Document 6444506

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Document 6444506
Growth of Children with
-Thalassemia Major
Louis C.K. Low
Department of Pediatrics and Adolescent Medicine, The University of Hong Kong, QueenMary Hospital, Pokfulam
Road, Hong Kong SAR, PR China.
Abstract. Hypertransfusion and regular chelation therapy have allowed improved survival in patients with thalassemia major
(TM). Despite medical advances, growth failure and hypogonadism remain significant clinical problems in these patients in
adolescence. Disproportionate truncal shortening which is common especially among adolescents with thalassemia, is due to
platyspondyly resulting from a combination of factors like hemosiderosis, desferrioxamine toxicity or deficiency of trace
elements. Although growth hormone (GH) deficiency and GH neurosecretory dysfunction have been described in TM patients,
most short TM patients have normal GH reserve. The low serum IGF-1 and IGFBP-3 concentrations in TM patients despite
having normal GH reserve and serum GH binding protein levels suggest that a state of secondary GH insensitivity exists. The
pubertal growth spurt may be impaired in TM patients going through spontaneous or induced puberty and may have a negative
effect on final adult height. GH therapy in dosages ranging from 0.5-1.0 IU/kg/wk has resulted in a significant improvement
in growth velocity in short TM children without any adverse effects on skeletal maturation, blood pressure, glucose tolerance
and serum lipids. There is limited evidence that GH treatment can result in an improved final adult height in short TM children.
Careful and regular clinical and biochemical monitoring should be preformed on these patients while they are treated with GH.
[Indian J Pedlatr 2005; 72 (2) : 159-164] E-mail: Icklow@hkucc.hku.hk
Key words : Thalassaemia major; Truncal shortening; GH insensitivity
The thalassemias are a group of inherited hematological
disorders characterised by early onset of anemia resulting
from reduced synthesis of one or more globin chains
which can be caused by m a n y different globin gene
mutations. ~-thalassemia major is the most c o m m o n
genetic variant of transfusion-dependent thalassaemia
seen in the Indian subcontinent, the Mediterranean basin,
Southeast Asia and China. Recent advances in medical
management of regular blood transfusion and chelation
t h e r a p y have allowed most of these patients to have
i m p r o v e d survival well into adult life and i m p r o v e d
quality of life24 Recently bone marrow transplantation
(BMT) in early childhood has resulted in disease-free
survival in patients with thalassaemia major and is now
an i m p o r t a n t alternative to regular t r a n s f u s i o n and
chelation therapy. ~ In children who received their BMT
before 7 years of age, their mean final adult height is not
significantly different from their mean target height. In
contrast, short stature is present in a significant proportion of thalassemic children transplanted later in life.7
Growth in Medically Treated Patients.with
~-Thalassemia Major
Before the introduction of hypertransfusion and chelation
therapy in the routine management of patients with ~thalassemia major, chronic tissue h y p o x i a and iron
Correspondence and Reprint requests : Dr. Louis C.K. Low,
Department of Pediatrics and Adolescent Medicine, The University
of Hong Kong, Queen Marg Hospital, Pokfulam Road, Hong Kong
SAR, PR China. Fax : (852) 2855 1523
Indian Journal of Pediatrics, Volume 72--February, 2005
toxicity f r o m t r a n s f u s i o n h e m o s i d e r o s i s h a v e b e e n
implicated as major causes of g r o w t h retardation. 2,8
P r o g r e s s i v e a c c u m u l a t i o n of iron in the b o d y in
t h a l a s s e m i c p a t i e n t s results f r o m r e p e a t e d b l o o d
transfusion and increased absorption of dietary iron
because of increased ineffective erythropoiesis. Without
chelation, hemosiderosis can lead to tissue damage due to
free radical formation, lipid peroxidation resulting in
mitochondrial, lysosomal and sarcolemal damage and
increased collagen deposition secondary to increased
activity of the i r o n - d e p e n d e n t protocollagen proline
hydroxylase enzyme activity?
M o d e r n medical t h e r a p y has allowed thalassemic
children to grow normally in the first decade of life but
g r o w t h r e t a r d a t i o n c o n t i n u e s to be o b s e r v e d in a
significant proportion of these adolescents. 2~,9-16BorgnaPignatti et al r e p o r t e d that a m o n g o v e r 250 Italian
adolescents, 29% of the females and 52% of the males
were short? In another recent report involving 476 Italian
thalassemic patients, the mean standing height SDS was
comparable to their mean target height SDS in the first
decade of life. 24 Short stature was still common in patients
in the 10 to 36 years age group and was present in 18% of
the patients. 14Kattamis et al reported that 21.7% of the
males and 13% of the females w e r e g r o w t h r e t a r d e d
among 405 Greek patients with thalassemia major with
the highest incidence of growth failure being detected in
the 15-20 years age group. 2 A more recent publication
from Greece reported that 8% of prepubertal boys and
none of the prepubertal girls (n=50%) were short. 25Short
159
Louis C.K. Low
final adult height was reported in 29% and 12% of male
patients with and without endocrinopathy and in 29%
and 15% of f e m a l e p a t i e n t s w i t h or w i t h o u t
e n d o c r i n o p a t h y a m o n g a c o h o r t of 95 G r e e k a d u l t
thalassemic patients. ~sA surprising finding was reported
from Italy that the growth rate of children receiving high
transfusion and early chelation in early childhood was
significantly slower than the childhood growth of patients
t r e a t e d w i t h c h e l a t i o n in late c h i l d h o o d or early
adolescence. 12This may have been due to the effect of
desferrioxamine toxicity which became recognised as
problem in late 1980s.
In our own cross sectional study of 68 children with ~thalassemia major in Hong Kong, 75% of the girls and
62% of the boys over the age of 12 years were below the
third percentile in height2 ~ A high prevalence of growth
and pubertal delay has been reported in thalassaemic
patients from T u r k e y and India? I'17 Cross sectional
studies on growth of thalassemic patients are problematic
and must been interpreted in the light that patients had
been treated with different transfusion regimes and
different d o s a g e s and age of initiation of chelation
therapy over time which would undoubtedly affect their
growth and final adult height. Patients treated with
hypertransfusion and early appropriate chelation therapy
with m e t i c u l o u s d o s a g e a d j u s t m e n t to avoid
desferrioxamine toxicity should lead to a more optimistic
growth outcome than depicted here.
In addition to short stature, an abnormal sitting height
has been reported in studies on thalassemic patients from
Australia TM a n d Italy. ~2,~4.~6A m o n g the s h o r t Italian
patients with thalassemia, the majority (77%) of the
patients had disproportionate short stature with short
trunk but with less severe impairment of subischial leg
length. ~2 In o u r s t u d y of 71 C h i n e s e c h i l d r e n and
adolescents with thalassemia, we f o u n d an u p p e r to
lower (U:L) segment ratio below the 10~ percentile in 60%
of the boys and 63% of the girls29 This abnormality of
body proportion was due to platyspondyly as revealed by
skeletal radiology and was present as early as 4 years of
age in our patients but was more common in adolescence.
The U:L segment ratio was not different among female
p a t i e n t s w i t h or w i t h o u t s h o r t s t a t u r e b u t was
significantly l o w e r in the boys with short stature as
compared to those with normal heights. We have no
obvious explanation for the sex difference observed but
this has not been reported in other studies, u,~8 It would
appear that short trunk frequently observed in patients
with ~-thalassemia is not necessarily the cause of the short
stature. P l a t y s p o n d y l y has been observed in patients
treated with transfusion but without chelation ~2and also
in p a t i e n t s w i t h low s e r u m f e r r i t i n level w h i l e on
hypertransfusion and regular chelation therapy since
early c h i l d h o o d . TM It is r e a s o n a b l e to s u g g e s t that
p l a t y s p o n d y l y in such patients can be the result of a
combination
of factors like h e m o s i d e r o s i s ,
desferrioxamine toxicity or deficiency of trace elements29
160
It is n o w recognised that short stature and skeletal
d y s p l a s i a can be i n d u c e d b y injudicious use of
d e s f e r r i o x a m i n e . 3,~6,2~ Clinically, the patients with
desferrioxamine-induced skeletal dysplasia have short
trunk, genu valgum, m e t a p h y s e a l w i d e n i n g of long
bones, joint stiffness and a decreased growth velocity.
Radiological changes include thickened growth plate with
widening and cupping of the metaphyses of long bones,
sclerosis of subchondral bone, osteoporosis and small
radioluscent metaphyseal lesions. Desferrioxamine can
inhibit DNA synthesis, fibroblast p r o l i f e r a t i o n and
collagen formation. TM The toxic effects of desferrioxamine
can also be due to a deficiency of trace elements such as
c o p p e r and zinc. TM In o r d e r to balance b e t w e e n the
efficacy and toxicity of desferrioxamine, the toxicity index
(mean daily dose of desferrioxamine in m g / k g , serum
ferritin in mg/L) should be monitored on a regular basis
and should not exceed 0.02522
The Growth Hormone-IGF-1 Axis in Patients with
Thalassaemia Major
The s t u d i e s on g r o w t h h o r m o n e (GH) s e c r e t i o n in
p a t i e n t s h a v e s h o w n b o t h n o r m a l 1~'23.24and r e d u c e d
r e s p o n s e 2s-28to a variety of pharmacological stimuli.
N o r m a l or subnormal s p o n t a n e o u s growth h o r m o n e
secretion has been reported in thalassemic patients. 2s-~~
The g r o w t h h o r m o n e r e s p o n s e to g r o w t h h o r m o n e
releasing h o r m o n e (GHRH) has been r e p o r t e d to be
normaF 3or reduced. 3t-~ In patients with delayed puberty,
the GH response to GHRH was reported to be impaired,
but the response improved with the onset of spontaneous
or induced puberty with sex steroids or gonadotropin. 32
In thalassemic patients with impaired GH response to
G H R H , the c o m b i n a t i o n of G H R H w i t h e i t h e r
pyridostigmine or arginine restored the GH response to
stimulation to a level comparable to that observed in
normal controls?~ This finding suggests that the impaired
GH secretion in some thalassemic patients may be due to
an increase in the somatostatinergic tone on GH release.
We h a v e f o u n d an i m p a i r e d G H response to insulin
induced hypoglycemia in 12% of 41 short thalassemic
children, all of whom were older than 9 years of age. 1~
GH deficiency was reported to be present in 24% and 50%
of short thalassemic patients from the United States 2s and
Great Britain. ~ The prevalence of GH deficiency among
65 short Greek thalassemic patients was found to be
20%. TM It is likely that as the patients survive longer, the
p r e v a l e n c e of G H d e f i c i e n c y or n e u r o s e c r e t o r y
d y s f u n c t i o n among these patients will increase with
advancing age.
The serum IGF-1 and IGFBP-3 levels have been shown
to be low in p a t i e n t s w i t h t r a n s f u s i o n d e p e n d e n t
thalassemia major2 ~ 1 7 6
The low serum IGF-1 level
in p a t i e n t s w i t h t h a l a s s e m i a has p r e v i o u s l y b e e n
attributed to a decreased hepatic synthesis due to liver
d a m a g e from t r a n s f u s i o n h e m o s i d e r o s i s b u t this is
u n l i k e l y to be the i m p o r t a n t c a u s a t i v e factor. No
Indian Journal of Pediatrics, Volume 72--February, 2005
Growth of Children with ~-Thalassemia Major
evidence for a defect in growth hormone binding to liver
membranes was found in patients with thalassemia
major. ~ We have found that serum GH binding protein
(GHBP) level was normal in short thalassemic patients
without GH deficiency 34 and this finding has been
confirmed in subsequent studies. 2s We also found no
difference in the serum IGF-1 levels between Chinese
thalassemic children (both prepubertal and pubertal) with
or without growth failure suggesting that the growth
failure in patients with thalassemia may not be
specifically related to the GHRH-GH-IGF-1 axis. ~~
The IGF-1 generation test following GH administration
was reported to be subnormalin thalassemic patients by
some investigators.27~ However normal IGF-1 generation
tests have also been found in similar patients following
GH administration~~ In thirteen non-GH deficient short
thalassemic children, GH therapy resulted in significant
improvement in the growth velocity as well as a dramatic
rise in the serum IGF-1 and IGFBP-3 levels)7The present
evidence (of normal GH reserve and serum GHBP levels
with low serum IGF-1 and IGFBP-3 concentrations)
suggests that a partial secondary GH insensitivity state
exists in patients with transfusion-dependent thalassemia
major and that supraphysiological doses of GH can
overcome this resistance and lead to an improvement in
the growth of such patients.
Hypogonadism and Growth in Adolescence
H y p o g o n a d i s m is the most frequent endocrine
complication in patients with thalassemia and is an
important cause of growth retardation in adolescence. In
a multicentre study from Italy involving 1861 patients,
hypogonadism was present in 47% of girls older than 15
years of age and secondary amenorrhoea in 23%,
menstrual irregularity in 14% and arrest of sexual
maturation in 13%. Hypogonadism was present in half
the male patients28 Similarly high prevalence of
disordered puberty has been reported in other
studies. ~~
Abnormal sexual maturation and
hypogonadism were reported in 36% of the male and 67%
of female patients from Australia.TM Bronspiegal-Weintrob
et al. reported that chelation therapy with desferrioxamine
before puberty can help thalassemic children to attain
normal sexual maturation. They observed that 90% of
patients who received adequate chelation before 10 years
of age had normal sexual development as compared to
38% in patients receiving chelation therapy after this age?3
Favourable outcome in similar patients following medical
therapy has also been reported from England.26However
even in patients who have gone through spontaneous
puberty, secondary amenorrhoea and hypogonadism will
invariably develop with time. ~
Hypogonadotropic hypogonadism is due to damage
from iron deposition in the hypothalamus and pituitary
gland but occasionally primary gonadal failure can also
occur. The pituitary gonadotropes are particularly
sensitive to oxidative damage induced by iron overload.
Indian Journal of Pediatrics, Volume 72--February, 2005
Magnetic resonance imaging (MRI) of the anterior
pituitary has shown that a decrease in signal intensity of
spin-echo images of the pituitary is associated with
increasing iron deposition in the anterior pituitary, and
may be a useful investigative tool in the assessment of
pituitary hemosiderosis. It has been shown that the
gonadotropin response to gonadotropin releasing
hormone stimulation is correlated with the grading of
MRl-assessed iron deposition in the pituitary gland)9 It
has also been shown recently that patients with certain
globin gene mutations (homozygous or double
heterozygous mutation for [339 and IVSInt110) may be
particularly susceptible to the development of
hypogonadism due to iron overload. 16
De Sanctis et al reported that the peak growth velocity
during puberty was below the 10= percentile in 66% of
males and 70% of females who had low pre-transfusion
hemoglobin and were started on desferrioxamine late
between 14 and 15 years of age. u 100% of the males and
46% of the females who were given high transfusion and
started on chelation between 6 to 7 years of age had a
peak growth velocity below the 10= precentile, u In a
group of patients given transfusion and no chelation, an
attenuated growth spurt was reported in all females with
spontaneous or induced puberty and in 33% of boys
during testosterone replacement. 40 In a study of 41
patients attending our centre who were over the age of 14
years, spontaneous puberty only occurred in 32% of the
patients. ~9A significant pubertal growth spurt with
spontaneous or induced puberty was observed in 46% of
the patients. A retrospective analysis of the growth of 20
patients between 3 years of age and their final heights
showed that the patients without a pubertal growth spurt
had a significantly higher serum ferritin concentration
and a shorter final height when compared to those
patients who experienced a growth spurt during
puberty. 19
Thus, it can be concluded that short adult stature in
transfusion-dependent thalassemia patients could be the
result of a number of factors including chronic anaemia,
hemosiderosis, endocrinopathy (disorder of the GH-IGF1 axis, hypothyroidism and hypogonadism), skeletal
dysplasia (hemosiderosis and desferrioxamine toxicity)
and impaired pubertal growth.
Growth Promoting Treatment in Patients with
Thalassemia Major
Over 130 children with thalassemia major and short
stature have been treated with growth hormone for the
past 20 years. 25,27~7,.1-4'These children were either GH
deficient or had normal growth hormone reserve and they
were treated with GH in dosages varying from 0.5 IU/
kg/week to 1.0 IU/kg/week. All the studies were open
label studies with the exception of the study by Arcasoy et
al." which was a randomised controlled trial. All the
studies have demonstrated that short term GH treatment
for one year resulted in significant increase in the growth
161
Louis C.K. Low
velocity without increase in rate of skeletal maturation
(Table 1). De Sanctis et al found no response in 4 out of 15
thalassaemic c h i l d r e n w i t h s h o r t s t a t u r e and G H
deficiency after one year of treatment with recombinant
GH in a dose of 06-0.8 I U / k g / w e e k and recommended
the use of higher GH dosage for the treatment in such
children. ~
In our experience, a positive effect on growth was still
present in children with thalassaemia major treated with
GH for 3 to 4 years with improvement in the height SDS
for both bone age and chronological age2 ,49 In contrast,
Cavallo et al. reported that the positive growth response
to GH treatment in the first year did not persist during the
second and third years of treatment. 5~A positive growth
response to GH was demonstrated in the second year of
treatment in the report by Wu et al2 z The discrepant
results in these studies may be due to a difference in GH
dosage, the p r e s e n c e of other e n d o c r i n o p a t h i e s like
h y p o g o n a d i s m , h y p o t h y r o i d i s m or the p r e s e n c e of
skeletal dysplasia due to desferrioxamine toxicity.
Information on thalassaemic patients treated with GH
until final h e i g h t is still limited. T h e o d o r i d i s et al.
reported the final height in 13 patients treated for 1.66 to
9 years with growth hormone at a dose of 0.5 I U / k g /
week. The final height SDS of -1.75 _+0.3 in boys (n=4)
and -1.58_+0.6 in girls (n=9) after G H t r e a t m e n t was
significantly better than the pre-treatment height SDS for
chronological age of -3.7_+1.0 in boys and -2.8_+0.5 in
girls tS. We have reported the final height data of 10 nonGH deficient thalassaemic patients treated with GH at a
dose of 1.0 I U / k g / w e e k from a mean age of 11.64_+2.06
years for 2.5 to 7 years. 51Treatment resulted in significant
improvement in the final height SDS of-0.61_+1.65 from a
p r e t r e a t m e n t h e i g h t SDS for c h r o n o l o g i c a l age of
-
2.39+1.05. The final adult height SDS was better than the
target height SDS of -1.02___0.71 based on the patients'
parental heights.
Insulin d e p e n d e n t d i a b e t e s mellitus is a k n o w n
complication in children with transfusion-dependent 6thalassemia and tends to occur in adolescence. The acute
and chronic effects of GH on glucose homeostasis and
insulin action are well established. One of our patients
d e v e l o p e d glycosuria while on G H treatment but no
impairment of glucose tolerance was demonstrated after
oral glucose challenge one w e e k after s t o p p i n g G H
treatment. In eight prepubertal patients, there was no
significant change in the fasting glucose, fasting insulin,
s e r u m f r u c t o s a m i n e and insulin sensitivity indices
derived from intravenous glucose tolerance test in our
patients during the 3 years of GH therapy. 49~1GH therapy
in these patients did not result in any worsening of the
body disproportions. 3 We also addressed the concern of
G H therapy on lipid metabolism in our thalassaemia
patients. A significant increase in apolipoprotein(a) (Lpa)
was demonstrated in 12 patients after 3 months of GH
t h e r a p y b u t the e l e v a t e d Lp(a) levels r e t u r n e d to
pretreatment values within 12 months of treatment and
r e m a i n e d at the basal level after 36 m o n t h s of G H
therapy. 52Our patients all had low pretreatment total and
high density lipoprotein-cholesterol (HDL-C) and there
was a further significant fall in the total cholesterol
concentration with GH treatment. Long-term GH
t h e r a p y in thalassaemic patients did not p r o m o t e an
atherogenic lipid profile, s2 There was no significant
change in the blood pressure, the blood count, renal and
liver function tests, morning cortisol and thyroid function
during GH therapy. 49-5~However, meticulous monitoring
of blood pressure, insulin sensitivity, biochemical and
T*SLE 1. Published Studies on the Short-Term Efficacy of Growth Hormone Therapy in Short Children with Thalassaemia Major
n
Scacchi Met al. 199141
Masala A et al. 199242
Oerter KE et al. 1993:5
GH
Duration
GV (cm/yr)
Pre
Post
8 GHD
2O
4 GHD
(3 with S)
13 N G H D
19 GHD
6 GHD
15 GHD
0.6 I U / k g / w k
0.6 I U / k g / w k
0.3 m g / k g / w e e k
1 year
1 year
I year
2.1+0.45
2.3•
2.1_+1.2
1.0 I U / k g / w k
0.6-0.8 I U / k g / w k
18 I U / m 2 / w k
0.6 I U / k g / w k
1 year
1 year
1 year
1 year
3.6_+0.7
2.5•
3.8•
-1.86_+1.76 SDS
(HV SDS)
(HV SDS)
Theodoridis C et al. 199815
9 girls GHD
4 boys GHD
0.5 I U / k g / w k
0.5 I U / k g / w k
1 year
1 year
2.72•
2.33•
5.67•
8.0•
Arcasoy A et al. 1999 ~a
0.7 I U / k g / w k
Katzos G e t al. 20004s
10 GHD
10 control
10 NGHD
28 IU/m2/wk
1 year
I year
I year
2.47+0.48
2.86_+0.39
4.22_+0.81
6.27•
3.99_+0.34
-7.61•
Sartorio A 2000~
5 GHD
0.6 I U / k g / w k
I year
2.3i-0.2
6.1•
Wu KH et al. 2003.7
8 GHD
0.7 I U / k g / w k
1 year
2 years
3.1+0.4
7.1+1.6
6.8_.+1.3
Low LCK et al. 199537
De Sanctis V e t al. 199748
Soliman AT et al. 199827
CavaUo Let al. 199843
4.1•
6.47•
6.1•
(with S)
6.9
8.0_+1.2
5.5•
7.2•
1.39•
SDS
* Randomised controlled trial; GHD: growth hormone deficient; NGHD: non-growth hormone deficient; S: sex steroid; HV: height velocity
162
Indian Journal of Pediatrics, Volume 72--February, 2005
Growth of Children with ~-Thalassemia Major
h o r m o n e p a r a m e t e r s s h o u l d b e d o n e o n all p a t i e n t s
regularly while they are o n G H treatment.
T h e a d m i n i s t r a t i o n of l o n g a c t i n g t e s t o s t e r o n e
p r e p a r a t i o n of 1 m g / k g / m o n t h was g i v e n in 11 n o n - G H
deficient b o y s w i t h t h a l a s s a e m i a a n d d e l a y e d p u b e r t y
a g e d 14.97_+1.2 y r s for 1 to 3.6 y e a r s . A n d r o . g e n
r e p l a c e m e n t p r o d u c e d a s i g n i f i c a n t i m p r o v e m e n t in
height velocity from 2.39_+0.9 c m / y r to 7.5_+1.7 c m / y r 15.
This was similar to the results reported by investigators
f r o m Italy. 53 H o w e v e r w e a n d o t h e r s h a v e p r e v i o u s l y
s h o w n that sex h o r m o n e r e p l a c e m e n t in t h a l a s s a e m i c
p a t i e n t s do n o t n e c e s s a r i l y lead to a significant g r o w t h
s p u r t . 12,19
8.
9.
10.
11.
12.
CONCLUSION
Despite advances in medical therapy, growth retardation
a n d h y p o g o n a d i s m c o n t i n u e to be p r o b l e m s observed in
t r a n s f u s i o n - d e p e n d e n t patients with thalassemia major.
A b n o r m a l G H s e c r e t i o n m a y b e s e e n in s o m e of the
patients b u t the m a j o r i t y of the short thalassemic patients
do n o t h a v e G H deficiency. The low s e r u m IGF-1 a n d
IGFBP-3 concentrations in short thalassemic patients with
n o r m a l G H r e s e r v e a n d s e r u m G H B P levels s u g g e s t a
s e c o n d a r y G H i n s e n s i t i v i t y state. S u p r a p h y s i o l o g i c a l
doses of G H can o v e r c o m e this partial G H i n s e n s i t i v i t y
state in these p a t i e n t s r e s u l t i n g in i m p r o v e m e n t in the
s h o r t - t e r m g r o w t h as w e l l as l i m i t e d e v i d e n c e o n a n
i m p r o v e m e n t in the f i n a l a d u l t h e i g h t . G H t h e r a p y
a p p e a r s to be safe b u t careful regular m o n i t o r i n g for the
d e v e l o p m e n t of side effects s h o u l d be p e r f o r m e d while
the patients are o n G H treatment.
Acknowledgement
13.
14.
15.
16.
17.
18.
19.
The author would like to thank Ms J Cheng for her help in the
preparation of the manuscript.
REFERENCES
1. Olivieri NF, Nathan DG, MacMillan JH et al. Survival in
medically treated patients with homozygous thalassemia
major. NEnglJMed 1994;331:574-578.
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