T., first referred by her general practitioner at the age of 20 years, had also seen a
succession of consultants from different specialities, including some rheumatologists,
before reaching a specialised clinic devoted to inherited conditions of collagen. Most
of the doctors in her local hospitals had declared themselves ‘perplexed’ by her condition. A Beighton score of 9/9 only touched the surface, and a characteristic of her
condition was extreme laxity at certain joints. She also fulfilled the criteria for benign
joint hypermobility syndrome, though her case was far from ‘benign’.
As a child, she had seen geneticists when brachydactyly type B was suggested as
a cause of the shortening of some fingers. She also considered herself extremely
flexible, talented at sports as a child but was aware of limitations in the back with a
propensity to acute episodes of back pain and spasm, probably reflecting intermittent prolapse of a disc. Radiographs of the spine revealed a mild scoliosis of the
spine complicated by a corkscrew twist and a mild degree of spina bifida occulta
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around L5. The joints, whilst capable of contortion, appeared uncontrolled with
poor proprioception.
In childhood, she had experienced Raynaud’s phenomenon, but this was normally
mild, bilateral and precipitated by cold weather. During the 3 years she has been
under review, a more complex picture has emerged characterised by extreme localised symptoms of vascular disturbance, analogous to reflex sympathetic dystrophy,
specifically sparked by subluxation of one of her most flexible joints often, though
not always, one of those displaying most bony abnormality. Nevertheless, a pattern
has emerged that upon subluxation, particularly of the elbow but sometimes the
shoulder, an episode of reflex sympathetic dystrophy is triggered, as often occurs
after a surgical operation. A further specific feature has been the tendency for muscles around the joints that sublux to go into disproportionate spasm. In spite of intensive physiotherapy tuition in the weeks before her wedding, she still had the
misfortune to sublux her right ankle on the wedding eve.
Comment: The subject illustrates the greater complexity of the management of
hypermobility that is disproportionately severe at certain joints. Whilst the widespread laxity at all joints of the body points to collagen structure as a cause, the
disproportionately severe hyperlaxity only at certain joints is almost certainly a feature of mild bony dysplasia. Moreover, it is the dysplastic joints that seem to prompt
the episodes of her presumed sympathetic dystrophy, though the tendency of these
patients to exhibit a widespread autonomic neuropathy may also be a predisposing
factor. Pharmacological management in her case has been complicated by the need
to use muscle relaxants to counteract the spasm that is typical of her dislocations but
only in doses that do not aggravate the laxity at other joints. When high doses of
muscle relaxants are unavoidable, temporary extra physical protection needs to be
provided for joints that will be aggravated.
Case 7.6:
Arnold–Chiari Malformation and Specialised
Physiotherapy
E.B., an American citizen and university lecturer, was first seen at the age of 24 years.
Her Beighton score was 5/9, and she conformed with criteria for hypermobility syndrome. Nevertheless, the skin was markedly hyperextensible at certain sites, particularly around the eyes, with a velvety texture raising the possibility of overlap with the
Ehlers–Danlos spectrum. Her joints had always been susceptible to subluxation,
though scars had healed well. Her periods had been controlled by the fitting of a
Mirena coil (a progestogen depot preparation), which she considered had not made
her joints worse. As a child in the USA, she had experienced headaches from the age
of 14 years. These were initially attributed to migraine, but following the development of more widespread neurological symptoms in the upper cervical core and later
around the base of the brain, a Chiari malformation was suspected and confirmed on
investigation. At the age of 19 years, neurosurgeons widened the foramen magnum
and performed a laminectomy at C1/C2, which improved the headaches and all the
Case 7.7:
The Performing Artist
121
symptoms that could be attributed to neurological compression at the foramen magnum. Investigations showed no syrinx in the lumbar area. At one point, bilateral
carpal tunnel and bilateral cubital syndromes were suspected but these resolved
spontaneously. After neurological decompression, as a good witness, she felt she
became more susceptible to fainting attacks. These also were investigated; tilt table
testing confirming a postural orthostatic tachycardia.
An interesting feature of the joint laxity was that whilst ‘cold’, and therefore at
conventional clinical examination, this was moderate with a Beighton score of 5/9.
After only a brief warm up with a little stretching, this became much more pronounced with a Beighton score of 9/9.
Further imaging showed that some 8 years after her surgical decompression, no
recurrence of the malformation had occurred. She had, however, recently experienced bowel symptoms of increasing severity attributed by the surgeons to intermittent intussusception, sometimes complicated by rectal prolapse, and she had also
experienced pelvic floor urinary tract symptoms for which she is currently being
investigated. Any pelvic floor repair, which is under consideration at present, will
need to attend both to bladder and bowels, possibly with surgeons working in
combination.
Comment: This case draws attention to the probable association between
Arnold–Chiari malformation and variants and patients where hypermobility is
indicative of certain types of EDS. This well-informed subject considered, as so
often occurs, that conventional physiotherapy practices barely helped her symptoms. She has controlled the flexibility of her joints, and the symptoms from them,
by an almost obsessive dedication to her hobby, which is the practice of Ashtanga
Yoga. As one of the most active variants of yoga, this combines elements of cardiovascular training, strengthening and the acquisition of flexibility. Whilst she feels it
is the flexibility that most relieves symptoms, the muscular control that is required
as a series of stretched asanas are built together into a sequence provides reassurance. The added complexity here has been the design of a programme that confers
no extra risk in the light of the previous neurosurgery. In turn, elements of conventional physiotherapy (stretching and strengthening) are combined in the form of a
hobby that is enjoyed and practised to a higher standard than might be achieved in
a conventional hospital physiotherapy department.
Case 7.7:
The Performing Artist
If the previous cases have dwelt on the disadvantages of hypermobility, this case
illustrates the potential advantage of the syndrome but also the need for its precise
specialised management. K.A. reached a clinic devoted to inherited complications
of connective tissue through the auspices of the British Association for Performing
Arts Medicine which had arranged onward referral in view of her musical prowess.
First seen when she was 25 years old, she had then relinquished her ambitions to be
either a professional musician or a professional dancer and, in a sea of despondency,
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had taken a job as a nursing care assistant where the strain placed on her joints was
making her more symptomatic.
As a child and adolescent, she had sought a variety of medical opinions in the
rural area where she lived, often to be given conflicting advice. Her pattern of joint
laxity was predominantly that of hyperflexible hips and dislocating shoulders,
though evidence of joint laxity was also present at other joints to the trained eye.
Her brother, who has not been seen, was probably not hyperlax, but a younger sister,
also not seen, has almost certainly had a degree of congenital dislocation of the hips.
There is a tradition in the family both of sporting prowess and excellence in the
performing arts.
As a child and adolescent, she excelled not only at dance (ballet and contemporary)
but also at music (cello and piano). She achieved at least regional standing with the
award of prizes and the offer of scholarships both in music and dance with the resultant dilemma of which to select. Conflicting advice was given but in view of the flexibility of the ankles and instability of the hips a ‘sensible’ decision was made to
concentrate on the cello, after which over the years her shoulders and the thoracic
spine became more symptomatic with a tendency for the shoulders to dislocate. When
the right (bowing) wrist became symptomatic, a well-intentioned orthopaedic operation was offered, shaving the bone at the ulnar styloid and rendering the wrist less
mobile, which made playing much more difficult. When first seen, x-rays of the spine
showed a mild S-shaped thoracic scoliosis within a superimposed corkscrew twist and
a convincing Schmorl’s node on MRI scan. The Schmorl’s node resulted in considerable local pain and muscular spasm necessitating the use of potent analgesics as well
as some muscle relaxants.
To date, further surgery has been avoided, a more suitable job has been found and
a home exercise programme with adaptations to computer and chair at the workplace have enabled the subject to embark on a career as a university administrator
with dancing relinquished and music teaching (piano, cello and theory) adopted as
a part-time evening hobby.
Comment: This case illustrates the complexity in advising and managing the
hypermobile performing artist, although equal prowess in dance and the playing of
an instrument and the need to choose between them is unusual (though not exceptional). The predominant factor here of restricting her career as a professional cellist
is probably the well-intentioned, though problematic, attempt at stabilisation of the
wrist, though the different mechanical functions to which the two subluxing shoulders are put in the playing of this particular instrument are also problematic. The
slight corkscrew twist in the spine can be an asset or liability according to whether
it is or is not in the direction of the slight angulatory movement required of the spine
as the artist rotates forward over the cello. Ironically, early career advice towards
dance rather than music might have been a safer option in pursuit of fame and excellence though this would be less sustainable as a hobby into old age.
References
123
References
1. Grahame R, Bird HA, Child A, et al. The revised (Brighton 1998) criteria for the diagnosis of
benign joint hypermobility syndrome (BJHS). J Rheumatol. 2000;27:1777-1779.
2. Keer R, Edwards-Fowler A, Mansi E. Management of the hypermobile adult. In: Keer R,
Grahame R, eds. Hypermobility Syndrome: Recognition and Management for Physiotherapists.
Edinburgh/London/New York: Butterworth Heinemann; 2003.
Chapter 8
Hypermobility in the Performing
Arts and Sport
Individuals endowed with hypermobility may excel in certain artistic occupations. The professional activities of dancers, contortionists, musicians and sportsmen are all influenced by their
range of joint movements. The wider implications of this situation are reviewed in this chapter.
8.1
8.1.1
Dancers
Are Ballet Dancers Born or Made
In the performance of their art, ballet dancers display impressive ranges of joint
movement, which are clearly beyond the ability of lesser mortals. How much of
this joint laxity is the result of painstaking regular training, often initiated in childhood, and how much is it due to an inherent laxity that may have acted in favour of
recruitment to dancing? The answer is almost certainly that both factors are
operative.
In order to test the hypothesis that generalised hypermobility may confer positive
advantage in the selection of would-be ballet dancers for training, a comparative study
of joint mobility was undertaken in 53 students attending the Royal Ballet School in
London and 53 student nurses at Guy’s Hospital.1 The results showed that, compared
with the nurses, the ballet students showed a significantly higher incidence of hypermobility of joints, not only of the spine, hips and ankles, which would be affected by
training, but also of joints such as the knee, elbow and wrist, which become unaesthetic in the hypermobile range (Fig. 8.1). Interestingly, 13% of the dancers but none
of the nurses knew of a first-degree relative who suffered from recurrent knee effusions (a known complication of hypermobility) supporting the concept that generalised hypermobility can be inherited.
There is evidence that over the age of 11–15 years, female dancers retain the
level of joint laxity that they enjoyed at an earlier age, while non-dancer controls
show a significant reduction in Beighton et al.2 hypermobility score over the same
period.3
125
126
8
Hypermobility in the Performing Arts and Sport
Fig. 8.1 Hyperflexion of the wrist and hyperextension
of the elbows produces an unaesthetic appearance
8.1.2
Is Generalised Joint Laxity an Asset or a Liability
in Ballet Dancing?
On the credit side is the increased facility for undertaking the spectacular range of
movement, notably of the spine, hips and ankles that is required of a ballet dancer.
In the tighter-jointed individual, this can be achieved only by dint of hard work,
usually with graded stretching exercises.
On the debit side, generalised laxity of ligaments can pose problems for the
dancer. Indeed, an enhanced range of movement may result in an unacceptable
appearance. This is seen, for example, in the so-called ‘swayback knee’ or genu
recurvatum (Fig. 8.2). However, even when gross, this can be corrected satisfactorily by careful voluntary muscular control (Fig. 8.3). Hyperlaxity of the tarsal joints
and the first tarsometatarsal joint of the great toe (Fig. 8.4) can create serious and
even disastrous problems when one attempts to dance ‘en pointe’. To a certain
extent, this lack of stability can be circumvented by improving muscular tone with
exercise therapy.
Hypermobile dancers are vulnerable to all the ailments to which loose-jointed
persons are susceptible, but because of the greater physical demands imposed by
ballet dancing they are at even greater risk.
8.1
Dancers
Fig. 8.2 The ‘swayback knee’
Fig. 8.3 The same knee corrected by
voluntary muscular control
127
128
8
Fig. 8.4 Instability of the
first metacarpophalangeal
joint precludes the possibility
of dancing ‘en pointe’
Not surprisingly, back, knee and foot complaints figure prominently amongst
hypermobile dancers, many of whom are forced to abandon their career
prematurely.4
Miller et al.5 compared the problems of the professional ballet dancer with those
of a vigorous athlete, and cited osteochondral fractures, fatigue fractures, sprains,
chronic ligamentous laxity of the knee, meniscal tears, degenerative arthritis of
multiple joints and low back pain as problems which were frequently
encountered.
In a systematic radiological survey of 28 members of the Cincinnati Ballet
Company, evidence of stress fractures was seen by the weight-bearing bones of the
lower limbs.6 These were recognised in the femoral necks, anterior aspects of the
mid-shafts of the tibiae and the lower half of the fibulae. In the feet, cortical thickening was present in the first, second or third metatarsal shafts in 23 out of 28 dancers
but there were no fractures.
A postal survey of injuries sustained in dancing, conducted throughout the USA
and some other countries, revealed that ligamentous injuries were by far the commonest lesions.7 These occurred in the knee, ankle and foot, in descending order of
frequency. Fractures constituted the second most frequent injury and the majority of
these were in the metatarsals and phalanges.
8.1
Dancers
129
Fig. 8.5 Radiograph of the foot of a ballet
dancer who complained of pain in the second right
metatarsal shaft. There is hypertrophy of the
cortex but no fracture
A hypermobility score of 4 or more by the Beighton et al. criteria was present in
36 (9.5%) of 377 ballet dancers studied by Klemp et al.8 Forward flexion correlated
significantly with the duration of dance training, indicating an acquired training
effect with regard to this movement, whilst the high prevalence of joint hypermobility in dancers’ families indicated a strong hereditary influence on generalised laxity.
Injuries were significantly more numerous in the hypermobile dancers than in the
non-hypermobile ones.
Scintigraphy has been used to bring to light stress lesions in dancers presenting
with pain and tenderness in the bones of the foot with normal appearance on radiography.9 Such a case is illustrated in Figs. 8.5 and 8.6, when little is shown on
conventional radiography, although there is increased uptake in the scan in an area
corresponding to the shaft of the second right metatarsal. This 16-year-old ballet
student had experienced pain in the affected region for the previous 18 months and
had been precluded from doing her pointe work. After a 3-month rest, her symptoms remitted and a repeat bone scan was normal. Similar findings have been
reported in athletes.10 If generalised joint laxity represents one aspect of a multisystem heritable connective tissue disorder, it is conceivable that fractures, at least in
some dancers, may be a further facet of the same problem.
Another factor favouring the development of fractures is osteoporosis associated
with oestrogen deficiency in adolescent female dancers with delayed menarche and/
or amenorrhoea.11,12 Such problems appear to be a combination of the degree of
exercise and self-imposed dietary deficiency.13
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8
Fig. 8.6 A scintiscan using technetium-99m
diphosphonate. Increased uptake of the isotope
on the region of the second right metatarsal is
indicative of a ‘stress lesion’ (Reproduced with
permission from Grahame et al.9)
8.1.3
The Prevention of Injury
Attention at dance schools has recently been directed to the screening of pupils and
the prevention of injury. Applicants with joint hyperlaxity may sometimes be recommended to undertake a course of strengthening exercises before commencing the
arduous routine inherent in professional dancing. Two recent articles have reviewed
the prevalence and treatment of injury with comments on perception of causes.14-16
Although factors such as being overtired, overworked, unsuitable flooring, inadequate warm-up and difficult choreography all figure as causes of injury, many of the
injuries described were those classically associated with hypermobile subjects. One
quarter of all injuries occur at the foot or ankle, problems of the patella dominating
knee complaints. Male dancers, with less laxity, have problems analogous to weight
lifters, such as acute and chronic back and shoulder injuries. Female dancers were
particularly susceptible to foot and ankle injuries, especially when these joints were
relatively lax. Overuse injuries figure as prominently amongst dancers as amongst
musicians. Imbalance or stress such as occurs between the plantar and dorsiflexors
of the feet17 is increasingly recognised as a factor predisposing to injury. A Swedish
study18 drew attention to the way in which poor training accounts for increased
musculoskeletal complaints amongst 147 professional dancers.
8.2
Contortionists
131
A spondylolysis and spondylolisthesis, both common associations with joint
hypermobility, are frequently found as causes of back pain in dancers. The incidence of spondylolysis in dancers has long been known to be four times that in
the general population19; although this is sometimes attributed to the increased
flexion extension inherent in dancers, an alternative explanation is that hyperlax
subjects, favoured at audition, already have such an abnormality. Oblique radiographs or computer tomography may demonstrate stress fractures.20 Trunk
strength as well as pilates exercises are helpful, and early diagnosis is important.
Spondylolisthesis is also common amongst dancers. A grade 1 spondylolisthesis
is not a contraindication to dance, and it is possible to dance with spondylolisthesis of even greater severity.
8.2
8.2.1
Contortionists
Historical Background
Contortionists were certainly active 4,000 years ago, as evidenced by an engraving
on the hilt of the sword, which now rests in a museum at Heraklion, on the island of
Crete. This depicts a lithe youth in the Palace of Knossos, balancing himself on the
tips of his toes and the crown of his head, which arched over the point of the blade.
Extreme joint laxity seems to have excited interest in many cultures.
During mediaeval times, contortionists performed in fairgrounds, attracting an
audience by their peculiar abilities. When a crowd gathered, their assistants would
sell patent remedies such as ‘slippery worm oil’, claiming that it was efficacious in
the treatment of sore and stiff joints. The contortionist’s performance was obvious
proof of the benefits to be obtained from regular applications of the oil! These acts
were the forerunners of America’s nineteenth-century travelling medicine show
wagons. Further information is available at ‘The Contortion Home Page’ at http://
contortionhomepage.com.
8.2.2
Nosology and Semantics
There has been much confusion in the past as to the differences, from a professional
point of view, between the ‘India Rubber Man’ and the ‘Elastic Lady’. Although
these terms were more or less interchangeable in the circus world, the India Rubber
Man was usually a joint-bending contortionist, while the Elastic Lady was a skinstretching exhibitionist. The elastic people could take hold of the skin of their face
or trunk and pull it out for several inches. On release, it would immediately spring
back to its former position. These individuals had Ehlers–Danlos syndrome (EDS),
which is a familial disorder of connective tissue (see Chap. 9). Articular hypermobility is also a feature of EDS, and the elastic people were therefore equipped to
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Fig. 8.7 A professional contortionist demonstrating her prowess (From Beighton71)
perform contortions. However, in view of their cutaneous fragility and unstable
joints, it is doubtful whether they indulged in this activity.
The contortionist’s act is centred around the ability to hyperextend or hyperflex the spine. In circus terminology, the performer is either a ‘front bender’ or
‘back bender’, and all the facets of the act are built on these movements. Many
contortionists have considerable athletic prowess, and they may be able to
indulge in such variations as placing their feet around their necks, whilst standing on one hand.
The forward bending is usually the ‘funny man’, as he can take up ludicrous
positions and perform amusing feats. In contrast, the backward bender or ‘posturer’ has a more serious act. The posturer is often an attractive young woman
who can perform speciality acts, or incorporate her abilities into a graceful
dance routine.
8.2.3
Training
Many contortionists develop their skills by rigorous training. This must begin in
childhood, and the French author, Guy de Maupassant, described how mountebanks
would steal children for this purpose. Legislation to preventing training of children
in Great Britain was enacted at the beginning of the present century.
Contortionists who have acquired their joint laxity by years of training must
practise for several hours each day, and even a week of inactivity will result in a
marked stiffening of the joints. In the same way, a long warming-up period is
required before the performance. However, some contortionists have inherent articular laxity, and these individuals are in a much more fortunate situation, as they
require very little in the way of training or warming-up. They are usually able to
perform forward and backward bending with equal facility, and inactivity does not
lead to loss of joint mobility (Figs. 8.7–8.9). On the other hand, their joints may be
unstable, and they may be unable to perform feats of strength. Although able to roll
up into a tiny ball, they cannot do this while balanced on their fingers! This type
of joint laxity is often a genetic trait, and these individuals may have familial
8.3 Musicians
133
Fig. 8.8 and Fig. 8.9 A contortionist with inherent
articular laxity is usually
able to perform forward
and backward bending with
equal facility (From
Beighton71)
hypermobility (see Chap. 9). The disorder is usually inherited as an autosomal dominant,
and a number of affected persons are members of well-known circus families.
8.2.4
Socio-medical Implications
It is a surprising fact that osteoarthritis does not seem to affect elderly contortionists, and indeed, many of them retain hypermobility in old age. Ferry the Frog could
still wrap his feet around his head at the age of 72 years, and he attributed his good
health to his professional activity. Dad Witlock was performing in an American
circus when he was 79 years old, and Norwood, the Flexible Fellow, retained much
of his flexibility in his 80s (Fig. 8.10).
Perhaps the secret of their continuing health is their good nature and their readiness to please other people. In the theatrical world, it is axiomatic that the ‘Elastic
Ladies’ are always prepared to stretch a point, while the ‘India Rubber’ people are
renowned for their willingness to bend over backwards to be of assistance!
8.3
Musicians
Manual dexterity is essential to the handling of many orchestral instruments, and
hypermobility may be an asset. Dancers and contortionists tend to use both halves
of the body equally. In musicians, the requirements of the instrument may dictate
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Fig. 8.10 ‘Norwood the Flexible Fellow’ a professional contortionist in the days of the music
halls
quite separate uses of the two sides; this is most pronounced in string players. Such
musicians act as their own control, adding interest to the study of this group of
players.
Nicolo Paganini (1778–1840) is frequently quoted as having extreme hand
hypermobility. Contemporary accounts describe his tall, thin frame and spider-like
features associated with a chest deformity and striking laxity of the hands, endowing
him with a technical prowess, which enabled him to play his difficult compositions.
Some have suggested that he had Marfan’s syndrome.
8.4
Occupational Ills of Instrumentalists
135
Attention has recently been directed to the increasing digital skill, particularly with
respect to the neglected fifth digit, that is inherent in the development of instrumental
music over the centuries as both instruments and techniques have become more complex.21 Unilateral laxity of one hand is particularly helpful in classical guitarists.22
It has recently been argued that several composer pianists, including Liszt and
Rachmaninov, were endowed with joint hypermobility in the hands, enabling them
to compose and then play their extremely difficult works. Plaster of Paris casts of
Liszt’s hands show them to be relatively large, and pupils of Rachmaninov who still
survive attest to the considerable lateral laxity of the middle fingers in his hands that
allow him to play stretched chords with great facility. Such chords figure prominently in his piano writing. It does not follow that a composer such as Mozart had
hypomobile hands – the technical limitations of the instrument of his time, together
with contemporary taste, also have influence on the final composition.
The laxity of hands has been determined in 650 individuals at a music school.
Hypermobility was found to be predominantly a female characteristic in this population. Age differences, as anticipated, were demonstrated. Attention was drawn to
the way in which hypermobility could affect only a small number of joints (or even
in a solitary joint), this pauci-articular hypermobility being more prevalent than the
generalised variety in musicians. Whether this was acquired as a result of musical
training or reflects selection of musicians by virtue of hyperlaxity in the hands
remains unanswered.23-25 Playing instruments can certainly cause music-related
upper limb pain,26 probably through overuse, though this study did not determine
whether the frequency of pain was specifically associated with joint hyperlaxity.
8.4
The spectrum of rheumatic complaints seen in a music clinic has been outlined in
considerable detail from several countries. Hochberg et al.27 describe their experience with 100 musicians presenting to an American clinic, and Fry28 describes patterns of overuse seen in 658 instrumental musicians, mainly from Australia. One
review based on the Eastman School of Music, University of Rochester, New York,
devotes particular attention to the influence of joint hypermobility on musical injuries.23 Additional reviews available include those by Hoppman and Patroni29,
Lambert30 and Greer and Panush.31
Ironically, musicians are not matched anatomically and physiologically to instruments at the start of their training. This means that some individuals devote many
years of practice to instruments for which they are anatomically unsuited. Inevitably,
when they come to pursue a professional career, musculoskeletal difficulties occur,
leading to much anxiety and sometimes loss of employment.
In woodwind players, the main difficulty is holding a relatively heavy instrument
(in the case of the oboe and clarinet) at a position of mechanical disadvantage for long
periods of time. This leads to musculoskeletal problems in the shoulders, and
difficulties can also occur with the mouth and lips. Pianists also develop bilateral
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8
problems concentrated at the wrists and the fingers. The span required between fingers
may be greater than the lesser spans required for the key systems of woodwind instruments, so hand hypermobility may be advantageous for pianists, particularly in interpretation of works of the late romantic era. Pianists with relatively stiff hands may be
advised to concentrate on earlier composers. With players of stringed instruments,
considerable differences in function are required between the two arms.
Players of the double bass and cello may also have back and seating problems,
particularly affecting the lower back muscles, whereas woodwind players need postural support of the upper body, particularly if the instrument is held sideways, as
with the flute. Particular problems are seen with cellists who have a slight curvature
of the spine, particularly if this is a corkscrew twist. The natural position for cello
playing requires a slight rotation towards the instrument. If a cellist has a slight
spinal rotation in the opposite direction, overuse problems often ensue. By contrast,
a slight spinal twist in the direction appropriate for the instrument confers advantages. Additional problems have been seen in classical cellists who convert to the
electric cello, which requires the use of a foot pedal. This can upset the alignment
of the spine, especially if there is a slight scoliotic twist prior to the transition.
For violin and viola players, one hand holds the bow and is subject to musculoskeletal strain, particularly at the shoulder and elbow. The other hand stops the strings,
so lateral laxity of the fingers may be advantageous, enabling the hand to span a long
distance on the sounding board. The greatest divergence of function occurs with the
guitar. The hand that plucks the strings has a relatively easy task. The hand that spans
the sounding board benefits from considerable hand hypermobility, the stretches
required being greater than those in the violin or viola. It is tempting to hypothesise
that in string players, especially those who have practised for many years, proprioception
might be enhanced in the left hand, the fingers of which require precise positioning on
the strings compared to the right hand where the function of the fingers is largely supportive of the bow with no great need for enhanced position sense. Studies of this sort,
using the Leeds Proprioceptometer (see Chap. 2), are in progress.
In the Rochester assessment of 660 individuals from a music school, musicians
were examined for laxity of the thumbs, fingers, elbows, spine and knees. Of these,
178 (27%) had one lax joint, and only 20 (3%) possessed all five features. The proportion of women to men displaying two features was 2:1, the ratios for the occurrence of
three, four and five features being 4:1, 8:1 and 3:1, respectively. Joint laxity declined
with age though not to a statistically significant degree. In males, the decline started in
the mid-20s, but in women, joint laxity persisted unaltered through the mid-40s. The
authors did not attempt a correlation of patterns of joint laxity with the playing of
individual instruments, so the question of whether the hyperlax individuals represented a normal occurrence within the population or whether they acquired their
hypermobility by regular training from an early age remains unanswered. The
Gaussian distribution of observed joint laxity was confirmed in this population.
Additional surveys of instrumental musicians with overuse syndromes and with
other musculoskeletal problems are available in the literature. Lederman and
Calabrese32 have reviewed overuse syndrome in instrumentalists as seen in American
musicians. Fry38 has described overuse syndrome in musicians as seen in Australia.
8.4
137
Fig. 8.11 The left wrist of
the guitarist exhibiting
traumatic synovitis
(Reproduced with permission
from Bird and Wright34)
His subsequent articles review patterns of overuse in 658 affected instrumental
musicians28 and treatment of overuse syndrome in 175 patients.33
8.4.1
Musicians attending a rheumatology clinic in Leeds fall into three main categories:
1. Those with hypermobility of the hands
2. Those with normal laxity of the hands but with overuse syndromes
3. Those who have acquired systemic rheumatic diseases but who still wish to
continue their playing
The overuse syndromes now account for the most referrals. Typical case histories
are presented from each of these three groups.
8.4.1.1
Hypermobility: Traumatic Synovitis in a Classical Guitarist
PD, a 31-year-old male, was a student of the classical guitar. He practised for up to
5 h each day for the last 10 years and was an advanced performer with a national
reputation. In June 1978, he noticed pain at the back of the left wrist associated with
swelling, exacerbated by practising the guitar. It was not present in the other hand,
and no other joints were involved. In December 1978, he sought the advice of his
general practitioner, and a cystic swelling on the dorsum of the left wrist was
ascribed to traumatic synovitis (Fig. 8.11). He considered himself to be
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8
‘double-jointed’ in comparison with other members of the class, and there was an
unusual degree of joint laxity present in both hands. In May 1979, he was seen in
the rheumatology clinic at Leeds. The swelling of the dorsal aspect of the left wrist
had persisted, but his symptoms were controlled by indomethacin 25 mg three times
daily. There was no early morning stiffness and no other symptoms apart from
possible intermittent swelling of some proximal interphalangeal joints.
His father had regarded himself as ‘double-jointed’, and a maternal aunt and
grandmother were both said to have had rheumatoid arthritis. Although his score for
generalised hypermobility was on 4/9, he had marked hypermobility in both hands.
There was no clinical evidence of rheumatoid disease at the metacarpal or metatarsal heads or at the ulna styloid. All other joints were normal. Routine haematological and serological investigations yielded normal results, and radiographs of the
hands and feet revealed no abnormality.
He was treated with a single local injection of steroid and a short period of rest.
This produced immediate and lasting improvement in spite of a subsequent return
to regular guitar practice. He had only minimal symptoms for a period of 2.5 years;
these did not require further steroid injections and were controlled by indomethacin
capsules, which were taken as required, two or three before a concert. He was then
lost from the clinic.
The apparent association between the patient’s joint laxity, his occupation and
the synovitis prompted study of other members of the guitar class.34 Details were
collected of age, sex and duration of guitar playing. Hyperextension of the metacarpophalangeal joint of the left index finger was measured by the Leeds Finger
Hyperextensometer (35; see Chap. 2) and assessment of the lateral laxity of the fingers made by eye and graded +, ++, +++. The finger hyperextensometer was also
used to assess laxity of the same joint in 100 normal people, drawn at random from
a Caucasian population.
The degree of joint laxity found in the other members of the guitar class
(11 male, 3 female) was in no instance as marked as in this particular individual.
Overall, the females exhibited slightly more laxity than did the males. Hand laxity
did not correlate with the duration of guitar playing, and the observations suggested
that hereditary factors were more important than regular training in producing the
observed laxity. Even when an allowance was made for the age differences, the only
member of the class who exhibited synovitis (PD) had by far the most striking laxity
in the hands. This was not only in an antero-posterior plane, but also in a lateral
plane. Indeed, PD was the only member of the class who could reasonably be
described as ‘double-jointed’.
It is of interest that guitar players overall have a lower degree of hyperextension
than normal members of the population. This possibly reflects their greater muscular control since studies on athletes confirm that the range of movement at other
joints in the body is reduced by regular athletic training (see below). In the case of
PD, there was a strong history of joint hypermobility on his father’s side of the
family and it seems that his hypermobility was inherited. Only the stretched hand
developed a synovitis and it is in this hand that he has had the majority of
musculoskeletal symptoms associated with benign hypermobility. Lateral instability
8.4
139
in the loaded joint may be the most important factor on the aetiology of traumatic
synovitis.
8.4.1.2
Overuse Syndromes: Synovial Trauma in a Violinist
PN, a 27-year-old violinist had performed to a high standard for almost 10 years,
often playing for up to 8 h a day. His symptoms had always been confined to the left
hand and wrist, and he attributed this to the greater stress placed upon this hand by
his playing. He did not consider himself to be ‘double-jointed’, and there was no
evidence of generalised joint hypermobility.
The history was of 4 weeks of pain in the left wrist, most pronounced when he
flexed the joint and accentuated by rapid finger work. Like many patients with overuse syndrome, he had identified a critical threshold above which symptoms occurred.
He had noticed that if he was able to rearrange his work schedule (which was difficult with his appointment) so that the critical threshold was never exceeded, the
symptoms abated over a period of a few days. Examination showed no general or
localised hypermobility, though there was a localised point on the extensor tendon
expansion over the left wrist at which pain could be reproduced.
A diagnosis of overuse syndrome was made, and the patient was advised to
immobilise the joint for 4 days. The symptoms disappeared, and this schedule was
then changed for a compromise between immobilisation and playing that did not
exceed the trigger threshold. The localisation of symptoms to one hand strongly
supports the mechanical aetiology of overuse syndrome. In many patients, chronicity develops and anxiety can exacerbate symptoms as well.
8.4.1.3
Acquired Systemic Disease: Generalised Osteoarthritis in a Violinist
Mrs. EM, aged 68 years, had been Leader (Concert Master) of a respected local
orchestra for 20 years. She played the violin regularly for 50 years and had also
taught this instrument.
There was a family history of progressive generalised osteoarthritis, and examination confirmed this diagnosis with the presence of Heberden’s nodes and typical
osteoarthritic deformity. There is no evidence of rheumatoid disease in the form of
muscle wasting, vasculitis, nodule formation or synovial proliferation. Nevertheless,
a remarkable degree of osteoarthritic deformity existed in her joints, possibly attributable to the additional mechanical insult of playing her instrument over many
years. She had never considered her hands to be hypermobile, though examination
confirmed the presence of an unusual degree of joint hypermobility for a 68-yearold woman. In part, this may be attributed to her earlier treatment with a small dose
of oral prednisolone.
Management has been with analgesics, anti-inflammatory agents and as required and
the occasional increase in the dose of prednisolone to enable her to perform well at an
important concert. Musicians are often of high intelligence, and it is remarkable how
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they learn to adapt their playing technique in the face of arthritic deformity. Even patients
with rheumatoid arthritis are often able to continue pursuing their musical hobby.
8.4.2
Repetitive Strain Syndrome
This accounts for most maladies experienced by musicians.36 It is characterised by
pain and loss of function in muscles and joint ligaments of the upper limb but can
affect other muscles, for example the mouth and soft palate in wind players.37
Physical signs of tenderness can often be elicited in affected structures, and the
condition is typically brought on by an increase in the duration and intensity of
practice or playing.38,39
Opinions vary on treatment, which ranges from absolute immobility at one
extreme to a more cautious approach integrating periods of rest with a gentle return
to playing.40 The syndrome has been a major cause of litigation in Australia.41
If the condition is mechanical in aetiology and if joint hypermobility behaves as
a graded trait with a Gaussian distribution throughout the population, research is
likely to be directed to seeking possible correlations between these two common
conditions. The anecdotal impression that repetitive playing of an instrument is
more likely to invoke discomfort in hands that are hypermobile, rather than nonhypermobile, is a strong one. There is also an impression that in violin players,
symptoms of repetitive strain are more likely to be present in the left hand, whether
this is dominant or non-dominant, compared to the right, reflecting the quite different hand function in the two arms.
It has been claimed that the repetitive strain syndrome is characterised by an increase
in type 1 muscle fibres and a decrease in type 2 fibres, with mitochondrial changes and
other ultrastructural abnormalities in a controlled study of muscle biopsy in this
condition.42 Overall, the frequency of this condition appears to be reducing particularly
in certain countries such as Australia where an apparent epidemic of 5 years ago was felt
partly to be attributable to the wide number of conditions, with vague definition, for
which industrial compensation was available. Musicians, unlikely to benefit from litigation in view of the parlous financial state of orchestras and music schools, do not illustrate such trends, and in general, the percentage of musicians experiencing overuse
syndromes such as repetitive strain disorder has remained relatively constant.
8.5
Sport
All sportspeople attest to the need for ‘flexibility’, a useful attribute, which is said by
coaches to improve performance in a wide variety of sports. There is a Gaussian distribution of ‘flexibility’ throughout the population and in sports; this natural variation
may be altered by regular training. A stiff person may become more supple but may
never reach the level achieved by individuals who have greater natural endowment.
8.5
Sport
141
The range of movement at any given joint depends upon a variety of actions,
including muscular tone, laxity of the ligaments and joint capsules and the shape of
bony contours. In the hip, for example, either acetabular dysplasia or ligamentous laxity may produce an abnormally wide range of movement. Individuals must be considered on their own merits according to their sport, and different joints within the same
person are likely to respond to different training programmes. For example, all the
best hurdlers may have a small degree of acetabular dysplasia, which enables them to
achieve the wide range of lateral movement at the hip joint that is required in this
sport. Regular training of the individual without this particular bone structure may
never achieve the range of movement required, no matter how much attention is given
to the factors which may be altered, such as muscle tone and ligamentous stretching.
In Eastern European countries, the selection of individuals who are suitable for
particular sports reached a high level of sophistication. Schoolchildren were screened
for their body attributes and directed into the sport in which they were most likely
to succeed. This selection was followed by a lengthy and detailed training programme at specialist state-subsidised schools.
The range of movement that can be achieved at joints varies not only between
persons but also between different joints in the same individual. ‘Flexibility’ may
not always be of value to the sportsperson. Joint hypermobility at the elbow, a feature deliberately sought on the Carter and Wilkinson43 scoring system, may be a
severe disadvantage to a gymnast who has to stand on his or her hands. The elbows
may give way under the weight of the body, and regular training is required to
increase the muscle tone around the elbow joint in order to achieve stabilisation.
Similarly, hyperextension of the knee joint, a feature also sought in the Carter and
Wilkinson scoring system, places runners at a disadvantage, particularly when running downhill. Conversely, the ability to hyperextend the knee confers a mechanical
advantage in uphill running.
The virtue of evaluating joint laxity in sport is to enable individuals to be directed
towards the sport for which their joints are most suited. Thereafter, where necessary,
training programmes should be directed at improving the performance of the joints
in terms of the requirements of that particular sport. This may involve either inducing hypermobility in a stiff person or stabilising laxity in an individual who is initially too supple. Certain sports where hypermobility is especially relevant, or to
which the author’s attention has been directed, are reviewed below.
8.5.1
Joint Hypermobility in Selected Sports
Gymnasts have much in common with ballet and hypermobility would at first sight
be deemed an advantage. A wide range of movement at the lumbar spine, hips and
shoulders is required. Although parts of women’s gymnastics place emphasis on
suppleness at many joints, marks are also rewarded for tumbling which requires
considerable momentum of a stable body. Instability of the elbows would be a
disadvantage in performing a handstand, and strength is needed in the sub-sport of
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8
acrobatics where human pyramids are built. Gymnastics coaches prefer a relatively
stiff newcomer to a novice who is too supple. Appreciation of each individual’s
attributes is required. Thus, the ‘crab’ or backbend position can be achieved in several ways. Provided that a total sum of 180° of hyperextension is achieved, the
precise joints that hyperextend can be varied according to the individual’s ability.
Some will hyperextend the back; others will compensate for a stiff back with hyperextension of the shoulders and hips.44 It has been suggested that idiopathic scoliosis
may be more frequently encountered in gymnasts than in other sportspersons and
that, in turn, a degree of hypermobility that might be beneficial in gymnastics has
actually predisposed to the presence of a scoliosis.45
Swimmers are aware of the beneficial effects of practising in warm water,
which enhances the range of movement at joints. Many swimmers cite a particular
stroke as their preferred one and this is often based upon anatomical attributes.
Thus, the butterfly stroke requires the greatest flexibility of all at the shoulders,
though considerable strength as well and is tiring, requiring power in the legs. The
back stroke requires slightly less (though still substantial) flexibility in the shoulders and is less tiring on the body. The crawl (freestyle) occupies an intermediate
position requiring only modest flexibility of the shoulders and reasonable strength
in the legs. For these reasons, it is the most popular stroke and most frequently
encountered. The breaststroke is compatible with relative stiffness in the shoulders but requires substantial flexibility in the hips and knees to adopt the ‘frog’
position that is required for it. Diving combines the attributes of swimming and
gymnastics46 especially from the highest board.
In athletics, a small physique is suited to long-distance running whereas the taller
individual will excel at the long jump. For high jumping and hurdling, flexibility of
the spine and hip, respectively, may be advantageous. Javelin throwers need flexibility at the shoulder.
Racquet sports require flexibility of the shoulder, though neuromuscular
co-ordination with good reflexes and good eyesight may be more important attributes in the selection of students.
In team sports such as soccer, rugby and hockey, joint hypermobility will not
contribute extensively to the individual’s sporting performance, though it may influence the pattern of sports injuries the player is likely to sustain. The same applies to
cricket, though laxity of the fingers may help spin bowlers to impart a greater rotation on the ball as it leaves the hand.
Work from Leeds47 quantified the range of joint movement using hydrogoniometry
at a wide selection of joints in an athletic population selected for joint hyperlaxity.
This included gymnasts competing at national club level, divers and dancers as well
as non-specialised physical education students who acted as controls. The greater laxity of females in youth was confirmed and the influence of training recorded. A graded
increase in laxity from controls through novice gymnasts, divers, dancers, to competitive
gymnasts was observed in that order. A group of patients recruited because of their
symptoms had an even higher degree of laxity recorded on a Carter and Wilkinson
scale as measured by a postal questionnaire.
8.5
Sport
8.5.2
143
Joint Hypermobility in Cricket
If a single sport were to be selected as being most closely entwined with hypermobility, it would probably be cricket with the arm actions required of the bowlers.
It also provides an interesting example of inter-ethnic aptitude. In general, the
elbows, wrists and fingers of Caucasians are relatively inflexible. Genetic mutation
would probably be required to give them the prowess enjoyed by competing ethnic
groups. As might be expected, West Indians of Afro-Caribbean descent tend to have
a little more hyperlaxity than their Caucasian competitors (see Chap. 2).
Asymptomatic hypermobility, especially of the fingers, seems to be a trait of
individuals from the Indian subcontinent, particularly the southern part, which probably accounts for the prowess of spin bowlers from India. Lateral laxity of the fingers is required both to hold the ball and to impart the spin. If strength is acquired
in the index and ring fingers, the ball can be held between the two, the middle finger
depressed such that not only is the ball spun but also it is virtually impossible for the
batsman to read the direction of the spin procured (The Doosra).
By contrast, anatomical variation in the elbow, arguably particularly pronounced
in the northern part of the Indian subcontinent (characterised politically as Pakistan),
has led to attempts to rewrite the rules of cricket. If natural hyperextension of the
elbow occurs in fast bowlers, the force of the action will cause the hyperextension
to be pronounced, leading to the criticism of ‘throwing’. This is clearly a quirk of
natural selection in individuals so endowed and would therefore not necessarily
carry any implication of cheating.
The philosophy of whether extreme natural selection is compatible with ‘fair
play’ also intrigues. Much ink has been spilt on the importance of chromosome
testing in athletes with the implication that the resultant differential concentration of
male and female sex hormones might confer unfair advantage. By contrast, AfroCaribbeans, with their explosive power in sprint events or hyperlaxity of the spine
conferring an advantage in tall, thin, high jumpers, would not attract such criticism.
The distinction between selecting individuals for sports deliberately by virtue of
their anatomical endowment and then implying that this confers unfair advantage,
analogous to cheating, would seem to be a fine one.
8.5.3
Joint Hypermobility in Yoga
Although not strictly a sport, yoga also raises intriguing issues both ethnic and
therapeutic. That yoga may have originated on the Indian subcontinent where
individuals are often endowed with asymptomatic hyperlaxity may not have arisen
by chance. Legend sometimes has it that those who devoted unlimited time to
religious practices had ample time to refine the art form.
Philosophical implications apart, there exists a wide variety in the anatomical
and physiological requirements for each of the many yoga styles. At one extreme
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are the philosophical variants where time is spent observing a candle burn, which
may in itself provide relaxation analogous to cognitive behavioural therapy that
has sometimes been claimed to be helpful in the management of hypermobility
syndromes. At the opposite extreme are the severely physical, even acrobatic,
types of yoga with Ashtangar yoga as the most obvious example. A little less
severe than Ashtangar and concentrating deliberately on an exact balance of agonist and antagonist movements around a given joint is Miyengar yoga. All have
their advocates, not least in the treatment of hypermobility syndromes.
This raises the extent to which yoga is beneficial in hypermobility and, indirectly, whether physiotherapy routines should concentrate on strengthening or
stretching or aim to combine both. This last is probably the most appropriate, and
discussion with yoga teachers attending or assisting in our own clinics devoted to
hypermobile patients suggests that a combination of two-thirds strengthening and
one-third stretching may well be optimum for patients, though there is considerable
variation between individuals and ideally a programme should be tailor-made to the
attributes of each individual set of joints.
8.6
Hypermobility and Injury
Injuries rarely occur in yoga but are more frequently seen in competitive contact
sports such as American football. In one large study,48 American footballers were
divided into ‘stiff-jointed’ and ‘loose-jointed’ individuals. The former were particularly susceptible to tearing injuries, and the latter were susceptible to stretching injuries. Physiotherapy programmes and training schedules were modified
accordingly so that hypermobile joints were stabilised by enhanced muscle power.
The injury rate declined. These general findings have been confirmed whenever
other sports are studied.
Although injury patterns in gymnasts follow this general rule,44 most injuries
result from falls or even from faulty apparatus rather than from joint hypermobility.49 In a study to determine whether injury-prone gymnasts could be identified using simple test procedures, 22 with relatively high body weight were
found to be most susceptible to injury. As a result, an injury score that could be
applied to trainee gymnasts in the field was devised. Of the injuries, 70% could
be predicted from consideration of weight, height, mesomorphy, lumbar posture
and age.50 That ligamentous laxity makes a relatively minor contribution to
injury is confirmed in a study in which 166 American footballers and 116 basketball players were compared to 400 normal age-matched subjects not involved
in interscholastic sports. No correlation could be found between ligamentous
laxity and the occurrence or type of injury.51 With renewed social interest in
keep-fit programmes, it should be recalled that individuals who are unaccustomed to regular training develop rheumatic symptoms, particularly in hypermobile joints, after performing ‘aerobics’.52 Knee injuries have been the subject
of research. A physiological study to examine the hypothesis that excessive
training of the knees by exercises led to acquired increased ligamentous laxity
8.6 Hypermobility and Injury
145
that might predispose to injury showed a significant increase in joint laxity
(p = 0.02) after an appropriate exercise programme.53 Females may be particularly susceptible in view of the increased knee joint laxity inherent in a normal
female population. It has been argued that female athletes may be better protected by vigorous training regimes, and the degree of potential knee laxity
should be considered when females are selected for serious training in different
sports.54 In a study of basketball-related injuries in 76 females, the knee was the
most common site of injury and anterior cruciate ligament rupture accounted for
25% of all injuries seen. This injury was more common in female than in male
basketball players, and joint laxity, along with a weak quadriceps mechanism,
player position and hormonal background were postulated as reasons for the
difference between sexes.55 Joint laxity has also contributed to injuries at a variety of joints in soccer players.56
The role of knee meniscus injury also merits attention. Medial meniscectomy
often predisposes to osteoarthritis.57,58 Whether this is because the operation leads
to altered joint mechanics, or whether individuals who require operation already
display a genetic susceptibility to osteoarthritis mediated by the presence of faulty
collagen that causes the initial damage, is not clear. In a radiological survey of
physical education teachers, premature osteoarthritis was not seen significantly
more frequently than in an age-matched control population but, on the odd occasion when it occurred, usually after meniscectomy, it was severe in the physical
educationalists.59 When stress radiography for antero-posterior mobility of the
knees was performed on 17 patients who had undergone medial meniscectomy and
10 patients who had undergone later meniscectomy, an increase in varus mobility
following medial meniscectomy was primarily attributed to compression of the
medial compartment space. Anterior and total antero-posterior mobility were bilaterally greater in patients with medial meniscectomy compared with lateral meniscectomy and were also greater than values obtained with 28 normal knees. On this
evidence, the biomechanical joint laxity induced by the operation may be the greatest risk factor, and individuals who already have hyperlax joints might benefit from
counselling prior to operation and more intensive physiotherapy after it.60
A graded exercise programme, individualised for each subject, providing
strengthening exercises around joints that were particularly lax and providing
stretching exercises around joints that were particularly stiff has been shown to be
effective in improving performance. This stabilisation of hypermobile joints, in
particular, was pronounced and maintained using the standard method favoured
by sports physiologists advising sporting coaches.47
8.6.1
Training Methods to Improve Joint Flexibility
It may be advantageous for the athlete and coach to increase the range of joint
movement. A variety of methods have been validated for this. Massage and
warming-up are beneficial61, and static stretching exercises and stationary
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8
cycling both proved equally effective in increasing the range of movement of
the hip joint, retaining the increase for a 15-min period in a controlled environment.62 Stretching by jogging is less helpful in increasing mobility than simple
stretching exercises.63
One of the most effective methods of enhancing the range of joint movement is
proprioceptive neuromuscular facilitation (PNF). This hypothetically induces
relaxation of the muscle to be stretched through spinal reflexes.64,65 Studies show
that a static contraction preceding muscle stretch facilitates stretching activity
through lingering after discharge in the afferent limb of the stretch reflex. A muscle is initially more resistant to change in length after a static contraction. In an
electromyographic investigation of muscle stretching techniques in which static,
contraction/relaxation cycles and PNF were compared in 21 female gymnasts,
hamstring stretch produced the greatest increase in range of joint movement and
was associated with significantly greater hamstring length.66 Although the efficacy of PNF is not doubted, the long-term risk of its use on muscles and ligaments, if any, still has to be determined. Experience from North America, where
the method has been used for many years and where the results of its use are well
documented, does not at present cause undue anxiety.
A small pilot study in which plain stretching, ballistic stretching and PNF were
compared in a group of medical students who were amateur dancers suggests that
both ballistic stretching and PNF are superior to ordinary passive stretching in procuring extra flexibility. However, since the benefits from PNF, although most pronounced, were also normally short-lived, ballistic stretching under appropriate
careful supervision was judged to be the most effective. This would also conform
with the view of many sports coaches.
More comprehensive details of the many methods available for improving the
range of joint movement for athlete pursuits are to be found elsewhere.67,68
8.6.2
Hormonal Aspects
That dancers and, perhaps, other sportspersons for whom a small frame is considered advantageous might also have implications in relation to hypermobility is
something that has not so far attracted much attention. In the management of
hypermobility syndromes, evidence is accumulating that progestogens tend to
make previous asymptomatic hypermobile joints symptomatic, while oestrogens
tend to stabilise and reduce symptoms. With menarche sometimes delayed in the
case of dancers and young female gymnasts, there may be implications for joint
laxity as well as for bone strength. In the case of male football players, maturity,
defined as the difference between chronological age and skeletal age, plus training
and playing hours, together in a formula, predict injury in schoolboy footballers 69.
Joint mobility was not measured in this study but may also have contributed.
Epidemiologically, the ratio of finger length between the second and fourth fingers has been championed as a predictor of sporting prowess in females.70 The
References
147
reason is unclear and probably depends upon the diverse gender and hormonal
related traits, including cognitive ability, disease susceptibility and sexuality.
A relationship with testosterone has also been postulated, perhaps influencing
joint laxity, as well as muscular strength.
Clearly, a variety of factors may have relevance of which joint laxity is only one.
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5. Miller EH, Schneider HJ, Bronson JL, McLain D. A new consideration in athletic injuries. The
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29. Hoppmann RA, Patrone NA. A review of musculoskeletal problems in instrumental musicians.
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58. Tapper EM, Hoover NW. Late results after meniscectomy. J Bone Joint Surg Am. 1969;51:
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59. Bird HA, Hudson A, Eastmond CJ, Wright V. Joint laxity and osteoarthrosis: a radiological
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Chapter 9
Heritable Hypermobility Syndromes
The heritable hypermobility syndromes are a group of disorders in which joint
laxity is a prominent feature. In some of these conditions, the loose joints predispose to a wide variety of articular complications and, despite their rarity, they are of
considerable rheumatological importance.
The best-known disorders of this type are Ehlers–Danlos syndrome (EDS) and
Familial Articular Hypermobility syndrome (FAHS). Joint laxity is also a feature of
several inherited connective tissue disorders, such as Marfan syndrome and osteogenesis imperfecta, together with certain dwarfing skeletal dysplasias and other
genetic entities. These conditions are reviewed here from the rheumatological standpoint, and a selective bibliography is provided.
9.1
Ehlers–Danlos Syndrome
The Ehlers–Danlos syndrome is an inherited disorder of connective tissue which is
characterised by the clinical triad of articular hypermobility, dermal extensibility
and cutaneous scarring.1,2 The manifestations are very variable, although usually
fairly consistent within any kindred, and it has become increasingly evident that the
EDS is very heterogeneous.
The joint laxity in EDS leads to a wide variety of rheumatological complications
which are outlined in this chapter. Detailed accounts of the condition can be found
in the following books:
The Ehlers-Danlos Syndrome, Beighton (1970)3
McKusick’s Heritable Disorders of Connective Tissue, Beighton (1993)4
Connective Tissue and Its Heritable Disorders, Royce and Steinmann (1993)5
Articles in the online GeneReviews series, which are regularly updated, provide
expert overviews of the various forms of the EDS.
151
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9
EDS Classic Type (Wenstrup and De Paepe 2008)6
EDS Hypermobility Type (Levy 2007)7
EDS Vascular Type (Pepin and Byers 2006)8
EDS Kyphoscoliotic Type (Yeowell and Steinmann 2008)9
EDS is of topical interest because of the protean nature of its clinical complications, the unfolding heterogeneity and the ongoing elucidation of the biomolecular
determinants. The level of attention that is being given to the EDS can be obtained
from the fact that in 1991, the world literature concerning the condition comprised
about 500 articles. By 2009, this figure had risen to over 1500. In 1966, the combined population frequency of all forms of the EDS in southern England was estimated at about 1 in 150,000, while the current estimates for the USA are as high as
1 in 5,000. The latter figure is indicative of increasing awareness of the condition,
together with diagnostic accuracy and medical interest. The development of lay
associations for affected families, the availability of information on the internet and
the establishment of dedicated Hypermobility clinics are other relevant factors.
9.1.1
General Features
There is considerable variation in the extent to which individuals may be affected by
EDS, and the clinical manifestations and complications are by no means consistent.
Nevertheless, the components of the diagnostic triad of extensible skin, loose joints
and fragile tissues are always present in some degree (Figs. 9.1–9.3).
The skin splits on minor trauma, forming gaping lacerations. These heal slowly
and wide papyraceous scars develop which are often darkly pigmented and are typically found over the knees and elbows. Raisin-like swellings known as molluscoid
pseudotumours are present in scarred areas and hard calcified subcutaneous spheroids may be palpated in the forearms and shins.
The joint laxity predisposes to instability, sprains, subluxations and dislocations.
Pes planus and hallux valgus are frequent, while spinal malalignment is a less common complication. Limb and joint pains of uncertain pathogenesis are an inconsistent but important problem.
Complications are encountered in virtually every system of the body; these have a
common basis in connective tissue extensibility and fragility. In the minority of
affected persons with the Vascular form (previously EDS IV), sudden death can occur
from rupture of large arteries, dissection of the aorta or gastrointestinal perforation
and bleeding.
9.1.2
Nosology
Heterogeneity was initially suspected on clinical and genetic grounds.10,11
Further delineation was achieved by the recognition of the basic biochemical
9.1 Ehlers–Danlos Syndrome
153
Fig. 9.1 Dermal extensibility is a
prominent feature of EDS. On release,
the skin springs back to take up its
former position (From Beighton3)
Fig. 9.2 Thin pigmented scars over the bony prominences result from trivial trauma (From
Beighton3)
154
9
Fig. 9.3 Articular hypermobility is variable in
degree, but often very marked (From Beighton3)
abnormality in some affected individuals and nine major forms of EDS were
eventually proposed. A nomenclature and subclassification of EDS, together
with information concerning the mode of inheritance, was subsequently promulgated as the ‘Berlin Nosology’.11a
The continuing elucidation of biochemical and molecular defects and the widening of clinical experience soon necessitated expansion.12 In 1997, a new version of
the Nosology was compiled at Villefranche-sur-Mer, France, under the auspices of
the Ehlers-Danlos Support Group (UK) and the Ehlers-Danlos National Foundation,
USA.12 This simplified version, which listed six major types of the EDS, is presented in Chap. 1.
It has emerged that about 50% of families with the comparatively common EDS
types I and II have defects of the proa1 or proa2 chains of type V collagen determined
by the COL5A1 and COL5A2 genes; these conditions are now lumped together as the
‘Classic’ type of the EDS. The former EDS III is retained as the ‘Hypermobility’ type,
in which the basic defect is still unknown, although the glycoprotein tenascin-X has
been implicated in a few instances.13 EDS IV, in which type III collagen is defective,
is now codified as the ‘Vascular’ type. The uncommon EDS VI, previously known as
the ‘Ocular’ or ‘Scoliosis’ form, is characterised by major spinal problems, while the
eyes are often normal. For this reason, it is now termed the ‘Kyphoscoliosis’ type; the
basic defect is deficiency of the collagen-modifying enzyme, lysyl oxidase.
The former EDS VII was an incompletely delineated category, which has
now been subdivided on a biomolecular basis. The new ‘Arthrochalasia’ type
is an autosomal dominant condition with predominant joint laxity and extensible skin which results from a defect in type I procollagen, due to a skipping
mutation of exon 6 in the COL1A1 gene. The other former component of EDS
VII, an autosomal recessive disorder with skin laxity and fragility which is
now termed the ‘Dermatosporaxis’ type, is the consequence of deficiency of
155
procollagen 1 N -terminal peptidase in collagen type I. The clinical manifestations of these two rare entities are very disparate.
The former EDS V, VIII and X are now regarded as private syndromes or of doubtful syndromic status, while EDS IX and XI have been reclassified. Further discussion
is outside the scope of this review but details of the biomolecular defects in the EDS
can be found in Chap. 3 and in articles referenced at the end of this chapter.
In clinical practice, the majority of affected persons have the Classical type of EDS
(formerly EDS I gravis and II mitis). Another large group of individuals have the
Hypermobility type (formerly EDS III) and as discussed elsewhere, this category is
frequently overdiagnosed. In the uncommon potentially lethal Vascular type (formerly
EDS IV), the propensity for arterial and bowel rupture overshadows the other conventional syndromic manifestations. The remaining forms of the EDS are rare.
9.1.3
Diagnostic Considerations
The initial diagnosis of the various forms of the EDS is usually made on a basis of
the clinical manifestations and pedigree data. It must be emphasized, however, that
there is considerable phenotypic overlap and precise categorisation is often very
difficult. In these circumstances, it may be possible to obtain an objective diagnosis
by biochemical studies involving cultured fibroblasts or by molecular investigations. Histological and electron microscopical investigations of skin biopsy specimens yield conflicting results and they are not of great diagnostic value.
A firm diagnosis facilitates accurate prognostication and meaningful genetic
counselling. Related issues such as prenatal diagnosis, pre-implantation diagnosis
and carrier detection may arise, and in these situations, the identification of a specific mutation by molecular techniques is necessary. The banking of DNA for future
studies is another issue which warrants consideration. In view of the increasing
sophistication of laboratory technology and the rapid accumulation of knowledge, it
is anticipated that routine molecular genetic testing in the EDS will be increasingly
available.
The practical implications of the common forms of the EDS and the current
status of biomolecular testing in these conditions are summarised below:
1. Classical form (OMIM 130000:130015)
The Classical form of the EDS is the archetype of the disorder and affected persons have the characteristic skin and articular features in greater or lesser degree.
Autosomal dominant inheritance is well established and large affected families
have been documented. The geographical distribution is wide and a population
prevalence of 1 in 20,000 has been estimated for the USA.
In the premolecular era, the electron microscopical ‘cauliflower’ configuration of
collagen fibrils in skin biopsy specimens was used as a diagnostic indicator. These
changes have proved to be inconsistent, and this test has fallen into disuse. Biochemical
investigations are unhelpful but molecular studies have proved to be of value.
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9
Mutations in the COL5A1 gene identified by sequence analysis are present in
about 45% of affected families and in the COL5A2 gene in 5% of families.14-16 In
the remainder, the determinant genes have not been identified.17 In clinical practice, molecular investigations for the COL5A1 and COL5A2 genes are widely
available in Europe and the USA.
2. Hypermobility form (OMIM 130020)
Articular laxity in the absence of other syndromic manifestations is a common
problem in the rheumatological setting. In this situation, diagnostic distinction
between the Hypermobility form of the EDS, the Familial Articular Hypermobility
syndrome and persons at the end of the normal spectrum of joint mobility can be
a difficult matter.17a
The molecular basis of the Hypermobility form is the focus of considerable current interest. The usual mode of inheritance is autosomal dominant, but in a rare
autosomal recessive variety, deficiency of the glycoprotein tenascin-X encoded by
the TNXB gene at the chromosomal locus 6p21.3 has been implicated.18,19 Some
heterozygotes in an affected family had joint laxity.20 In a separate group of 80
sporadic persons with joint laxity, 6 had deficiency of tenascin-X and the corresponding gene mutation was identified in 2 of them.21 These observations have
considerable potential implications for diagnostic categorization, but it must be
emphasized that at the present time, tenascin deficiency has been detected in only
a very small minority of persons with articular laxity. These tests are not currently
available on a routine basis.
3. Vascular form (OMIM 1300500)
The potentially lethal Vascular form of the EDS is uncommon, and a population
prevalence of about 1 in 250,000 has been estimated for the USA. Despite this low
frequency, reports of dramatic arterial and visceral complications and their management predominate in the literature. The surgical management of spontaneous bowel
perforation was discussed by Fuchs and Fisherman.22 and Hawk et al.23 The occurrence of spontaneous carotid cavernous fistulae was reviewed by Chuman et al. and
the surgical management of this complication was outlined by Hollands et al.24
Naidu et al.25 reported percutaneous embolisation of a lumbar pseudoaneurysm. The hazards of surgical intervention have been emphasised by Freeman
et al.26 and Oderich et al.27 and a review of 400 affected persons provided objective information concerning the natural history of the condition.28
In view of the unfavourable prognosis, diagnostic confirmation in the Vascular
form is routinely obtained by biomolecular investigations on blood or skin biopsy
specimens. The conventional approach is biochemical demonstration of abnormal type III collagen in proteins synthesised in cultured skin fibroblasts, followed by molecular analysis of the COL3A1 gene.29,30 These tests are readily
available in Europe and North America.
4. Kyphoscoliotic form (OMIM 225400)
The autosomal recessive Kyphoscoliotic form of the EDS is most often encountered in Greece, Turkey and the Middle East, and it is uncommon in Western
Europe and the USA. The condition resembles the Classic form of the EDS
with the additional features of a propensity to early onset progressive
157
kyphoscoliosis, arterial rupture and occasional spontaneous perforation of the
ocular sclera.
The diagnosis is made by biochemical assessment of the activity of the enzyme
lysyl hydroxylase I indirectly in urine specimens31 or directly in cultured fibroblasts.32 Determinant mutations in the PLOD-1 gene at the locus 1p36.3–p36.2 can
be identified by molecular sequencing or deletion-duplication analysis.33 Diagnostic
confirmation and gene carrier detection is available in specialised laboratories.
9.1.4
Rare Forms of the EDS
For the sake of completion, rare forms of the EDS are summarised below. These
conditions are unlikely to be encountered in routine rheumatological practice.
9.1.4.1
EDS Arthrochalasis Type (Formerly EDS VIIA and B)
Congenital dislocation of the hip is a presenting feature of this rare autosomal dominant form of the EDS. Skin extensibility, a mild scarring propensity and marked
articular laxity are other manifestations.34 Mutations in the COL1A1 or COL1A2
genes underlie mRNA deletions of exon 6. Investigation of collagen fibril ultrastructure may be of diagnostic value.35
9.1.4.2
EDS Dermatosparaxis Type (Formerly EDS VIIC)
Skin fragility and laxity are the major manifestations of this autosomal recessive condition. Joint laxity is minimal but short stature, stubby digits and blue sclerae are syndromic concomitants. Activity of the enzyme procollagen-N-proteinase is deficient.36
9.1.4.3
EDS Progeroid Type
In addition to joint laxity and dermal extensibility, affected persons have an aged
appearance, with thin wrinkled skin and fine hair. The basic defect in this rare autosomal recessive disorder is defective activity of galactose transferase 7 due to
homozygosity for mutations in the B4GALTZ gene.
9.1.4.4
EDS Cardiac Valvular Type
In this autosomal recessive disorder, the manifestations of the Classic form of the
EDS are accompanied by significant abnormalities of the valves of the heart.
Mutations in COL1A2 gene have been implicated.37
158
9.1.4.5
9
Classic EDS with Arterial Rupture
A few individuals with the Classic EDS phenotype plus a propensity to arterial
rupture have been documented.38 This autosomal dominant disorder results from a
mutation in the COL1A1 gene.
9.1.4.6
Spondylocheiro Dysplastic form of the EDS
This unusual autosomal recessive entity is the consequence of homozygosity for
mutations in the zinc transporter gene SLC39A13.39
9.1.4.7
EDS: Osteogenesis Imperfecta phenotype
There have been a few reports of persons with a combined EDS-Osteogenesis
Imperfecta phenotype. The basic defect has been documented as partial duplication
of the COL1A2 gene,40 and as a specific cysteine substitution in type I collagen.41
9.1.4.8
Occipital Horn Syndrome (Formerly EDS IX)
This X-linked disorder is no longer classified as a form of the EDS, but it is included
in this section for the sake of completion. It is characterised by articular hypermobility, and skin which is lax but not fragile. Palpable occipital protuberances or
‘horns’ are a pathognomonic feature. Diagnosis is confirmed by biochemical detection of disordered copper transportation.
9.1.5
Articular Manifestations
Hypermobility of the joints is a cardinal manifestation of EDS and articular problems
are frequently encountered. The complications which were present in a series of 100
patients of all ages have been reviewed.42 The majority of these individuals had the
former EDS I and II, which are now grouped together as the Classical type.
The general implications of articular laxity are similar in the various forms of the
EDS. The Classical and Hypermobility types are by far the most common in rheumatological practice, and the details set out below pertain to either. In general, these
facts also hold true for the other rarer forms of the EDS in which the joints are lax,
and for the Familial Articular Hypermobility Syndrome.
9.1.5.1
Disclocations
The degree of articular hypermobility and the incidence of dislocations are closely related,
although in some persons a surprising range of joint movement can occur without causing
159
Fig. 9.4 In some persons with EDS,
articular laxity may be extreme and it is
not surprising that a large variety of
musculoskeletal complications may
occur
clinical problems. The joints most frequently affected are those of the digits, elbows,
shoulders and patella, while dislocation of the sternoclavicular joints has also been
recorded. Congenital dislocation of the hips is well documented but infrequent.43 Recurrent
temporomandibular joint subluxations are more common than previously supposed.44,45
Dislocations are often recurrent and may be spontaneous, but reduction is usually easy and often spontaneous, particularly in the digital and shoulder joints.
The degree of hypermobility and the incidence of dislocations often lessen with
ageing although musculoskeletal disability does not usually decrease.
9.1.5.2
Joint Instability
The more hypermobile persons are frequently troubled by instability of the joints,
particularly the ankles and knees (Figs. 9.4 and 9.5). For this reason, such activities
as running or the wearing of high heels may be impossible. Instability of the finger
joints may also be a problem and simple actions such as typing or unscrewing bottle
tops can be very difficult.
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9
Fig. 9.5 An affected girl with instability of the knee
and ankle. Her shins bear the characteristic scars
It must be stressed that not all affected individuals have articular problems.
Amongst persons known to have EDS were a racing cyclist, a weight-lifter and an
amateur boxing champion. The implications for athletic activity in individuals with
the EDS have been reviewed by Schroeder and Lavallee.46
9.1.5.3
Joint Effusions
Persistent or recurrent effusions are commonly encountered. The usual site is the
knee joint, but the ankles, elbows and digits may also be affected. These effusions
are related to activity and often appear at the end of the day. Haemarthroses may
occur in a minority of patients in whom the bleeding tendency is severe.47
9.1.5.4
Hypotonicity
Many affected individuals have muscular hypotonicity, which is probably directly
associated with their lax joints. In infancy, the recognition of EDS may be very
161
difficult, particularly as all babies are somewhat hypermobile. The EDS should
certainly be considered in the differential diagnosis of any ‘floppy infant’. It is
relevant that misdiagnoses of a variety of neuromyopathies have been made in
neonates with the EDS. The Kyphoscoliotic form which presents with severe
neonatal hypotonia is vulnerable in this respect.48
9.1.5.5
Spinal Abnormalities
Spinal malalignment of greater or lesser degree is present in a proportion of affected
persons and it is the hallmark of the Kyphoscoliotic form of the EDS. Thoracolumbar
scoliosis is the commonest abnormality of this type, and vertebral wedging may
occur at the apex of the kyphotic element of the curve when a severe scoliosis is
present. Spondylolisthesis is an uncommon complication.49
The fact that spinal changes are uncommon in affected children suggests that
scoliosis in adults is caused by the strains imposed by the upright stance on vertebral
joints which have lax ligaments.
9.1.5.6
Thoracic Asymmetry
Asymmetry of the thorax and sternal depression may occur, particularly in conjunction with spinal malalignment. When severe, the thoracic deformity may cause displacement of the heart, which in turn can lead to a cardiac murmur and an abnormal
electrocardiogram. It is relevant, however, that a floppy mitral valve is more common in the EDS than previously suspected.50
9.1.5.7
Foot Involvement
Talipes equinovarus is present at birth in a proportion of persons with EDS. As
intrauterine malposition is a causative factor in the pathogenesis of the club foot, it
is reasonable to postulate that individuals with abnormally mobile joints would be
at an unusually high risk for this complication.
Pes planus is a frequent abnormality in the EDS. During childhood, the longitudinal arch frequently appears to be normal when no weight is being borne, but by
the age of 30 years, the majority of persons with flat feet show both static and
dynamic pes planus deformity. The most severe flat feet usually give no pain, and
difficulty in fitting shoes is the main problem.
Hallux valgus, claw toes and plantar keratomata are other common problems in
the feet. The extensible skin may contribute to an appearance of ‘moccasin feet’
where the affected individual seems to be wearing an oversize pair of
ankle socks.
Pain on weight bearing can result from the presence of piezogenic papules on the
margins of the soles of the feet. These pea-shaped lumps result from herniation of
globules of fibro-fatty tissue through the dermis.
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9
The implications of foot pain and disability in the EDS upon daily life activities
have been reviewed by Berglund et al.51
9.1.5.8
Osteoarthritis
It seems likely that the development of osteoarthritis is related directly to the
magnitude of hypermobility and the frequency and degree of trauma to which a
particular joint is exposed. Nevertheless, there is a lack of consensus in this matter
and the issue has not been settled. Osteoarthritis in the EDS and FAHS has been
observed in the hands, knees, ankles and shoulders, but involvement of the hip
joint is uncommon.
9.1.5.9
Bursae
Bursae may develop in association with the Achilles tendon, hallux valgus
and in the olecranon and prepatellar regions. It is sometimes difficult to
distinguish these bursae from haematomata or from molluscoid pseudotumours,
which also occur at these sites. The results of excision of these bursae are
usually good.
9.1.5.10
Limb Pain
A considerable proportion of persons with the EDS experience cramps in the leg
muscles. These usually occur at night and are most severe during childhood,
often resolving in adult life. In addition, ill-defined muscular pain is relatively
common and may cause considerable handicap.52 The pathogenesis is unknown,
but it is possible that the pains are caused by the overstretching of the muscles
which is permitted by the abnormal range of movements of the lax joints.
In addition to cramps and muscle pains, non-specific discomfort may also involve
the joints. This symptom is occasionally severe and may warrant consideration in
the differential diagnosis of any child with polyarthralgia.
Limb pain is a major reason for referral to special Hypermobility Clinics and a
great deal of effort has gone into the elucidation of this problem. Protocols for management include sophisticated physiotherapy and psychological support. The pathogenesis and management of limb and joint pain in the EDS and the Hypermobility
syndrome is discussed in detail in Chap. 6.
9.1.5.11
Peripheral Circulatory Phenomena
Acrocyanosis occurs in many affected persons, while a minority experience the
Raynaud phenomenon.
9.1.5.12
163
Bony Abnormalities
A variety of bony features have been encountered in isolated instances, including
radioulnar synostosis, lack of development of the proximal phalanx of the little
finger, syndactyly, spina bifida occulta and abnormalities of cranial ossification. It is
unlikely, however, that these changes are directly related to EDS, as a majority of
affected persons do not have any significant primary bony abnormality. The incidence of fractures is no higher than in normal individuals, and bone healing is
uneventful. There is no increased liability to musculoskeletal neoplasia.
9.1.5.13
Handshake
Affected individuals have a characteristic handshake. The musculoskeletal structure
of the hand seems to collapse on pressure and the hands feel like a bag of bones.
9.1.5.14
Gait
Persons with EDS can often be recognised by their gait. The feet are placed firmly
and flatly upon the ground. The hips are hyperextended during weight-bearing to
counteract the genu recurvatum, thus enabling the pelvis to remain balanced with
respect to the feet. This gait is accentuated by the concomitant pes planus, and
resembles that of tabes dorsalis.
9.1.6
Orthopaedic Management of Articular Problems
The orthopaedic management of the EDS is determined by the strict application of
basic principles. It is an important practical point that surgical procedures may be
complicated by the fragility of the tissues. Sutures often cut out, and closure of
operation sites may be difficult. Surgeons have aptly described attempts at skin
suture as being ‘like trying to sew porridge’.53 Similarly, angiographic procedures
have caused major lacerations of the femoral artery. Nevertheless, the majority of
affected persons do not have operative problems of this magnitude.
A bleeding tendency may be present in some individuals. Although the majority
of patients have trouble-free operations, massive haemorrhage has occurred in a few
instances. The bleeding diathesis has been variously ascribed to changes in the
coagulation mechanism, vessel walls or perivascular connective tissues, but no
consistent abnormality has been demonstrated.54
Postoperative haematoma formation may delay wound healing. The alteration of
normal tissue elasticity, which would usually prevent the expansion of such haematomata is probably significant.
164
9
Due to the tissue fragility, a small skin incision may extend spontaneously to
become a gaping wound. Fine suture material, the avoidance of tension and a meticulous technique increase the chances of satisfactory operative results.
Healing is often slow and wounds may reopen when sutures are removed.
Surgical scars are usually thin and they may widen and distract with the passage of
time, even when initial healing has been satisfactory.
In some affected persons, especially those with the Kyphoscoliosis type of EDS,
spinal malalignment may require correction.55 In view of the potential surgical problems, it would be prudent for a major procedure of this type to be undertaken only
after due consideration.
Despite the potential problems in orthopaedic intervention in the EDS, total
knee arthroplasty has been successfully accomplished.56 Likewise, sternoclavicular joint stabilization57 and orthoscopic tendon arthroplasty have been
undertaken.58
Anaesthetic techniques need to be chosen with cognisance of the syndromic
manifestations and potential complications. The Vascular form of the EDS is
especially important in this respect.59,60 Local anaesthesia may be ineffective in
the EDS and the hypermobility syndrome. The basis of this problem has not yet
been elucidated.
Lax joints are generally best left lax as stabilisation procedures, apart from
fusion, are rarely successful. The quote ‘I was doing well before they operated
on me’ is often apt.
9.1.6.1
A Patient’s Viewpoint of His Articular Problems
A young man with EDS wrote the following excellent description of certain aspects
of his condition.
My skin is rather loose and my knee joints will extend about 2 inch further back than a
normal person’s knees. If I stand with my knees straight I have to use my leg muscles to
hold them there. If I let my knees extend backwards to their locked position it doesn’t take
long until they ache from the awkward position which they are in. The weight of my body
rests on my knees at a slight angle from the vertical, which results in a strain being put upon
them. Not only is my skin loose but the supporting tissue under the skin is soft. Although I
am a construction electrician and work with my hands, I do not form callous on them.
Sometimes when I lift something heavy I feel the tissue give way between the bones of my
fingers and the object that I am lifting.
9.1.7
Non-articular Complications
Apart from the articular complications, a wide variety of problems in other systems
may arise from the underlying connective tissue abnormality. These are briefly
reviewed below.
9.1.7.1
165
Cardiovascular
Structural cardiac defects were initially thought not to be a primary feature of
EDS, but with the introduction of sophisticated investigation techniques, a variety
of cardiac abnormalities have been recognised.61,62 As in other inherited disorders
of connective tissue, a ‘floppy mitral valve’ is fairly common and mild dilation of
the aortic root may occur. Cardiac assessment of all affected persons is warranted
and if cardiac abnormalities are detected, annual cardiological surveillance is
recommended.
The potentially lethal complications of dissection of the aorta and spontaneous
rupture of large arteries are virtually confined to the Vascular form of the EDS.
These problems have been reviewed by Pepin et al.63
9.1.7.2
Abdominal
Structural anomalies of the gastrointestinal tract result form the undue tissue laxity.
These abnormalities include hiatus hernia, gastric, duodenal and colonic diverticulae, and rectal prolapse. Inguinal, femoral and umbilical herniae are also common,
and urinary bladder diverticulae may occur.
Gastrointestinal haemorrhage, with or without perforation, is a feature of the
Vascular form of the EDS. These events may be spontaneous, or follow minor
trauma, and several deaths have been reported.
9.1.7.3
Neurological
Intracranial vascular abnormalities are uncommon but dangerous complications of
EDS. They are probably due to distensibility and fragility of the walls of the blood
vessels, and the problems which arise can be compounded by a bleeding tendency.
Aneurysms of the internal carotid arteries, carotid cavernous sinus fistulae and subarachnoid haemorrhage have all been reported. Angiographic investigations of
intracranial lesions of this type are hazardous.
Haematomata may compress peripheral nerves and the occurrence of recurrent
neuropathy in the EDS has been documented. Spinal malalignment can result in
cord compression, but this complication is rare.
9.1.7.4
Ophthalmological
Involvement of the scleral connective tissue permits distortion of the eyeball
leading to myopia and divergent strabismus. Uncomplicated convergent squint
is common, due to laxity of the tendons of the extrinsic muscles of the eye.
Scleral perforation and potential visual loss are features of the Kyphoscoliosis
form of the EDS.
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9
Epicanthic folds and redundant skin on the upper eyelid may produce undesirable cosmetic effects. In this context, Méténier’s sign (ease of eversion of the upper
eyelid) is one of the minor diagnostic features of EDS.
9.1.7.5
Obstetric
Although there are many potential complications in pregnancy, the majority of
women with the Classic form of the EDS do not experience any difficulties.
Nevertheless, antenatal surveillance and hospital delivery are desirable. One aspect
of the EDS which is regarded as advantageous is the fact that striae gravidarum do
not usually develop during pregnancy.
Antepartum and postpartum haemorrhage are not infrequent, and it may be
difficult to achieve haemostasis. Precipitate labour, severe lacerations of the
perineum and uterine prolapse are relatively common.64 If the foetus has
inherited the condition, the amniotic and chorionic membranes will be fragile.
These may rupture at an early stage, causing premature labour. The sequelae
of pregnancy include uterine prolapse leading to dyspareunia and urinary
incontinence.
The vascular form of the EDS is especially liable to serious obstetrical complications. The tissue fragility and bleeding tendency pose special hazards during pregnancy, and expert antenatal care and delivery is essential. In one horrific episode,
forceps delivery in an affected woman resulted in extraction of the infant, together
with the uterus, bladder and ureters.
9.1.7.6
Dental
Tissue fragility in the EDS can lead to damage to the gums on brushing the teeth,
with consequent gingival periodontitis.65,66 Dental extraction may also be complicated by this fragility, with the additional hazard of abnormal bleeding, especially
in EDS IV.67 Articular hypermobility underlies pain and instability of the temporomandibular joints, and accidental dislocation can occur during extraction of teeth
from the mandible. Numerical and structural abnormalities of the teeth are uncommon and inconsistent.68
9.1.7.7
Breast Mammography
Routine mammographic screening for neoplasia of the breasts has revealed
that tissue calcification is a feature of the Classical form of the EDS.69,70, 71 This
abnormality is probably analogous to the subcutaneous spheroids found in the
limbs. Breast calcification may arouse suspicion of neoplasia, and awareness
that it can be a syndromic complication in the EDS can avert an unnecessary
mastectomy.
9.2
Familial Articular Hypermobility Syndromes
9.1.8
167
Resources: Patient Support Groups
Ehlers-Danlos Support Group
PO Box 337
Aldershot Surrey GU12 6WZ
UK
Phone: 01252 690940
Email: director@ehlers-danlos.org
www.ehlers-danlos.org
Ehlers-Danlos National Foundation
3200 Wilshire Boulevard
Suite 1601 South Tower
Los Angeles CA 90010
Phone: 800-956-2902; 213-368-3800
Fax: 213-427-0057
Email: staff@ednf.org
www.ednf.org
Canadian Ehlers-Danlos Association
88 De Rose Avenue
Bolton ON L7E 1AB
Canada
Phone: 905-951-7559
Fax: 905-761-7567
Email: ceda@rogers.com
www.ehlersdanlos.ca
Association Francaise des Syndrome d’Ehlers Danlos
34 rue Léon Joulin
37 000 Tours
France
Email: m.h.boucand@wanadoo.fr
www.afsed.com
9.2
The familial hypermobility syndromes are a heterogeneous group of disorders in
which generalised joint laxity is the primary clinical manifestation. The EDS and
other rare genetic conditions which have additional non-articular stigmata are
excluded from this category.
Semantic confusion still occurs, since the term ‘hypermobility syndrome’ is often
employed in a clinical context for any patient with articular symptoms which are the
consequence of lax joints, in the absence of a specific syndromic diagnosis. The major
problem lies in distinguishing between individuals who are at the upper end of the
spectrum of the normal range of joint movements and those who have an inherited
connective tissue disorder which presents with articular laxity (i.e. the familial articular
hypermobility syndrome). This problem is discussed at length in Chap. 2.
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9
It is probable that the general category of loose-jointed persons with articular
symptoms comprises a very heterogeneous group of simple and complex genetic
conditions. The limits of syndromic resolution at a clinical level have been reached
and further delineation will depend upon the recognition of specific biochemical or
molecular markers. The identification of deficiency of the glycoprotein tenascin-X
in a small proportion of persons with the Hypermobility form of the EDS may be a
precursor to future molecular categorisation.
9.2.1
Nosology
Early accounts of familial hypermobility were given by Key72 and Sturkie.73
The generation-to-generation transmission of loose-jointedness in association
with multiple dislocations was documented by Hass and Hass74 under the designation ‘arthrochalasis multiplex congenita’. The patients reported in this article
included individuals with EDS and no attempt was made to differentiate the
separate entities. Carter and Sweetnam 75,76 and Carter and Wilkinson77 drew
further attention to the association of familial generalised joint laxity and
dislocations.
In addition to the generalised hypermobility syndromes, familial joint laxity
is sometimes localised to a single site. For instance, Whitney78 described autosomal dominant inheritance of hypermobility which was confined to the interphalangeal joint of the thumb, whilst a kindred with joint laxity in four
generations and a propensity to recurrent dislocation of the patella was reported
by Shapiro et al.79
Beighton and Horan80 documented two kindreds in which joint laxity was transmitted as an autosomal dominant trait and introduced the designation ‘Familial
Generalised Articular Hypermobility’ (Figs. 9.6 and 9.7). The first was a family of
contortionists who had experienced few orthopaedic problems during their professional activities, while the second family had multiple dislocations and deformities
which were attributable to their hypermobility. A further family with autosomal
dominant generalised joint laxity and multiple dislocations was described by Horton
et al.81 These authors reviewed the literature and proposed the designation ‘familial
joint instability syndrome’ for the condition. Thereafter, the Berlin Nosology listed
separate ‘uncomplicated’ and ‘dislocating’ types of the familial articular hypermobility syndrome (see Chap. 1).
The autosomal dominant Familial Articular Hypermobility Syndrome differs
from the Hypermobile type of EDS (formerly EDS III) only by virtue of additional
dermal extensibility in the latter disorder. If this manifestation is of minor degree,
exact diagnostic categorisation may be impossible. The problem is compounded by
the fact that an ill-defined velvety texture to the skin and minimal cutaneous extensibility may be present in both conditions. It is possible that involvement of the
tenascin-X gene could explain the similarity of these disorders.20
9.2
Fig. 9.6 A young woman with familial
generalised articular hypermobility
(From Beighton3)
Fig. 9.7 She was able to maintain her joint laxity
without any special training (From Beighton3)
169
170
9
Fig. 9.8 Spontaneous
dislocation of the right shoulder
in the familial hypermobility
syndrome (From Beighton3)
Autosomal recessive inheritance of familial articular hypermobility was recognised in two sisters born in a consanguineous French-Canadian kindred.82 Both had
gross generalised joint laxity and a soft, velvety skin. The younger sister had experienced numerous orthopaedic problems but the elder was asymptomatic. With
hindsight, it seems possible that the former could have been homozygous for
Tenascin-X deficiency, while the latter might have been heterozygous. This concept, however, is speculative.
The genetic basis of the articular hypermobility syndromes has been reviewed by
Malfait et al.83
9.2.2
Articular Complications
The Familial Articular Hypermobility syndrome and the common, apparently nonfamilial Hypermobility syndrome are very variable in severity. In clinical practice,
they may be indistinguishable and the range of their potential complications is probably identical.
In some hypermobile families, a wide spectrum of dislocations and subluxations
may occur, while in others, there is a predisposition to dislocation or subluxation of
a particular joint (Fig. 9.8). Following the reports of Carter and Sweetnam,75,76 recurrent dislocation of the patella and shoulder has been repeatedly recorded in families
with hypermobility. Shapiro et al.79 mentioned recurrent dislocations of the patella
in four generations of a loose-jointed kindred.
9.3
Miscellaneous Joint Laxity Syndromes
171
The occurrence of hip dislocation in families with hypermobility has been
documented by Carter and Wilkinson,77 Wynne-Davis84,85 and Bjerkreim and van
der Hagen.86 Fredensborg87 described an unusual patient with unilateral congenital dislocation of the hip and joint laxity which was present only on the
same side.
Apart from recurrent dislocations and subluxations, hypermobile individuals,
familial or otherwise are liable to develop other orthopaedic complications due to
their joint laxity. These include sprains, effusions, spinal malalignment and pes
planus. Hallux valgus may also occur.88 It has been shown that hypermobility is
associated with osteoarthritis at the base of the thumb but not in the interphalangeal
joints.89 The issue as to whether or not hypermobility is related to the common
forms of degenerative osteoarthropathy remains unsettled.90
9.2.3
Other Phenotypic Manifestations
Inguinal herniae are often encountered in hypermobile individuals and it seems
likely that they are a genuine complication of the syndrome. In view of the
underlying generalised connective tissue abnormality, this propensity for hernia
is not unexpected. A link with the carpal tunnel syndrome and an association
with mitral valve prolapse has been recognised.91 There are few, if any, other
structural non-articular complications.92 The occurrence of non-specific limb
and joint pains in hypermobile persons has attracted considerable attention.93-95
The clinical implications and management of Hypermobility are discussed in
Chaps. 5 and 6.
9.3
In addition to EDS and the familial articular hypermobility syndrome, joint laxity is
present in a number of inherited disorders. In some it is a major feature, while in
others the hypermobility is overshadowed by other syndromic components.
9.3.1
Joint Laxity in Inherited Connective Tissue Disorders
Hypermobility is a clinically important facet of a few well-established connective
tissue disorders, the most important of which are Marfan syndrome and osteogenesis imperfecta. A full description of these conditions and related disorders can be
found in Heritable Disorders of Connective Tissue96 and Connective Tissue and Its
Heritable Disorders.5
172
9
Fig. 9.9 A boy with Marfan syndrome;
arachnodactyly and thoracic asymmetry are
evident
9.3.1.1
Marfan Syndrome [154700] (See also Chap. 3)
The Marfan syndrome is relatively common, with a population frequency of about 1
in 5,000–10,000 individuals. The hallmarks of Marfan syndrome are disproportionate
limb length in relation to the trunk and arachnodactyly (long slim digits). The establishment of a firm clinical diagnosis of the Marfan syndrome is often difficult and
‘partial’ examples are frequent.97,98 The most common of these are the mitral valve
prolapse syndrome (MVP) and the MASS phenotype (myopia, mitral valve prolapse,
mild aortic root dilation and variable skin and skeletal abnormalities). In addition,
a marfanoid habitus, including lax joints, are a feature of several rare syndromic entities. These include familial aortic aneurysm, familial ectopic lentis, the Shprintzen–
Goldberg syndrome and the Loeys–Dietz syndrome. Other well-established conditions
which can be confused with the Marfan syndrome include the EDS, congenital contractural arachnodactyly, homocystinuria and the Stickler syndrome. The promulgation of diagnostic criteria for the Marfan syndrome has been helpful in clarifying
this situation.98a
In the Marfan syndrome, thoracic asymmetry and spinal malalignment are sometimes present and dislocation of the ocular lenses and aortic and mitral valvular
disease are additional features (Fig. 9.9). Aneurysmal dissection of the aorta in
adulthood is a common mode of death. Joint laxity is maximal in the wrists, but
other joints may be hypermobile to some degree (Fig. 9.10). Orthopaedic complications which are related to the laxity include recurrent dislocation, especially of the
shoulder and patella, spinal malalignment, pes planus and hallux valgus.
9.3
173
Fig. 9.10 Articular laxity is maximal in the wrist joint in Marfan syndrome (Reproduced with
permission from Beighton et al.12)
Inheritance is autosomal dominant but phenotypic expression is very variable
and mildly affected persons may be difficult to distinguish from normal individuals.
The identification of the chromosomal locus of the Marfan gene represented a major
advance in the elucidation of the disorder. Molecular sequencing has revealed considerable intragenic heterogeneity. Diagnostic confirmation can be obtained by
molecular investigation of the FBN-1 gene on 15q21.1 which encodes the protein
fibrillin-1.99
The clinical manifestations, management and pathogenesis of the Marfan syndrome have been comprehensively reviewed by Dietz.100
9.3.1.2
Osteogenesis Imperfecta [120150]
Osteogenesis imperfecta (OI) is a well-known genetic disorder in which bone
fragility is associated with blue sclerae and wormian bones in the skull (Figs. 9.11
and 9.12).
Hypermobility of digits is present in some affected persons, and in a minority,
joint laxity may be widespread. In a review of the historical background of OI,
Weil101 drew attention to several reports in the early literature of hypermobility and
recurrent dislocations. Ligamentous laxity probably plays a significant role in the
development of the spinal deformities which occur in a small proportion of individuals with OI. In affected persons, joint mobility and muscle strength are significant factors in functional ability and rehabilitation.102 The effective treatment of
affected children with bisphosphanates has revolutionised the medical management
of OI.103 A rare form of OI, the Bruck syndrome, is characterised by articular rigidity
rather than joint laxity.104
174
9
Fig. 9.11 A young man with
osteogenesis imperfecta, showing severe
deformity of the long bones (Reproduced
with permission from Beighton et al.12)
A detailed account of OI has been presented online in the series in
‘GeneReviews’.105
9.3.1.3
Other Bone Fragility-Joint Laxity Syndromes
In the osteoporosis-pseudoglioma syndrome [259770], the radiological appearance of the skeleton and the presence of wormian bone are reminiscent of OI.
These features are associated with mild mental retardation and potential blindness in infancy due to pseudogliomatous retinal detachment and the other ocular
complications.106 Ligamentous laxity is present but does not cause clinical
problems.
Using the designation ‘OI associated with the Ehlers–Danlos syndrome’ Biering
and Iverson107 reported the occurrence of gross generalised osteoporosis, articular
laxity with dislocations, dermal extensibility and blue sclerae. There have been a
few additional reports of this unusual condition (see EDS section 9.1.47).
9.3
175
Fig. 9.12 The digits are sometimes lax in
osteogenesis imperfecta
A family with autosomal recessive inheritance of blue sclerae, keratoconus,
deafness and spondylolisthesis was described by Greenfield et al.108 Biglan et al.109
reported five patients from two families with a similar disorder in which keratoglobus, blue sclerae, hearing loss, mottling of the teeth and generalised joint laxity
were the main features. Inheritance was autosomal recessive. Robertson110 detected
hypermobility in 50% of a series of 44 patients with keratoconus and made a reasonable suggestion that the ocular and ligamentous abnormalities shared a common
pathogenesis.
9.3.2
Skeletal Dysplasias with Predominant Joint Laxity
Joint laxity is a major feature of a few uncommon genetic skeletal dysplasias and
malformation syndromes. In these conditions, multiple dislocations may result from
alteration in the mechanical properties of ligaments and joint capsules. Moreover,
disordered growth may lead to alteration of bony contours in the joints, thereby
176
9
Fig. 9.13 A girl with Larsen
syndrome, showing epicanthus and
the characteristic broad flat nasal
bridge
increasing the liability to dislocation. If ligamentous laxity is a significant syndromic component, this propensity is greatly enhanced. In these circumstances, concomitant dysplasia of the odontoid peg and marked joint laxity can render the
cervical spine unstable and predispose to atlanto-axial subluxation and potentially
lethal spinal cord compression.
Articular hypermobility with or without subluxation and dislocation of single
joints is a frequent but inconsistent feature of numerous malformation syndromes.
In this context, joint laxity is not an important diagnostic indicator. It is also relevant
that unilateral congenital dislocation of the hip is the most frequent abnormality in
this category.
Bilateral dislocation of multiple joints, notably the hips and elbows, is strongly
suggestive of syndromic identity, and the more important conditions of this type are
outlined below. In these disorders, lack of full extension and rotation of the elbows
may be present; this paradoxical situation is the result of dislocation of the radial
heads and it can be misleading in the clinical context.
9.3.2.1
Larsen Syndrome [150250; 245600]
Larsen syndrome is characterised by marked generalised hypermobility in association with stunted stature, mid-facial hypoplasia, flattening of the nasal bridge and
spatulate digits (Figs. 9.13 and 9.14). Joint laxity is maximal in the knees, and genu
9.3
177
Fig. 9.14 In the Larsen syndrome, the digits are lax and
their tips are spatulate
recurvatum and instability commonly occur. Initial presentation is as a ‘floppy
infant’ and other complications include dislocation of the hips and radial heads, and
talipes equinovarus.111 In later childhood, the ligamentous laxity predisposes to spinal malalignment, which may be progressive and difficult to manage.112,113
Distinct mild autosomal dominant and severe autosomal recessive forms of the
Larsen syndrome have been documented.114,115 The basic defect in the latter is carbohydrate sulfotransferase 3 deficiency.116
9.3.2.2
Desbuquois Syndrome [251400]
Desbuquois syndrome is a rare autosomal disorder in which joint laxity is associated with stunted stature, broad terminal phalanges, polydactyly and protuberant
eyes. Supernumerary ossification centres are present in the carpus and there is a
characteristic prominence of the lesser trochanter of the femur.117 Desbuquois syndrome is potentially lethal118 but survival time is very variable.119
9.3.2.3
Spondyloepimetaphyseal Dysplasia with Joint Laxity and Severe
Progressive Kyphoscoliosis (SEMDJL) [271640]
More than 20 children with a syndrome comprising skeletal dysplasia, gross generalised joint laxity and severe spinal malalignment have been documented in South
178
9
Fig. 9.15 A boy with spondyloepimetaphyseal dysplasia with joint laxity (SEMHJL) in which
dwarfism, gross kyphoscoliosis and articular laxity are the major features
Africa (Fig. 9.15). The skin is rubbery and extensible but not fragile. Numerous
orthopaedic problems are related to the hypermobility, including dislocation, subluxation, genu valgum, genu recurvatum, talipes equinovarus and pes planus.120,121
Inheritance is autosomal recessive.122 The biomolecular defect has not yet been elucidated in this disorder.
9.3.2.4
Spondyloepimetaphyseal Dysplasia with Leptodactyly [603546]
The leptodactylic type or Hall type of SEMDJL has been documented in Europe123
and the USA.124 The term ‘leptodactyly’ pertains to the length and slender configuration of the tubular bones of the hands and feet. The clinical and radiological manifestations of both forms of SEMDJL are otherwise similar.125 In distinction to the
South African form of SEMDJL, however, the leptodactylic type is inherited as an
autosomal dominant trait.126
9.3.3
Dwarfing Dysplasias with Variable Joint Laxity
9.3.3.1
Pseudoachondroplasia [177170]
Pseudoachondroplasia is a comparatively common dwarfing skeletal dysplasia
in which joint laxity is a variable component (Fig. 9.16). The digits are
often stubby, with an impressive range of movement. In some affected persons
9.3
179
Fig. 9.16 Pseudoachondroplasia; short-limbed
dwarfism and genu varum are the major stigmata.
Loose stubby digits are characteristic of some forms
of this heterogeneous disorder
the hypermobility is sufficiently severe to cause dislocation, deformities
and spinal malalignment, while in others the range of articular movement is
normal.127,128
9.3.3.2
Morquio Syndrome [253000]
The eponymous designation ‘Morquio’ is sometimes applied to any dwarfing syndrome in which spinal malalignment is a major feature, but in the strict sense, the
term pertains to Mucopolysaccharidosis type IV (MPS IV). Dwarfism, thoracic
deformity, aortic incompetence and progressive corneal clouding are the major clinical features, and the diagnosis may be confirmed by demonstration of the radiographic changes of dysostosis multiplex and excessive excretion of keratan sulphate
in the urine.
In distinction to the other Mucopolysaccharidoses, the joints are lax in MPS
IV. This feature is most obvious in the digits, but the hypermobility predisposes to
orthopaedic complications including genu valgum, spinal malalignment and pes
180
9
Fig. 9.17 A boy with MPS IV showing the typical
barrel chest, short neck and spinal malalignment.
The digital laxity which is present in this condition
is a useful diagnostic discriminant from the other
mucopolysaccharidoses
planus (Fig. 9.17).129 It is of special clinical importance that the odontoid process
is often hypoplastic in MPS IV, as the combination of this defect and joint laxity
places affected persons at risk of subluxation of the cervical vertebrae and spinal
cord compression.130
9.3.3.3
Metaphyseal Chondrodysplasia Type McKusick [250500]
This condition, also known as cartilage-hair hypoplasia, is characterised by fine
hair, disproportionate dwarfism and lax stubby digits. Affected persons have a
propensity to Hirschsprung disease and severe varicella. The disorder has been
extensively studied among the inbred Amish community of Pennsylvania131 and in
the population of Finland.132
9.3.3.4
Hypochondroplasia [146000]
Hypochondroplasia is a relatively common dwarfing dysplasia, in which the clinical
and radiographic features are similar to, but milder than, those of Achondroplasia.
There may be some generalised joint laxity in hypochondroplasia, but this rarely
causes clinical problems.133
9.3
9.3.3.5
181
Other Dwarfing Skeletal Dysplasias
The knee joints are lax in the Ellis–van Creveld syndrome [225500]134 and the
digits may be hypermobile in acromesomelic dysplasia [201250].135 Hypermobility
is also present in the classical form of spondyloepiphyseal dysplasia congenita
[183900]136 and in metatropic dysplasia [156203].137,138 These disorders are all
rare and unlikely to be encountered in routine practice.
9.3.4
Genetic Syndromes in Which Hypermobility
Is Overshadowed by Other Manifestations
9.3.4.1
Hajdu-Cheney Syndrome [102500]
The Hajdu-Cheney syndrome is a rare autosomal dominant disorder which was first
identified in a small family in Michigan, USA. The major stigmata are acro-osteolysis,
osteoporosis, hypoplasia of the mandible, stunted stature, bone fragility, early loss of
teeth and multiple wormian bones. Articular laxity is a variable feature which does not
cause significant complications. Polycystic kidneys are an occasional syndromic
component.139
9.3.4.2
FG Syndrome (Opitz–Kaveggia) [305450]
The Opitz–Kaveggia FG syndrome is an X-linked multiple malformation disorder
in which a characteristic facies, mental retardation and imperforate anus are the
most constant features.140,141 The designation FG is derived from the initials of the
patients’ surnames, and more than 50 affected males have been reported. Articular
laxity predisposes to sloping shoulders, lumbar lordosis and club feet.
9.3.4.3
Trichorhinophalangeal Syndrome, Type II (Langer–Giedion
Syndrome) [120230]
The manifestations of the Trichorhinophalangeal syndrome (TRP) type II resemble
those of the better-known TRP type I. The most obvious features of both are sparse
scalp hair, a bulbous nose and cone-shaped phalangeal epiphyses.142 Mental retardation and multiple exostoses are diagnostic features of TRP type II. Articular laxity is
variable, but may cause spinal curvature and lead to presentation as a ‘floppy infant’.
9.3.4.4
Aarskog Syndrome [305400]
The main features of the Aarskog syndrome are short stature, cryptorchidism, a
shawl scrotum and a characteristic facies.143 The metacarpophalangeal joints are
182
9
very lax and when they are extended concomitant flexion occurs at the proximal
interphalangeal joints. The hypermobility is sometimes generalised, with secondary
consequences such as genu recurvatum, pes planus and metatarsus adductus.
Bilateral anterior dislocation of the hips has been documented.144 Hypermobility of
the cervical spine in conjunction with odontoid hypoplasia may lead to spinal cord
compression. Inheritance is X-linked with minor manifestations in some females
who carry the determinant gene.
9.3.4.5
Cohen Syndrome [216550]
The major features of the Cohen syndrome are variable mental retardation, truncal
obesity with onset in the first decade, muscle hypotonia, narrow hands and feet and
delayed puberty. Generalised joint laxity predisposes to genu valgum and spinal
malalignment.145
9.3.4.6
Multiple Endocrine Neoplasia Type 2 [171400]
Persons with multiple endocrine neoplasia syndrome type 2, also known as the multiple neuroma syndrome, have a marfanoid habitus, a characteristic facies and a
propensity to medullary thyroid carcinoma and phaeochromocytoma. Abdominal
symptoms may result from colonic ganglioneuromata. Joint laxity leads to spinal
malalignment, genu valgum and foot deformity.146
9.3.4.7
Down Syndrome
Down syndrome, or trisomy 21, is a common chromosomal disorder characterised
by mental retardation, stunted stature and a typical facies. Joint laxity is a variable
feature, which has been incriminated in the pathogenesis of atlanto-axial subluxation.147 Other orthopaedic and articular complications are inconsistent.
9.3.4.8
Joint laxity is a variable component of several rare genetic disorders. The best
known of these are listed below, with relevant references:
Lowe oculocerebrorenal syndrome [309000]148
Coffin–Lowry syndrome [303600]149
Kabuki syndrome [147920]150
Seckel syndrome [210600]151
RAPADILINO syndrome [266280]152
De Barsy syndrome [219150]153
Coffin–Siris syndrome [135900]154
Stickler syndrome [108300:184840]155
References
183
It can be anticipated that this list will continue to expand, with the continuing
delineation of new genetic conditions. In this respect, computerised databases
have proved to be of value in the diagnostic process.
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Chapter 10
Future Avenues for Research
This edition, the fourth in a series spanning some 25 years since the publication of
the first edition in 1983, is likely to be the last prepared under the current authorship. In addition to chronicling further progress in the field, it seems appropriate to
add a final chapter concerning areas that might be suitable, even ripe, for translational research in the future. This chapter, at times unashamedly speculative, synthesises the ideas of all three authors, each approaching the field from their slightly
different perspectives. We apologise to readers if some of our suggestions prove
impractical or if we have failed to consider their own areas of particular interest in
this wide field.
10.1
Arterial Elasticity
Inflammatory polyarthritis and cardiovascular disease are undoubtedly closely
related. Some experts have suggested that occlusive cardiovascular disease and
autoimmune inflammation in joints represent extremes of organ involvement within
the same pathological spectrum. Much attention has been devoted to the inflammatory seed; much less attention to the soil on which it is sown.
Whether hyperlaxity of tissue with hypermobile joints acting as a surrogate for its
detection behaves as a graded trait, as has been suggested for the joint,1 or whether
separate clinical conditions exist such that the degree of hyperlaxity of the tissues is
required to cross a certain threshold before a clinical syndrome can be diagnosed, is
open to debate. Nevertheless, the familial hypermobility syndromes are well documented. More importantly, it is evident that hypermobility of joints alone can be associated with cardiovascular manifestations such as prolapse of the mitral valve and
aggravated Raynaud’s phenomenon. There is also likely to be a graded variation in
arterial elasticity between individuals for which joint hypermobility may or may not
act as a clue. By implication, hypermobility consequent upon collagen structure rather
than hypermobility consequent upon the shape of the bony articulating surfaces is
likely to be the better surrogate for detection of this situation.
191
192
10
An increasing number of imaging methods are available for the assessment of
vascular disease, with varying degrees of sensitivity. Central atherosclerosis is often
measured with high-resolution carotid ultrasound for the detection of plaque,
although the extent of carotid artery intima-media thickness (CIMT) conveys different information which is possibly just as important. B-mode ultrasound is a safe,
reliable and non-invasive method of measuring CIMT.2 The combined thickness of
the intima and media can be measured in various sections of the carotid artery,
although the common carotid artery appears to be the most reproducible and accurate site for assessment.3 The internal carotid is presently more difficult to measure
than the common carotid though techniques are improving all the time. Nevertheless,
a wide variety of confounding factors are emerging that impinge upon CIMT including age, gender and blood pressure for which allowance is required.
Amongst the other parameters for vascular change, distensibility is sometimes
quoted, presumably because it is easily visualised. This feature which may or may
not be synonymous with the more frequently described ‘arterial stiffness’, often
correspondingly impaired though usually measured by different methods.
Confounding factors also apply to stiffness, which is increased in most chronic
inflammatory disorders4 including rheumatoid arthritis5 and SLE.6 Stiffness is also
increased in the presence of vasculitis.7
One of the determinants of stiffness, only occasionally dissected out, is likely to
be elasticity. By implication, this reflects collagen structure that, in the case of the
arterial wall, is likely to be predominantly inherited. It is conceivable, however,
that once arterial disease becomes established, stiffness, of which elasticity is
likely to be only one component, will become impaired. Evidence from genetic
disorders suggests that the natural distribution of elasticity may vary along the
length of a blood vessel, not least as a consequence of mechanical anatomical tethering at certain anatomical sites such as bifurcation. It is likely to be also influenced considerably by non-vascular factors such as bony foramina and ligamentous
bands that tether the course of blood vessels. Even in the absence of pathology,
linear flow will surely be interrupted by variation in angle of the vessel wall, producing eddies well before such dynamic variations are further influenced by local
pathology and anatomy.
Imaging is becoming increasingly sophisticated with improved techniques for
Doppler sonography as well as improved resolution of MRI scans through the
advent of 3 T MRI scanners. Computer modelling is also increasingly available to
give a measure of arterial distensibility, in part correlating with elasticity.
We are not aware of any basic studies that might show whether or not the prevalence of acquired cardiovascular disease is less in persons with distensible arteries,
in whom hypermobile joints act as a surrogate and simple method for their detection. Consideration of local confounding factors would need to be added to such
studies. The uncommon genetic disorders such as Ehlers–Danlos syndrome (EDS)
and Marfan syndrome might also be used as models in this situation. Relations
between collagens are complex but it seems likely that collagen types I, III, V and
VI are those most likely to be involved in the determination of vascular elasticity.
Some collagens may even be key players in this field. Abundance of collagen III, as
10.2
Cytokine Modulation
193
in the vascular or arterial forms of the EDS [EDS IV] for example, confers particular
delicacy, even fragility.8 This may have more pathogenetical relevance than simple
mutation of the gene which determines collagen V, which determines EDS types I
and II in the classical nosology.
Conditions such as EDS type IV (the vascular variant), where a specific feature
is bursting of blood vessels (possibly micro-aneurysms) leading to catastrophic haemorrhage, might be a particularly fertile area for study as vascular imaging improves.
A modest degree of hyper-elasticity might yet be shown to be an asset in conveying
protection from acquired cardiovascular disease while more severe hyper-elasticity,
especially localised at the site of micro-aneurysm, might be a decided liability.
10.2
Cytokine Modulation
Recent advances in the understanding of the pathogenesis of Marfan syndrome
provide insight into the possible direction of specific therapy for the management
of inherited abnormalities, although cytokine modulation may be still at least a
decade away.
In earlier molecular research, the Marfan syndrome was linked to the gene for
fibrillin-1 on chromosome 15.9 Many accept this was not the whole story since it
failed to take account of overlap between Marfan syndrome and other conditions
(e.g. the ‘marfanoid EDS’).10 Fibrillin-1 shares a high degree of homology with the
latent transforming growth factor-b (TGF-b) binding proteins.11,12 TGF-b cytokines
are secreted as large latent complexes, which, after secretion, are sequestered by the
extracellular matrix. This homology has prompted the hypothesis that extracellular
microfibrils might participate in the regulation of TGF-b activation, and this might
additionally explain some clinical manifestations of Marfan syndrome such as the
bone overgrowth and even changes in the heart valve. Increased local activity of
TGF-b has recently been shown to be responsible for myxomatous cardiac valve
disease in fibrillin-1 deficient mice.13 It was subsequently shown that mutations in
the gene encoding the type II TGF-b receptor exactly recapitulate the classic Marfan
phenotype.14 Patients with Loeys–Dietz aortic aneurysm syndrome are also heterozygous for loss of function mutations in either of the genes encoding the type I or type
II TGF-b receptor.15
This scientific background has challenged conventional dogma on Marfan syndrome, which has been that susceptible individuals were born with a genetically
determined structural weakness in the tissues. An alternative possibility, gaining in
credibility, is that clinical manifestations of the Marfan syndrome may be in part or
entirely determined by a failed regulatory (as opposed to a structural) role of the
extracellular matrix. Suspicion points to deregulation of TGF-b activity and signalling, raising the theoretical prospect of prophylactic and, perhaps ultimately, even
preventative intervention with cytokines. In mice, the use of drug therapy to modify
TGF-b activity demonstrates that phenotypes can be manipulated by this means in
the post-natal period. That such manipulation might ultimately be available in man
194
10
is not too distant a step, with turnover upregulated such that artificially increased
formation of slightly faulty protein compensates for its biomechanical weakness.
10.3
Candidate Genes
In general, recent searches for candidate genes have proved disappointing. The
classical research study is based on the identification of a clear and discreet clinical
entity, present in several members of each of three generations in the same family,
all of whom are available to contribute material for DNA analysis. This material can
then be put out for testing against a panel of candidate genes. Many have been suggested, and tenascin is especially favoured. Unfortunately, a recent seminal study
in this area has been disappointing (M. Pope and P. Turnpenny 2009, personal communication). In this investigation, the selection of a candidate gene panel was
impeccable, including conventional genes for collagen, and others thought, with
good reason, to be relevant.
Perhaps the dilemma is that we are dealing with a very heterogeneous a group of
conditions. If joint hypermobility simply serves as a phenotypic marker to any of
the many factors that contribute to it, the search for candidate genes would need to
be extremely widespread, taking on board not only those that relate to collagen
structure but also those that relate to bony shape of the joints. In the event that
appropriate candidate genes were to be identified, the number of families to which
each appertained might also be quite restricted. In turn, arguably, cytokine modulation remains the more attractive way forward, on current evidence.
10.4
Disease Association: True or Artefactual?
The last three decades have seen an increasing realisation that symptoms can arise
from organ systems other than the musculoskeletal in hypermobile patients.
Research into such associations, although lacking some of the fundamental interest
of genetic research, is actually the approach most frequently requested by the
patients. This is also perhaps the most likely to provide immediate practical improvement in management. For all these reasons, it should not be neglected.
Traditionally, the unifying link has been considered to be the structure of collagen, including the laxity in the collagen of the arterial wall that produces vasospasm
and the laxity in the collagen of the bowel wall that leads to sacculation mimicking
irritable bowel syndrome; both are entirely plausible. A refinement, in the case of
the vasospasm, argues that abnormal neurological tone (perhaps analogous to the
muscular flaccidity that aggravates joint hypermobility in certain other conditions
such as Down’s syndrome) is a further contributing factor. Recently, however, firm
evidence has emerged to suggest that there might be an abnormality of the autonomic
10.5
Neurological Aspects
195
nervous system in its own right. Elegant functional studies on the bowel convincingly confirm the presence of autonomic neuropathy, which is specifically highly
correlated with joint hypermobility, even when confounding factors such as the laxity of collagen in the bowel wall are considered.16
A further surprise has been the convincing association of mild asthma with joint
hypermobility, demonstrated in controlled studies on both non-specific hypermobile
persons and individuals with the EDS.17 Several possible explanations arise.
Conventional interest has centred on tracheal and bronchiolar collapse but an abnormality detected by intrinsic respiratory function tests perhaps points to a more ubiquitous abnormality in the collagenous ground substance that contributes to the lung
structure, even though this is only distantly related to the collagen sub-types that
contribute to joint stability. Abnormal elastin is recognised to cause emphysema in
cutis laxa. Attention has recently also been drawn to difficulty in phonation experienced by some persons with hypermobility of joints.
The possible association between hypermobility and fibromyalgia is more contentious. That individuals with hyperlax joints should experience tiredness on exertion is plausible given the extra effort required to stabilise hypermobile joints before
they are put to use. Clinical support for this concept is provided when the symptoms
of tiredness are restricted in an individual to the muscles acting around the joints
that are the most hypermobile. It is also plausible that such persons, with a tendency
to nocturnal compression neuropathy depending on the position in which they lie,
might experience disturbed sleep.18 The link to a true more widespread fibromyalgia
with sleep disturbance (assuming such a syndrome exists) is more controversial.
Some medicinal therapy which is effective in the management of putative widespread fibromyalgia also seems to help to relieve the daytime joint symptoms of
individuals with hypermobility. The nocturnal use of a small dose of antidepressant,
normally a tricyclic, seems to be effective in this regard.19,20
10.5
Neurological Aspects
The contribution of proprioception to hypermobility has been long accepted (see
Chaps. 2 and 4), and impairment and abnormality in the reflex arc serving the
hypermobile joint is also established.21 Recent work from Ghent, Belgium, has
further refined the understanding of proprioceptive abnormalities, suggesting that
an abnormality in proprioception is a result of deficits in joint and muscle-tendon
receptors and not in cutaneous tactile receptors (L. Rombaut 2009, personal
communication).
A further feature, partly related, is the propensity of hypermobile patients to have
orthopaedic abnormalities of the spine. These are often scolioses, either a conventional scoliosis or a corkscrew twist or a forward slip leading to a spondylolisthesis,
but other features such as transitional vertebrae are often seen. This area of association perhaps reaches its zenith in the suggested association between EDS and the
Arnold–Chiari malformation. The latter is a structural condition (as opposed to the
196
10
autonomic neuropathy associated with hypermobility, which is arguably functional);
the basic abnormality is at the base of the skull with inadequate space for the cerebellar tonsils, sometimes requiring surgical decompression. A syrinx can be associated with this in the cervical spine or at lower levels of the lumbar spine. These
abnormalities can impinge on neurological functional capacity, even developmental
milestones. This issue remains an area of ongoing medical debate.
10.6
Podiatry
Even more immediate practical help may be available for patients from research
into podiatric aspects of hypermobility. Although the common hypermobile variant
is flat footedness, sometimes a high arch is found. A recent Arthritis Research
Campaign-funded study in Leeds has studied the use of orthoses. A striking feature
of the study was the variability of the different foot shapes in hypermobile subjects.
In particular, the involvement of the mid-foot (not always suspected) and the poor
correlation between different contours and hypermobility at other joints when only
the Beighton score of measurement is used (A. Redmond 2009, personal communication). Existing work in this field has been discussed in Chap. 4.
10.7
Hormonal Aspects
This area is ripe for further research. Accepted hormonal aspects of hypermobility
are the invariable changes during pregnancy when joints become more lax and more
symptomatic, and the delay in return to normal occasioned by breastfeeding when
prolactin levels are high. The frequent cyclical deterioration with menstruation has
already been discussed (see Chap. 6). By implication, hormones contribute symptomatically or probably through a direct loosening effect on collagen. It follows that
progestogens and prolactin are likely to enhance symptoms at hypermobile joints,
possibly by enhancing laxity. By contrast, oestrogens might even be protective.
In the experience of clinicians in the field, this hypothesis is upheld. A common
cause of deterioration in previously stable hypermobile joints, either manifested by
increased propensity to subluxation or by greater discomfort, is well-intentioned
hormonal manipulation. In the experience of one of the authors, the Mirena coil
(with its progesterone reservoir even though this is claimed to exhibit controlled
gradual release and therefore not to be a risk factor), the injected progesterone contraceptives and progesterone based oral contraceptive pills frequently aggravate
hypermobility. In the majority (though not all) cases, if the causative contraceptive
is replaced, symptoms improve. The preferred replacement would normally be
a combined oral contraceptive providing the progestogen component is not
Drospirenone, which is unusual amongst progestogens in view of its close chemical
relationship to Spironolactone. There is also an impression that the higher the dose
References
197
of oestrogen that can be tolerated in a combined oral contraceptive, the greater the
protection. Some menopausal women have also found symptoms from hypermobile
joints are reduced by the commencement of oestrogen replacement therapy.
10.8
Joint Hypermobility as a Model of Accelerated
Osteoarthritis
The putative and contentious link between hypermobility and osteoarthritis is
discussed in Chaps. 4 and 5.
A joint that is rendered hypermobile by poor proprioception bears a close relationship to the traumatic osteoarthritis induced in the Pond-Nuki dog model. If it
were to be accepted that hypermobility might provide an accelerated model of
osteoarthritis, such patients would provide a fertile testing ground for new generations of drugs that purport to have a disease-modifying effect in osteoarthritis. The
problem with developing such drugs in the past has been the lack of an accelerated
human model of osteoarthritis, as clinical trial design has to span at least 2 and
sometimes 5 years, making development unattractive. As national organisations
group their resources for the more efficient testing of disease-modifying drugs in
osteoarthritis, accelerated human models are likely to be at a premium.
Subjects with joint hypermobility might yet find themselves at the forefront of
drug development.
References
2. Heiss G, Sharrett AR, Barnes R, et al. Carotid atherosclerosis measured by B-mode ultrasound
in populations: associations with cardiovascular risk factors in the ARIC study. Am J Epidemiol.
1991;134:250-256.
3. O’Leary DH, Polak JF, Kronmal RA, et al. Thickening of the carotid wall. A marker of atherosclerosis in the elderly? Stroke. 1996;27:224-231.
4. Roman MJ, Devereux RB, Schwartz JE, et al. Arterial stiffness in chronic inflammatory
diseases. Hypertension. 2005;46:194.
5. Inaba M, Tanaka K, Goto H, et al. Independent association of increased trunk fat with increased
arterial stiffening in postmenopausal patients with rheumatoid arthritis. J Rheumatol.
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6. Chow P-C, Ho MH-K, Lee T-L, Lau Y-L, Cheung Y-F. Relation of arterial stiffness to left
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7. Ng WF, Fantin F, Ng C, et al. Takayasu’s arteritis: a cause of prolonged arterial stiffness.
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variable clinical phenotypes including acrogeria and vascular rupture. Br J Dermatol.
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9. Sakai LY, Keene DR, Engvall E. Fibrillin, a new 350-kD glycoprotein, is a component of
extracellular microfibrils. J Cell Biol. 1986;103:2499-2509.
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10. Bird HA. Heritable collagen disorder. In: Reports on the Rheumatic Diseases (Series 5):
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fibrillin, the defective gene product in Marfan syndrome. Hum Mol Genet. 1993;2:961-968.
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14. Mizuguchi T, Collod-Beroud G, Akiyama T, et al. Heterozygous TGFBR2 mutations in Marfan
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neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nat
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16. Farmer AD, Zarate-Lopez N, Mohammed S, Scott SM, Knowles CH, Grahame R, Aziz Q.
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17. Morgan AW, Pearson SB, Davies S, Gooi HC, Bird HA. Asthma and airways collapse in two
heritable disorders of connective tissue. Ann Rheum Dis. 2007;66:1369-1373.
18. Aktas I, Ofluoglu D, Albay T. The relationship between benign joint hypermobility syndrome
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19. Ofluoglu D, Gunduz OH, Kul-Panza E, Guven Z. Hypermobility in women with fibromyalgia
syndrome. Clin Rheumatol. 2006;25:291-293.
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Index
A
Aarskog syndrome, 181–182
Accelerated osteoarthritis, 197
A Disintegrin-like And Metalloprotease
domain with ThromboSpondin
(ADAMTS2), 36–38
Arnold–Chiari malformation, 120–121, 195
Arterial elasticity
‘arterial stiffness,’ 192
CIMT, 192
EDS, 192, 193
inflammatory polyarthritis
and cardiovascular disease, 191
Marfan syndrome, 192
Raynaud’s phenomenon, 191
Arthrochalasia, 154
Articular hypermobility syndrome, 7
Arts performance
ballet dancers
Cincinnati Ballet Company, 128
metacarpophalangeal joint, 126, 128
metatarsal shaft, 129
oestrogen deficiency, 129
Royal Ballet School, 125
‘stress lesion,’ 129, 130
‘swayback knee,’ 126, 127
voluntary muscular
control, 126, 127
wrist hyperflexion and elbow
hyperextension, 125, 126
contortionists
‘elastic lady,’ 131
front bender/back bender, 132
‘India rubber man,’ 131
‘slippery worm oil,’ 131
socio-medical implications, 133
training, 132–133
instrumentalists, occupational ills
joint laxity, 136
osteoarthritis, violinist, 139–140
repetitive strain syndrome, 140
rheumatic complaints spectrum, 135
rheumatology clinic, 137
traumatic synovitis, 137–139
violin and viola players, 136
woodwind players, 135–136
musicians, 133, 135
plantar and dorsi flexor, 130
spondylolysis and spondylolisthesis, 131
B
Beighton score, 14, 15, 118
Benign joint hypermobility syndrome
(BJHS), 22, 67, 119
Boston osteoarthritis knee, 59
British Association of Performing
Arts Medicine, 121
C
Carotid artery intima-media thickness
(CIMT), 192
Chronic fatigue syndrome (CFS), 106–107
Chronic pain syndrome, 117
Chronic regional pain syndrome (CRPS), 105
Cognitive behavioural therapy (CBT), 93
Congenital dislocation of the hip (CDH), 68
Cytokine modulation, 193–194
D
Dermatosporaxis, 154–155
Desbuquois syndrome, 177
DOI 10.1007/978-1-84882-085-2, © Springer-Verlag London Limited 2012
199
200
DNA analysis, 194
Down’s syndrome, 194
Drospirenone, 196
E
Ehlers–Danlos syndrome (EDS), 101, 102
arterial rupture, 158
arthrochalasis type, 36, 157
articular hypermobility, 152, 154
articular manifestation
articular laxity implications, 158
bony abnormalities, 163
bursae, 162
disclocations, 158–159
foot involvement, 161–162
gait, 163
handshake, 163
hypotonicity, 160–161
joint effusions, 160
joint instability, 159–160
limb pain and osteoarthritis, 162
peripheral circulatory phenomena, 162
spinal abnormalities, 161
thoracic asymmetry, 161
‘Berlin nosology,’ 154
biochemical abnormality, 152, 154
biomolecular determinants, 152
cardiac valvular type, 157
classical form, 155–156
collagen fibril assembly, 32–34
compression neuropathy, 2
congenital dislocation, 1
dermal extensibility, 152, 153
dermatosparaxis type, 36, 38, 157
elastic fibre abnormalities, 42
extra-articular manifestations, 3
fibril-forming collagens, 28–30
genotype and phenotype, 27
hypermobility form, 156
joint laxity, 1, 7, 12, 151
kyphoscoliotic, 38, 156–157
Marfan syndrome, 42
measurement of, 4
non-articular complications
abdominal, 165
breast mammography, 166
cardiovascular, 165
connective tissue abnormality, 164
dental, 166
neurological, 165
obstetric, 166
ophthalmological, 165–166
Index
occipital horn syndrome, 158
orthopaedic and rheumatological
symptoms, 1
orthopaedic management, 163–164
osteogenesis imperfecta phenotype, 158
patient support groups, resources, 167
premature osteoarthritis, 3
progeroid type, 157
raisin-like swelling, 152
rheumatological manifestations, 2–3
skin split, 152
SLRP, 36
spondylocheiro dysplastic form, 39, 158
syndromic associations, 5
tenascin-X, 40–41
traumatic synovitis, 4
trivial trauma, 152, 153
type I collagens
arthrochalasia, 35
biosynthesis, 31, 32
cardiac valvular, 34
COL1A1 and COL2A1 genes, 34–35
genes encoding, 30–31
N-propeptide, 35–37
proa1(I) and proa2(I) chains, 34–35
types, 154–155
types I, III, V and VI, 192–193
type V collagen, 39–40
biosynthesis, 31–32
genes encoding, 30–31
type VI collagen, 41
vascular form, 156
Ehlers–Danlos syndrome (EDS) II/III,
113–115
Electronic gravity goniometer, 19
Ellis–van Creveld syndrome, 181
Extracellular matrix (ECM)
Marfan syndrome, 193
mechanical properties, 27
tenascin-X, 40
TGF-b cytokines, 193
F
Fibrillin–1, 193
Fibro-fatty tissue, 161
Fibromyalgia (FM), 106–107, 195
H
Hajdu–Cheney syndrome, 181
Heritable disorder on connective tissue
(HDCT), 101, 102
Index
Heritable hypermobility syndromes
EDS
arterial rupture, 158
arthrochalasis type, 157
articular hypermobility, 152, 154
articular manifestation
and non-articular complications
(see Ehlers–Danlos syndrome)
‘Berlin nosology,’ 154
biochemical abnormality, 152, 154
biomolecular determinants, 152
cardiac valvular type, 157
classical form, 155–156
dermal extensibility, 152, 153
dermatosparaxis type, 157
hypermobility form, 156
joint laxity, 151
kyphoscoliotic, 156–157
occipital horn syndrome, 158
orthopaedic management, 163–164
osteogenesis imperfecta phenotype, 158
patient support groups, resources, 167
progeroid type, 157
raisin-like swelling, 152
skin split, 152
spondylocheiro dysplastic form, 158
trivial trauma, 152, 153
types, 154–155
vascular form, 156
familial articular hypermobility syndromes
arthrochalasis multiplex congenita, 168
articular complications, 170–171
autosomal dominant trait, 168, 169
inguinal herniae, 171
joint laxity, 167
syndromic resolution limitation, 168
tenascin-X deficiency, 170
‘uncomplicated’ and ‘dislocating’
types, 168
joint laxity syndromes (see Joint laxity
syndromes)
Hypermobility biomechanics
anaesthetised cats, 50
artificial lubricants, 57
autopsy specimens, 49
bony surfaces, 50–51
cartilage deformation, 49
collagen, 51–53
cryosectioning and cryodissection, 49
joint laxity, 50
knee joints, 49
neuromuscular control, 53–54
osteoarthritis
201
bisphosphonate therapy, 60
Boston osteoarthritis knee, 59
joint hyperlaxity, 57
joint instability, 58
knee internal derangement, 59
mechanical aetiology, 59
seronegative inflammatory
polyarthritis, 58
varus–valgus motion, 59
weight-bearing trauma, 58
podiatric aspects, 55
proprioception, 54
stiffness measurement, 56–57
surgical intervention, 60–61
synovial membrane lubrication, 55–56
I
Irritable bowel syndrome (IBS), 108
J
Joint hypermobility syndrome (JHS)
autonomic dysfunction, 106–107
Brighton criteria, 66
children, 70
chronic pain, 105–106
dancers, 78
EDS, 101, 102
gastrointestinal tract, 108–109
HDCT, 101, 102
impaired healing, 66
lax joints, 101
ligament and bone, 80
local anaesthetics, 106
MFS, 101, 102
mimic juvenile chronic arthritis, 71
musculoskeletal elements, 65
MVP, 104–105
OI, 101, 102
oxygen consumption, 72
pelvic floor
hernia, 103
rectal prolapse, 103
uterine prolapse, 103–104
physiotherapy, 85–86
proprioceptive impairment, 106
psychiatric disorders, 107–108
scoliosis, 71
wind straws, 109
Joint laxity syndromes
dwarfing dysplasias, variable joint laxity
202
Joint laxity syndromes (cont.)
Ellis–van Creveld syndrome, 181
hypochondroplasia, 180
metaphyseal chondrodysplasia type
Mckusick, 180
Morquio syndrome, 179–180
pseudoachondroplasia, 178–179
genetic syndromes
Aarskog syndrome, 181–182
Cohen syndrome, 182
Down syndrome, 182
genetic disorders, 182–183
Hajdu–Cheney syndrome, 181
multiple endocrine neoplasia type 2, 182
Opitz–Kaveggia FG syndrome, 181
TRP type II, 181
inherited connective tissue disorder, 171
autosomal recessive inheritance, 175
Marfan syndrome, 172–173
OI, 173–175
osteoporosis-pseudoglioma
syndrome, 174
skeletal dysplasias
atlanto-axial subluxation, 176
Desbuquois syndrome, 177
Larsen syndrome, 176–177
leptodactylic type, 178
multiple dislocations, 175
SEMDJL and severe progressive
kyphoscoliosis, 177–178
K
Kyphoscoliosis, 154
L
Labral tear and autonomic dysfunction,
116–118
Langer–Giedion syndrome, 181
Larsen syndrome, 176–177
Leeds finger hyperextensometer, 19, 20
Loeys–Dietz aortic aneurysm syndrome, 193
Lysyl hydroxylase, 38–39
M
Marfan syndrome, 172–173, 192
autosomal dominant disorder, 42
connective tissue disorders, 5, 171
cytokine modulation, 193
elastic fibre components, 42
HDCTs, 101
instability-induced osteoarthritis, 59
Index
Metacarpophalangeal (MCP) joint
measurement, 18–19
Mitral valve prolapse (MVP), 104–105
Morquio syndrome, 179–180
Muscle-tendon receptor, 195
Musculoskeletal features
adults
acute articular and peri-articular
traumatic lesions, 76–77
arthralgia and myalgia, 75–76
bone fragility, 79–80
chondromalacia patellae, 76
chronic polyarthritis/monoarticular
arthritis, 77
clinical manifestations, 74–75
joints dislocation, 77
lax ligaments, 74
premature osteoarthritis, 78
prevalence, 73–74
soft tissue lesions, 76
spinal complications, 78–79
TMJ, 77–78
articular complications
acupuncture and TENS, 93–94
analgesic and non-steroidal
anti-inflammatory drugs, 92
CBT, 93
cervical/lumbar discectomy, 90
chronic symptoms, 84
denervation procedures, 94
exercise therapy, 85–87
foot surgery, 91
general management, 82
home exercise regime, 84, 85
hypermobile patients, 81
local steroid injections, 83
massage, mobilisation, hydrotherapy
and water immersion, 92–93
osteoarthritis, 91
pain, 84
passive mobilisations, 84, 85
patient support and information, 94
persistent synovitis, 88
physiotherapy, 83–84
podiatry, 69, 87
postural awareness, 85
recurrent dislocation/joint
instability, 89–90
rest, 82–83
specific management, 82
surgical intervention, 87–88
symptomatic treatment, 91
Index
Brighton criteria, 66
children
arthralgia and muscle pain, 70–71
CDH, 68
epidemiology, 68
‘growing pains,’ 72
hypermobility and motor
development, 68–70
joint instability, 72, 73
soft tissue lesions, 72–73
spinal complications, 71
temporomandibular dysfunction, 73
clinical significance, 66–67
fibrous protein genes, 65
impaired healing, 66
ligamentous laxity, 65
musculoskeletal features, 67
soft tissue injuries, 65–66
203
R
Raynaud’s phenomenon, 120
EDS, 12
foot flexibility tests, 14
hinge goniometer, 15
hydrogoniometer, 15
joint hypolaxity, 22–23
joint laxity, 12, 21
joint proprioception, 19
limbs rotation, 18
manoeuvre, 12–13
MCP joint measurement, 18–19
measuring joint movement, 17
MIE clinical goniometer, 15, 16
Myrin goniometer, 17
passive dorsiflexion, 12
populations, joint laxity, 21–22
single joint requirements, 15
surface goniometry, 17
Small leucine-rich proteoglycans
(SLRP), 36
Spironolactone, 196
Spondyloepimetaphyseal dysplasia
with joint laxity (SEMDJL),
177–178
Sport performance
acetabular dysplasia/ligamentous
laxity, 141
American football, 144
athletics, 142
biomechanical joint laxity, 145
cricket, 143
‘flexibility,’ 140
Gaussian distribution, 140
gymnastics, 141–142
hormonal aspects, 146–147
knee meniscus injury, 145
physiotherapy programmes and training
schedules, 144
racquet sports, 142
swimmers, 142
training methods, 145–146
yoga, 143–144
Stickler syndrome, 118
Subluxation bony abnormality, 119–120
Subluxation complications, 119–120
S
Schmorl’s node, 122
Scolioses, 195
Scoring systems
back and spinal mobility, 17–18
ballet dancers, 12
Brighton criteria, 14–15
clinical applications, 22–23
T
Temporomandibular joint dysfunction
(TMJ), 77–78
Thoracolumbar scoliosis, 161
Transcutaneous nerve stimulator (TENS),
93–94
Transforming growth factor-b (TGF-b)
binding protein, 193
N
Nocturnal Idiopathic Musculoskeletal
Syndrome (NIMS), 72
O
Occipital horn syndrome, 158
Opitz–Kaveggia FG syndrome, 181
Oral prednisolone, 139
Osteogenesis imperfecta (OI), 173–175
P
Pelvic floor problems, 115–116
Podiatry, 196
Postural orthostatic tachycardia syndrome
(PoTS), 107
Progestogens and prolactin, 196
Proprioceptive neuromuscular facilitation
(PNF), 146
204
Traumatic synovitis
acute lesions, 76
guitarist, 137–139
joint hyperlaxity, 4
violinist, 139
Index
Trichorhinophalangeal (TRP) syndrome
type II, 181
U
Urinary tract symptoms, 119

Hypermobility of Joints

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