Simpson-Golabi-Behmel Syndrome

Transcription

H o s p i t a l
U n i v e r s i t a r i o
L a
P a z
M a d r i d
Simpson-Golabi-Behmel
Syndrome
Rome, November 2009
Pablo Lapunzina-INGEMM- Instituto de Genética Médica y Molecular
Instituto de Genética
Médica y Molecular
Simpson Golabi Behmel- Classification
Hospital Universitario La Paz
Described independently by Simpson et al.
(1975), Golabi & Rosen (1984) and Behmel et
al. (1984)
Renamed in 1988 by G. Neri & co. as
Simpson-Golabi-Behmel Syndrome
Simpson-Golabi-Behmel is an Overgrowth
Syndrome
Neri et al., Am J Med Genet. 1988 May-Jun;30(1-2):287-99.
5%
Overgrowth Syndromes. Classification
•
•
•
•
Hyperplasia
Hypertrophy
Increased interstitial fluid
Any combination of them
5%
OGS Classification
• A -TRUE:
• B –PARTIAL /
LOCALIZED
• C - MISCELANEOUS:
CHROMOSOMALENDOCRINOLOGY-OTHERS
Bannayan-Riley-Ruvalcaba
Beckwith-Wiedemann
Sotos
Weaver
Macrocephaly/capillary malformation
Perlman
Costello
Non-syndromic OGS with or without MR
Hemihypertrophy/hemihiperplasia
Klippel Trenaunay
Proteus
CLOVE
CLAPO
Chromosomal (Klinefelter; Pallister
Killian; Trisomy 8 mosaic; Fragile X;
Duplication 4p16.3; Deletion 22q13
Endocrinologic (son of diabetic mother;
hypophysis)
Other (Marfan/ Homocystinuria)
Cohen, Neri and Weksberg. Overgrowth Syndromes.Oxford University Press
5%
Overgrowth Syndromes. Characteristics
The OGS share some common characteristics:
Increased risk of mental retardation
Increased risk of tumours
5%
OGS. Mental retardation
• In some disorders
Sotos syndrome
Simpson Golabi Behmel syndrome
Macrocephaly- Capillary Malf.
Beckwith Wiedemann syndrome
∼ 70
∼ 30-50
∼ 40
∼ 2-3
%
%
%
%
5%
OGS. Tumoral Risk
High Tumor Risk
Mild Tumor Risk
•
•
Malignancies
Malignancies
Perlman
Beckwith-Wiedemann
Hemihypertrophy
Klippel-Trenaunay
Sotos
Weaver
Proteus
Macrocephaly- Capillary Malformation
•
•
Benign tumors
Proteus
Klippel-Trenaunay
Benign Tumors
Hemihypertrophy
Beckwith- Wiedemann
5%
SGBS- Common Clinical Findings
SIMPSON-GOLABI BEHMEL SYNDROME
•
•
•
•
•
•
•
•
•
Overgrowth (mainly in height and weight)
Coarse face
Dental crowding
Cleft palate- Cleft lip
Polydactyly
Lipomas and mesenchymatic tumors
Speech and language problems
Variable mental retardation
Increased tumor risk
5%
SGBS-Data from the SOGSR
Established in
November 2003 at
Hospital Universitario
La Paz (Madrid)
About 1200 entries of
at least 15 diff
disorders
Nation-wide with
participation of all
regions
RESSC- Registro Español de
Síndromes de Sobrecrecimiento
SOGSR- Spanish Overgrowth
Syndrome Registry
5%
SGBS- Clinical Findings - Face
Coarse face
Hypertelorism
Large mouth
Midline groove of tongue
Cleft lip
Cleft palate
Malposition of teeth
Congenitally missing teeth
Supernumerary teeth
Odontogenic keratocysts
Krimmel M, Reinert S. Br J Oral Maxillofac Surg. 2000 Jun;38(3):221-3
5%
SGBS- Facial features
5%
SGBS- Facial features
5%
SGBS- Clinical findings
5%
SGBS-Abdominal problems
•
•
•
•
Diaphragmatic herniae
Hepatomegaly
Splenomegaly (rare)
Extra nipples
Enns et al., Am J Med Genet. 1998 Sep 23;79(3):215-25
Slavotinek, Am J Med Genet C Semin Med Genet. 2007 May 15;145C(2):172-83
5%
SGBS- Abdominal findings
5%
SGBS- Clinical findings
5%
SGBS-Cardiovascular problems
Cardiovascular problems in 26%
• Ischemic stroke (dissection of internal
carotid )
• Hepatic vascular malformation
• Tachyarrhythmias
• Cardiomyopathy
• Other electrocardiogram abnormalities
Lin et al., Am J Med Genet. 1999 Apr 23;83(5):378-81
König et al., Am J Med Genet. 1991 Feb-Mar;38(2-3):244-7
Pénisson-Besnier et al., Am J Med Genet A. 2008 Feb 15;146A(4):464-7
Cureton et al, 26: Am J Med Genet A. 2007 Jun 15;143A(12):1379-81
5%
SGBS-Limbs anomalies
Broad hands
Short hands
Hypoplastic finger
nails
Postaxial hexadactyly
Deep plantar creases
5%
SGBS-Speech and language
Speech characterized by a
distorted articulation
Distorted resonance
Fluency failures
Stereotype prosody
Van Borsel et al. Genet Couns. 2008;19(2):241-9.
5%
SGBS- Other findings
Anal atresia
Hypospadias
Pseudo hermaphroditism
Severe mental
retardation
Hydrocephalus
Epilepsy
Obstructive sleep apnea
L
Young et al., Pediatr Neurol 2006;34:139-42; Paludetti et al., Int J Pediatr Otorhinolar 2003;67:1143-7
5%
SGBS- Evolving phenotype
5%
SGBS- Etiology & Causes
X-linked gene: glypican 3 (GPC3)
Maps Xq26
GPC3: more than 500 kb and 8 exons.
Protein: Glypican-3 has 580 amino acids.
Pillia et al., Nat Genet. 1996 Mar;12(3):241-7
Orth et al., Am J Med Genet. 1994 May 1;50(4):388-90
Xuan et al., Hum Mol Genet. 1994 Jan;3(1):133-7
5%
SGBS Mutations and Deletions
Li et al., Am J Med Genet. 2001 Aug 1;102(2):161-8
Rodríguez-Criado et al. Am J Med Genet A. 2005 Oct 15;138A(3):272-7
5%
SGBS- Germinal Mosaicism
Germinal Mosaicism
Mother
Patients
Romanelli y col., Clin Genet 2007; 72:384-386.
5%
SGBS. Genotype Phenotype correlation
No specific genotype-phenotype correlation
No major differences between patients with
deletions and point mutations
Mariani et al., J Pediatr Endocrinol Metab. 2003 Feb;16(2):225-32
Hughes-Benzie et al., 6: Am J Med Genet. 1996 Dec 11;66(2):227-34
5%
SGBS. Differential Diagnosis
Beckwith Wiedemann syndrome
Macrocephaly-capillary malformation
Sotos syndrome
Non-syndromal OG with or without mental
retardation
5%
SGBS. Differential Diagnosis
(Macrocephaly-Capillary Malforamtion)
•
•
•
•
•
•
•
•
•
Overgrowth
Capillary malformation
Nevus flammeus
Capillary malformation in the upper lip/philtrum
Asimmetry/Hemihypertrophy
Hemimegalencephaly
Macrocephaly
Polydactyly
Mental retardation 50%
5%
Differential Diagnosis- M-CM
75 %
5%
Differ. Diagnosis- Beckwith Wiedemann
5%
Differential Diagnosis-Sotos syndrome
5%
SGBS-Transgenic mice
Gpc3-deficient mice display a high incidence of :
Ventricular septal defects, common
atrioventricular canal and double outlet right
ventricle.
Delay in endochondral ossification
Somatic overgrowth, renal dysplasia, accessory
spleens, polydactyly, and placentomegaly
Perinatal death, cystic and dyplastic kidneys, and
abnormal lung development.
Mandibular hypoplasia
Imperforate vagina.
Chiao et al., 58: Dev Biol. 2002 Mar 1;243(1):185-206
Cano-Gauci et al., J Cell Biol 199;146:1; 255-264
Viviano et al., Dev Biol. 2005 Jun 1;282(1):152-62
5%
WT
Mandibular hypoplasia
Complete lack of mandible
in the mutant embryo.
Tg
Cano-Gauci et al., J Cell Biol 199;146:1; 255-264
5%
Gpc3/DeltaH19 double mutants (bialellic
expression of Igf2 gene by imprint relaxation),
Omphalocele and skeletal defects.
Compatible with a model positing that there is
downstream convergence of the independent
signalling pathways in which either IGFs or GPC3
participate
Chiao et al., 58: Dev Biol. 2002 Mar 1;243(1):185-206
5%
Glypican-3 inhibits Hedgehog signalling during
development by competing with patched for Hedgehog binding.
GPC3 null embryos display increased Hedgehog signalling
GPC3 inhibits Hedgehog activity
GPC3 interacts with Hedgehog but not with its receptor,
Patched
GPC3 competes with Patched for Hedgehog binding.
GPC3 induces Hedgehog endocytosis and degradation. The
heparan sulfate chains of GPC3 are not required for its
interaction with Hedgehog.
GPC3 acts as a negative regulator of Hedgehog signaling
during mammalian development and that the overgrowth
observed in SGBS patients is, at least in part, the
consequence of hyperactivation of the Hedgehog signaling
pathway.
Capurro et al., Dev Cell. 2008;14:700-11
5%
SGBS-Biology
Direct interaction of GPC3 with CD26
GPC3 without the GPI anchor is capable of
inducing apoptosis indicating that neither the GPI
anchor nor the membrane attachment is required
for apoptosis induction.
Davoodi J et al., Proteomics 2007;7:2300-10
5%
SGBS-Biology
Loss of glypican-3 induces alterations in Wnt signaling.
Matting of GPC3 knockout mice with insulin receptor substrate-1 (IRS-1)
nullizygous mice.
GPC3 regulates somatic growth independent of IRS-1,
GPC3 does not modulate IGF signaling.
GPC3 knockout mice exhibit alterations in the Wnt signaling pathway,
GPC3 led to the inhibition of the non-canonical Wnt/JNK signaling
pathway and activation of canonical Wnt/beta-catenin signaling.
At least in some cell types GPC3 serves as a selective regulator of
Wnt signaling, by potentiating non-canonical Wnt signaling, while
inhibiting the canonical Wnt signaling pathway.
SGBS may in part result from a loss of GPC3 controls on Wnt
signaling and requires the cooperation of both the protein and the
heparan sulfate moieties of the proteoglycan.
Song et al. J Biol Chem. 2005;280:2116-25.; De Cat et l., J Cell Biol. 2003;163:625-35
5%
SGBS-Oncogenicity
GPC3 bound specifically through its N-terminal prolinerich region to both Insulin-like growth factor (IGF)-II and
IGF-1R.
GPC3 stimulated the phosphorylation of IGF-1R and the
downstream signaling molecule extracellular signalregulated kinase (ERK) in an IGF-II-dependent way.
GPC3 knockdown in HCC cells decreased the
phosphorylation of both IGF-1R and ERK.
GPC3 confers oncogenecity through the interaction
between IGF-II and its receptor, and the subsequent
activation of the IGF-signaling pathway.
Cheng et al. Carcinogenesis 2008;29:1319-26.
SGBS-Biology
P
GPC3
IGF2
IGF1R
P
IGF
pathway
ERK
(-)
Patched
comp
(+)
(-)
5%
SGBS-Oncogenicity
Wilms tumour
Hepatoblastoma.
Hepatocarcinoma
Adrenal tumour
Buonuomo et al., Pediatr Hematol Oncol 2005;22:623-8
Lapunzina et al., J Med Genet 1998;35:153-6
Zynger et al., Am J Surg Pathol 2006;30:1570-5
5%
SGBS-Surveillance for WT
Surveillance for Wilms tumour
Should be offered to children at >5% risk of Wilms
tumour.
Should only be offered after review by a clinical
geneticist.
Should be carried out by renal ultrasonography every 34 months.
Should continue until 7 years.
Can be undertaken at a local centre, but should be
carried out by someone with experience in paediatric
ultrasonography.
Screen-detected lesions should be managed at a
specialist centre.
Scott et al, Arch Dis Child. 2006;91:995-9.
5%
Overgrowth Syndromes- Risk of Tumours
Lapunzina, Am J Med Genet C Semin Med Genet. 2005;137:53-71;
Gracia and Lapunzina, J Pediatr Endocrinol Metab. 2005 Dec;18 Suppl 1:1227-35
SGBS-Summary
Simpson-Golabi-Behmel syndrome
Rare, X-linked overgrowth syndrome
Typical craniofacial features
GPC3
Mild to moderate mental retardation
Tumour risk
Surveillance for embryonal tumours

Simpson-Golabi-Behmel Syndrome

Transcription

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