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https://doi.org/10.1016/j.phoj.2017.12.005
2468-1245/© 2018 Pediatric Hematology Oncology Chapter of Indian Academy of Pediatrics. Publishing Services by Elsevier B.V. This is an open access article under the CC
BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
P. Singh, A. Seth / Pediatric Hematology Oncology Journal 2 (2017) 98e106 99
Table 1
Comparative prevalence of endocrinal complications of children with TM.
Cyprus [2] Italy (1995) [3] Iran (2003) [4] TIF (2004) [5] North America (2004) [6] India (2014) [7]
Table 2 was evident from a prospective study to assess the age related
Factors contributing to growth failure in children and adolescents with TM. changes in serum IGF-1 concentrations in thalassemia patients
a. Chronic anaemia with ineffective erythropoiesis
compared to age and sex matched normal cohort. The normal
b. Under nutrition (Zinc Deficiency) healthy cohorts experienced a peak in IGF-1 levels at 13 years
c. Iron overload resulting in chronic liver disease and cardiac dysfunction (boys) @ 8e9 times the baseline. The thalassemia patients with
d. Transfusion associated infections like hepatitis C, B, HIV GHD did not show peak rise in IGF-1 levels till 18 years while the
e. Endocrinal dysfunctions- Defective GH-IGF-1 axis
subgroup with GHS reported a late and attenuated peak IGF-1
Defective Pituitary-Gonadal axis
Hypothyroidism, hypoparathyroidism levels at 16e18 years (@ 3 times from baseline) [16]. Further, the
Diabetes mellitus IGF-1 response to exogenous administration of GH is significantly
f. Side effects of chelation therapy on skeletal growth lower in children with thalassemia and GHD as compared to ones
g. Psychosocial stress who have idiopathic GHD [17]. There is another subgroup of thal-
assemia children who show a normal GH response to provocative
tests but their IGF-1 levels continue to be low suggesting a low GH
growth or during puberty with arrested or absent puberty and sensitivity (secondary to liver dysfunction) or a neurosecretory
absence of growth spurt. The growth plate fusion is also delayed in dysfunction. The latter manifests as an abnormal nocturnal GH
these children until the end of second decade and thus they have a secretory pulse pattern (due to high somatostatin tone) and lack of
potential for growing when most unaffected children have negative feedback regulation (in response to low IGF-1 levels) at
completed their growth. This is primarily due to iron load affecting the hypothalamus-pituitary level [17].
the Growth Hormone e Insulin like Growth Factor axis (GH-IGF Puberty (spontaneous/induced) plays a significant role in
axis) and the HPG axis. The anterior pituitary is particularly sen- achieving the desired growth spurt in adolescents by augmenting
sitive towards free radical oxidative stress from iron toxicity. the GH pulse amplitude that leads to a rise in IGF-1 and IGF-BP-3
The short stature (SS) encountered in thalassemia is often levels. There is a mutual amplifying effect in the concentration of
disproportionate with a low upper segment to lower segment ratio GH, IGF-1 levels and sex steroids observed during the progressive
[10]. The exact reason is not clear and an interplay of multiple stages of puberty that results in growth spurt, appearance of sec-
factors are responsible for it. In thalassemia, there is a progressive ondary sexual characteristics, increase in muscle mass and bone
impairment in spinal growth observed since early childhood [11]. mineral accretion. Children with thalassemia experience delay/ar-
Besides, other factors implicated in body disproportion include iron rest in puberty due to the hypogonadotropic hypogonadism with or
overload (impaired cartilage growth), early use of desferrioxamine without loss of gonadal function [18].
(DFO) for chelation and delayed puberty (hypogonadism). Use of
DFO between 2 and 5 years has a paradoxical adverse effect on
growth through inhibition of cell proliferation, DNA synthesis, and 2.1. Growth monitoring in children with thalassemia
collagen formation and trace mineral deposition like Zn and Cu
resulting in flattening of vertebrae (platyspondylosis) and reduced 1. A longitudinal record of weight and height (along with Mid
spinal height [12]. Short trunk, genu valgum, metaphyseal parental height (MPH) and Target range) and BMI should be
widening and joint stiffness is noted. The radiological changes seen maintained on a growth chart at six monthly interval to facilitate
are thickened growth plates with widening and cupping of meta- early detection of growth faltering. MPH is calculated by adding
physes, sclerosis of subchondral bone with small radiolucent areas 6.5 cm to the average of the mother's and father's height in the case
localised to the metaphyses and osteoporosis and increased of boy and by subtracting 6.5 cm in the case of girl. Statistically 95%
trabecular pattern of long bones. Off late, deferiprone treatment has of the children are expected to reach an adult height within a range
been reported to be associated with arthropathy mainly of the of about 8.5 cm above or below the MPH percentile (i.e. ±2SD on
knees [13,14]. MRI studies indicate that damage to the cartilage and either side of MPH). This range is called as Target range. The annual
the subchondral bone persist despite stopping treatment. growth velocity (GV) is assessed, if < 25th percentile consider it a
Several mechanisms influencing the Growth Hormone red flag.
Releasing Hormone (GHRH)-GH-IGF- axis have been proposed to 2. Compare the height indices (height for age) of the patient
explain the growth faltering in patients with TM [15]: (height SDS or centiles) with the population data as well as with the
(1) Hypothalamic GH-releasing hormone deficiency (2) pitui- mid-parental height (SDS or centiles).
tary GH deficiency; (3) neurosecretory dysfunction and (4) relative
GH insensitivity. Growth Hormone deficiency (GHD) is seen in
20e30% of thalassemia patients while the remaining 70e80% show 2.2. Definition of short stature
a peak growth hormone levels lower than those found in patients
with constitutional short stature in response to GH provocative Height is less than the 3rd percentile or 2 SD below the mean
stimuli like clonidine. Children with TM exhibit low IGF-1 levels in height for age and sex; OR
both GH deficient (GHD) and GH sufficient (GHS) subgroups. This Height is within normal but GV is consistently <25th percentile
over 6e12 months; OR
100 P. Singh, A. Seth / Pediatric Hematology Oncology Journal 2 (2017) 98e106
The patient is excessively short for his/her mid-parental height, i. Treatment of anaemia and optimizing chelation therapy.
though his absolute height may be within the normal ii. Correction of nutritional deficiencies if any, undernutrition
percentiles. and mineral deficiencies (zinc)
iii. Treatment of overt hypothyroidism
3. Assess for onset and progress of puberty (SMR using Tanners iv. GH treatment is indicated in established cases with GH
staging) annually for all children above 10 years of age. The varied deficiency.
phenotypes of pubertal delay are described in Table 3. v. Timely replacement therapy with sex steroids in children
with failure of spontaneous pubertal onset/poor progression
of puberty.
2.3. Assessment in a child with short stature vi. Psychosocial support
Table 3
Definitions in pubertal delay.
I. Delayed Puberty: Absence of gonadarche (Testicular Volume 4 ml) in males by 14 years and thelarche (appearance of breast bud) in females by 13 years.
II. Arrested puberty: Arrested puberty is defined as the absence of further pubertal progression once puberty has started for more than 1 year, where testicular volume in
boys never progressed beyond 6e8 ml and breast size in girls remained unchanged.
III. Primary amenorrhoea: Failure in menarche by 16 years.
IV. Secondary amenorrhoea: Absence of menstrual periods for >12 months after menarche.
P. Singh, A. Seth / Pediatric Hematology Oncology Journal 2 (2017) 98e106 101
supports the short term use of rhGH therapy in thalassemia pa- is needed for evaluating the pituitary ability to synthesize and
tients with short stature as it augments the linear growth velocity secrete gonadotropins. If LH and/or FSH are low (peak serum LH
with maximum benefit being observed in first year of therapy, level <5 IU/L after 4 h) after GnRH stimulation, it indicates that
However, data to demonstrate its long term benefit in improving pituitary is not yet primed to enter puberty, indicating delayed
final height is lacking [23,24]. There is uncertainty regarding the puberty or possible hypogonadotrophic hypogonadism (HH).
ideal time to start GH therapy and the dosage. Finally, the decision Rarely, pubertal failure may be due to direct gonadal damage this
to use rhGH therapy should depend on the patient profile (age, would be indicated by presence of elevated FSH and LH levels.
pubertal status), comorbidities (iron overload and chronic liver Bone age evaluation is useful for prediction of the remaining
disease), cost benefit ratio and the risk of adverse events (impaired growth potential and final adult height of these patients. Pelvic
glucose tolerance). During GH treatment, patients should be ultrasound is useful in assessing ovarian and uterine maturation.
monitored at 3-monthly intervals with a clinical assessment and an MRI pituitary (T2*) can be utilized as an early tool to detect iron
evaluation for parameters of GH response (growth parameters, deposits in the pituitary.
compliance) and adverse effects.
The prevalence of pubertal disorders in adolescents with thal- There are no standard recommendations to guide pubertal in-
assemia despite regular transfusions and optimal chelation therapy duction in chronic diseases like thalassemia. The protocols used to
ranges between 30 and 70% in various studies [2]. Early recognition induce puberty in constitutional delay of puberty can be applied in
and adequate management of such children can not only help in such cases with delayed puberty [19,25]. The primary goal in the
optimizing growth and puberty but also improve the quality of life management of delayed puberty is to mimic biological and
and restore the fertility potential. The key factor implicated is the biochemical pubertal events with concomitant promotion of sexual
iron overload that mediates its oxidative damage (through iron- maturation and linear growth. These goals can be achieved by
generated free radicals) to the hypothalamic- pituitary- gonadal pubertal induction at a bone age of >11 years and >12 years for girls
axis. The cause is usually damage to gonadotrophs in anterior pi- and boys respectively; in adolescents with pubertal delay. It is
tuitary leading to failure of adequate production of gonadotrophins underscored that the children planning to go to TM who have
LH & FSH. Direct gonadal damage by iron overload is much less delayed puberty should not undergo pubertal induction as that
likely. In fact, many patients have normal ovarian function and can simply increases the risk of infertility.
produce expected number of ova after stimulation and thus achieve The puberty induction should not be delayed beyond 14 years to
fertility. maximise growth potential and avoid deleterious effects on bone
The clinical presentation can range from a delay in the onset of mineral accrual. The optimal regime depends on the patient profile
puberty to pubertal arrest and complete failure (Table 3). Presence age, height and expected height, financial condition, psychological
of pubertal abnormalities has many implications apart from po- state, the set treatment goals and the personal experience of the
tential infertility. It contributes towards short stature due to absent/ treating endocrinologist. Chatterjee et al. [26] reported successful
poor pubertal growth spurt. Associated poor sexual development outcome of priming by low dose sex steroid in a small Indian
contributes towards poor body image in the adolescent subject cohort. In a 6-year prospective study of 55 Indian TM children
with thalassemia. Since sex steroids have an important role to play (15e18 years) with stunted growth and delayed/arrested puberty,
in pubertal bone mass accrual, these subjects fail to achieve opti- 80% reported favourable response to low dose sex steroid priming
mum bone mass, a factor that contributes towards osteopathy (6e12 months) with increase in height, growth spurt and
observed thalassemia. The adolescent girls usually suffer from completed pubertal maturation (Tanner stage 4e5) [26].
primary amenorrhea while secondary amenorrhea likely to be
encountered in the older age group (late twenties). The uterus and 3.2.1. Boys
gonads show a subnormal growth and reach a final size smaller Boys are treated with a depot testosterone preparation @ 50 mg
than their age matched healthy cohorts. Similarly, the boys fail to i.m every 4 weeks for a duration of 6 months [19,25]. This leads to
show the pubertal growth spurt, appearance/progression of sec- an increase in penile size and the appearance of pubic hair. If during
ondary sexual characteristics and increase in the testicular volume. this time an increase in testicular volume is observed, it indicates
MRI brain is a useful tool to assess the degree of siderosis in the activation of the H-P-G axis and release of gonadotrophins (FSH and
pituitary (reduced signal intensity in anterior pituitary) to provide LH). In this situation, no further doses are given and children fol-
an insight to the disease progression and prognosis. lowed closely for progression of spontaneous puberty.
3.2.3. Pubertal induction in boys and subsequently evolve to Type 1 Diabetes mellitus. The diabetes
In boys, therapy consists of gradually increasing doses of intra- in thalassemia differs from the classical Type 1 DM by the absence
muscular depot preparations of testosterone enanthate starting of Islet cell antibodies, no relation with HLA DR/DR4 and infrequent
from 50 mg every 4 weeks, with progressive increase in the dose association with DKA [40]. However diabetics with thalassemia are
every 6e12 months in increments of 50 mg until the adult more predisposed to develop nephropathy (oxidative stress) [41]
replacement dose is achieved (over a period of 3e4 years), which is and less likely to develop retinopathy (low IGF-1 levels) [42]. The
300 mg every 3 weeks In cases where testicular volume is pre/early progression from IGT to DM is usually slow and can-not be pre-
pubertal, the above therapy is combined with injection hCG @ dicted. In one of the prospective study, the progression from IGT to
500e1500 IU (s,c or i.m) on alternative days or a combination of DM was reported in 12.4% adolescent thalassemics over a period of
hCG and FSH (human menopausal gonadotropin, highly purified 10 years [32]. Beside iron overload, chronic anaemia, Zinc defi-
urinary FSH or recombinant FSH), the latter @ 75e100 IU (s.c or i.m) ciency and increased collagen deposition (secondary to increased
on alternate days. In this situation the therapy is initially started activity of iron dependent protocollagen proline hydroxylase
with injection hCG; and FSH added after 6e12 months if the enzyme) leading to disturbed microcirculation in the pancreas are
testicular volume plateaus [25]. implicated in the development of diabetes in thalassemia.
Table 4
Protocol to screen endocrinopathies in children with TM.
Issues Assesment
Under basal conditions, subclinical impairment of adrenocor- Since most endocrine complications make an appearance dur-
tical function in patients with thalassemia is of not much clinical ing the second decade of life and beyond, it is recommended that all
significance. However, it has relevance during stressful situations children with TM undergo a comprehensive annual endocrine
where in glucocorticoid supplementation may be indicated to screening beginning 9 years of age (Table 4) [19]. Prior to that, a
prevent adrenal crisis [63]. regular growth monitoring is done every 6 months from enrolment
and pubertal onset and progression are determined every 6 months
after the age of 10 years. The annual endocrine includes thyroid
8. Hypothyroidism function tests (free T4 and TSH), fasting glucose, oral glucose
tolerance test (if indicated), serum Calcium, serum phosphate
The thyroid dysfunction in thalassemia develops as a result of (fasting), vitamin D and PTH (if indicated by clinical symptoms or
thyroidal cell siderosis, usually seen in the second decade of life. biochemical features), and bone age. The LH, FSH, and sex steroids
Primary hypothyroidism occurs much before the iron toxicity af- are evaluated in the adolescents with delayed/arrested puberty. A
fects the hypothalamic-pituitary axis; making secondary hypothy- baseline DXA scan followed by annual/once in 2 years screening of
roidism a much rarer entity. The prevalence of hypothyroidism bone mineral density is also recommended.
varies from 0 to 18% as demonstrated in various studies [3]. The
mechanisms of injury are possibly lipid peroxidation, free radical 10. Summary and conclusions
release and oxidative stress due to iron overload. The degree of
thyroid dysfunction is directly related to the degree of iron over- Management of a child with thalassemia requires regular eval-
load, with the early stages being reversible by intensive chelation uation by an endocrinologist beginning second decade of life due to
therapy. However, the progression of subclinical to overt hypo- a high prevalence of endocrine dysfunctions seen in these patients.
thyroidism is not foreseeable and may take many years [64]. The Prevention is the best approach since efficacy of intensive chelation
patients are usually asymptomatic and have an impalpable thyroid in reversing established endocrinopathies is unknown. Thus, pre-
gland. Studies have reported serum ferritin to positively correlate venting anaemia through a regular transfusion schedule, optimum
with the TSH and USG of the thyroid gland (reduced echogenicity chelation, maintaining an adequate nutritional status and prompt
with reduced volume and thickening of the thyroid capsule), and recognition and treatment of co-morbidities form the cornerstones
predict the progression of the thyroid dysfunction in thalassemia of endocrinopathy prevention. However, the endocrinopathies are
[65]. Apart from contributing towards statural growth and bone still being seen because the majority of TM patients lack adequate
mineralisation, optimising thyroid functions is important for clinical care. Early identification and prompt management of the
improving the cardiac function, since cardiac failure is the most endocrine complications have a significant role in reducing
important cause of mortality in thalassemia. morbidity and mortality of thalassemia patients.
References
8.1. Assessment of thyroid functions
[1] Bannermann RM, Keusch G, Kreimer-Birnbaum M, Vance VK, Vaughan S.
It is recommended to have annual evaluation of thyroid function Thalassaemia intermedia with iron overload, cardiac failure, diabetes mellitus,
hypopituitarism and porphyrinuria. Am J Med 1967;42:476e86.
tests beginning at the age of 10 years (unless symptomatic hypo- [2] Toumba M, Sergis A, Kanaris C, Skordis N. Endocrine complications in patients
thyroidism is present) [19]. Assessment of thyroid functions in- with thalassemia major. Pediatr Endocrinol Rev 2007;5(2):642e8.
volves measurement of serum T4 (free) and TSH levels. The patient [3] Multicentre study on prevalence of endocrine complications in thalassaemia
major. Italian working group on endocrine complications in non-endocrine
can have biochemical features of subclinical (low or normal free T4 diseases. Clin Endocrinol (Oxf) 1995 Jun;42(6):581e6.
with a high TSH) or overt hypothyroidism (low free T4 with a high [4] Shamshirsaz AA, Bekheirnia MR, Kamgar M, Pourzahedgilani N, Bouzari N,
TSH). Habibzadeh M, et al. Metabolic and endocrinologic complications in beta-
thalassemia major: a multicenter study in Tehran. BMC Endocr Disord 2003
Aug 12;3(1):4.
[5] De Sanctis V, Eleftheriou A, Malaventura C. Thalassaemia international
8.2. Management federation study group on growth and endocrine complications in thalas-
saemia. prevalence of endocrine complications and short stature in patients
with thalassaemia major: a multicenter study by the Thalassaemia Interna-
Good compliance with chelation therapy may prevent or reverse tional Federation (TIF). Pediatr Endocrinol Rev 2004;2:249e55.
thyroid dysfunction in early stages. Sub-clinical hypothyroidism- [6] Cunningham MJ, Macklin EA, Neufeld EJ, Cohen AR. Complications of beta-
basal TSH 5e7 mIU/ml will require regular follow-up and opti- thalassemia major in North America. Blood 2004;104:34e9.
[7] Sharma R, Seth A, Chandra J, Gohain S, Kapoor S, Singh P, et al. Endo-
mizing chelation therapy [19]. Cases with overt hypothyroidism are crinopathies in adolescents with thalassaemia major receiving oral iron che-
managed with age appropriate dose of L-thyroxine. lation therapy. Paediatr Int Child Health 2016 Feb;36(1):22e7.
P. Singh, A. Seth / Pediatric Hematology Oncology Journal 2 (2017) 98e106 105
[8] Shalitin S, Carmi D, Weintrob N, Phillip M, Miskin H, Kornreich L, et al. Serum Endocrinol Metabol 1993;77:478e83.
ferritin level as a predictor of impaired growth and puberty in thalassemia [36] Cavallo-Perin P, Pacini G, Cerutti F, Bessone A, Condo C, Sacchetti L, et al.
major patients. Eur J Haematol 2005;74:93e100. Insulin resistance and hyperinsulinemia in homozygous beta-thalassemia.
[9] De Sanctis V, Roos M, Gasser T, Fortini M, Raiola G, Galati MC. Italian working Metabolism 1995;44:281e6.
group on endocrine complications in non-endocrine diseases. impact of long- [37] Pappasab S, Donohuea SM, Denver AE, Mohamed-Ali V, Goubet S, Yudkin JS.
term iron chelation therapy on growth and endocrine functions in Thalas- Glucose intolerance in thalassemia major is related to insulin resistance and
saemia. J Pediatr Endocrinol Metabol 2006;19(4):471e80. hepatic dysfunction. Metabolism 1996;45:652e7.
[10] Caruso-Nicoletti M, De Sanctis V, Capra M, Cardinale G, Cuccia L, Di Gregorio F, [38] Cario H, Holl RW, Debatin KM, Kohne E. Insulin sensitivity and beta- cell
et al. Short stature and body proportion in thalassaemia. J Pediatr Endocrinol secretion in thalassaemia major with secondary haemochromatosis: assess-
Metabol 1998;11(Suppl 3):811e6. ment by oral glucose tolerance test. Eur J Pediatr 2003;162:139e46.
[11] Low LCK. Growth, puberty and endocrine function in beta-thalassaemia ma- [39] Angelopoulos NG, Zervas A, Livadas S, Adamopoulos I, Giannopoulos D,
jor. J Pediatr Endocrinol Metabol 1997;10:175e84. Goula A, et al. Reduced insulin secretion in normoglycaemic patients with
[12] De Virgiliis S, Congia M, Frau F, Argiolu F, Diana G, Cucca F, et al. Deferox- beta-thalassaemia major. Diabet Med 2006;23:1327e31.
amine-induced growth retardation in patients with thalassemia major. [40] Pollack MS, Levine LS, Oberfield SE, Markenson AL. HLA-A, B, C, and DR an-
J Pediatr 1988 Oct;113(4):661e9. tigen frequencies in relation to development of diabetes and variations in
[13] Cohen AR, Galanello R, Piga A, De Sanctis V, Tricta F. Safety and effectiveness white cell antibody formation in highly transfused thalassemia patients.
of long-term therapy with the oral iron chelator deferiprone. Blood 2003;102: Transfusion 1982;22:279e82.
1583e7. [41] Loebstein R, Lehotay DC, Luo X, Bartfay W, Tyler B, Sher GD. Diabetic ne-
[14] Sharma R, Anand R, Chandra J, Seth A, Pemde H, Singh V. Distal ulnar changes phropathy in hypertransfused patients with beta-thalassemia. The role of
in children with thalassemia and deferiprone related arthropathy. Pediatr oxidative stress. Diabetes Care 1998;21(8):1306e9.
Blood Canc 2013 Dec;60(12):1957e62. [42] Incorvaia C, Parmeggiani F, Mingrone G, Sebastiani A, De Sanctis V. Prevalence
[15] Shehadeh N, Hazani A, Rudolf MC, Peleg I, Benderly A, Hochberg Z. Neuro- of retinopathy in diabetic thalassaemic patients. J Pediatr Endocrinol Metabol
secretory dysfunction of growth hormone secretion in thalassemia major. 1998;11(Suppl 3):879e83.
Acta Paediatr Scand 1990;79:790e5. [43] American Diabetes Association. Standards of medical care in diabetes-2017.
[16] Spiliotis BE, Chrysis DC, Alexandrides TK, Georgopoulos N, Koromantzou EV, J Clin Appl Res Edu 2017;40(Suppl 1):S11e24.
Beratis NG. IGF-I generation test as a potential marker of growth hormone [44] Albaker WI, Yousef AA, Khamis AH, Aldilaijan AF, AlMaghlouth NK. The
neurosecretory dynamics in b-thalassemia. In: Program and abstracts of the continuous glucose monitoring system (CGMS) in patients with beta-
10th international congress of endocrinology, San Francisco; 1996. p. 1e127. thalassemia major. Saudi J Med Med Sci. 2013;1:88e93.
[17] Soliman AT, El Banna N, Ansari BM. GH response to provocation and circu- [45] Choudhary A, Giardina P, Antal Z, Vogiatzi M. Unreliable oral glucose tolerance
lating IGF-I and IGF-binding protein-3 concentrations, the IGF-I generation test and HbA1C in Beta Thalassaemia major-A case for continuous glucose
test and clinical response to GH therapy in children with beta-thalassaemia. monitoring? Br J Haematol 2013;162(1):132e5.
Eur J Endocrinol 1998;138:394e400. [46] Noetzli LJ, Mittelman SD, Watanabe RM, Coates TD, Wood JC. Pancreatic iron
[18] Soliman AT, De Sanctis V, Elalaily R, Yassin M. Insulin-like growth factor- I and and glucose dysregulation in thalassemia major. Am J Hematol 2012;87(2):
factors affecting it in thalassemia major. Indian J Endocrinol Metabol 2015 155e60.
Mar-Apr;19(2):245e51. [47] Pepe A, Meloni A, Rossi G, Caruso V, Cuccia L, Spasiano A, et al. Cardiac
[19] De Sanctis V, Soliman AT, Elsedfy H, Skordis N, Kattamis C, Angastiniotis M, complications and diabetes in thalassaemia major: a large historical multi-
et al. Growth and endocrine disorders in thalassemia: the international centre study. Br J Haematol 2013;163(4):520e7.
network on endocrine complications in thalassemia (I-CET) position state- [48] Rombopoulos G, Tolis G. Effect of enhanced iron chelation therapy on glucose
ment and guidelines. Indian J Endocrinol Metabol 2013 Jan;17(1):8e18. metabolism in patients with beta-thalassaemia major. Br J Haematol
[20] Soliman AT, Khalafallah H. Ashour. growth and factors affecting it in thalas- 2006;134:438e44.
semia major. Hemoglobin 2009;33(Suppl 1):S116e26. [49] Christoforidis A, Perifanis V, Tsatra I, Vlachaki E, Athanassiou-Metaxa M.
[21] Theodoridis C, Ladis V, Papatheodorou A, Berdousi H, Palamidou F, Evolution of OGTT in patients with beta-thalassaemia major in relation to
Evagelopoulou C, et al. Growth and management of short stature in thalas- chelation therapy. Diabetes Res Clin Pract 2007;76:6e11.
saemia major. J Pediatr Endocrinol Metabol 1998;11(Suppl 3):835e44. [50] Dhouib N, Turki Z, Mellouli F, Ouederni M, Yahiaoui S, Nagi S, et al. Efficacy of
[22] LeRoith D, Yakar S. Mechanisms of disease: metabolic effects growth hormone metformin in the treatment of diabetes mellitus complicating thalassemia
and insulin-like growth factor 1. Nat Clin Pract Endocrinol Metabol 2007;3: major. Tunis Med 2010;88:136.
302e10. [51] Ladis V, Theodorides C, Palamidou F, Frissiras S, Berdousi H, Kattamis C.
[23] Cavallo L, De Sanctis V, Cisternino M, Caruso Nicoletti M, Galati MC, Glucose disturbances and regulation with glibenclamide in thalassemia.
Acquafredda A, et al. Final height in short polytransfused thalassemia major J Pediatr Endocrinol Metabol 1998;11(Suppl. 3):871e8.
patients treated with recombinant growth hormone. J Endocrinol Invest [52] Mangiagli A, Campisi S, De Sanctis V, Nicoletti MC, Cardinale G, Galati MC,
2005;28:363e6. et al. Study Group of the Italian Pediatric and Diabetes Soceity (SIEDP) on
[24] Ngim CF, Lai NM, Hong JYH, Tan SL, Ramadas A, Muthukumarasamy P, et al. endocrine complicaionts in non-endocrine disease. effects of acarbose in beta-
Growth hormone therapy for people with thalassaemia. Cochrane Database thalassaemia major patients with normal glucose tolerance and hyperinsu-
Syst Rev 2017 Sep;9. CD012284. linism. Pediatr Endocrinol Rev 2004 Dec;2(Suppl 2):276e8.
[25] Pozoa J, Argentea J. Ascertainment and treatment of delayed puberty. Horm [53] Jensen CE, Tuck SM, Agnew JE, Koneru S, Morris RW, Yardumian A, et al. High
Res 2003;60(suppl 3):35e48. prevalence of low bone mass in thalassaemia major. Br J Haematol 1998
[26] Chatterjee R, Mukhopadhyay TN, Chandra S, Bajoria R. Sex steroid priming for Dec;103(4):911e5.
induction of puberty in thalassemia patients with pulsatile reversible hypo- [54] Voskaridou E, Terpos E. New insights into the pathophysiology and man-
gonadotrophic hypogonadism. Hemoglobin 2011;35(5e6):659e64. agement of osteoporosis in patients with beta thalassaemia. Br J Haematol
[27] Bajoria R, Chatterjee R. Current perspectives of fertility and pregnancy in 2004 Oct;127(2):127e39.
thalassemia. Hemoglobin 2009;33:131e5. [55] Bachrach LK. Diagnosis and treatment of pediatric osteoporosis. Curr Opin
[28] Perera D, Pizzey A, Campbell A, Katz M, Porter J, Petrou M, et al. Sperm DNA Endocrinol Diabetes Obes 2014 Dec;21(6):454e60.
damage in potentially fertile homozygous beta-thalassaemia patients with [56] Moulas A, Challa A, Chaliasos N, Lapatsanis PD. Vitamin D metabolites (25-
iron overload. Hum Reprod 2002;17:1820e5. hydroxyvitamin D, 24,25-dihydroxyvitamin D and 1,25-dihydroxyvitamin
[29] Gamberini MR, Fortini M, De Sanctis V, Gilli G, Testa MR. Diabetes mellitus and D) and osteocalcin in B-thalassaemia. Acta Paediatr. 1997;86:594e9.
impaired glucose tolerance in thalassaemia major: incidence, prevalence, risk [57] IOM (Institute of Medicine). Dietary reference intakes for and vitamin D.
factors and survival inpatients followed in the Ferrara Center. Pediatr Endo- Washington, DC: The National Academies Press; 2011.
crinol Rev 2004;2(Suppl 2):285e91. [58] Wood JC, Claster S, Carson S, Menteer JD, Hofstra T, Khanna R, et al. Vitamin D
[30] Cavallo L, Trentadue F, Liuzzi S, Giobbe T, Leuzzi R, Sabato V, et al. A transverse deficiency, cardiac iron and cardiac function in thalassaemia major. Br J
and longitudinal study of pancreatic function and glucose tolerance in thal- Haematol 2008;141:891e4.
assemic patients. In: Ando S, Brancati C, editors. Endocrine disorders in [59] Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA,
thalassemia. Berlin: Springer Verlag; 1995. p. 153e5. Heaney RP, et al. Endocrine society. evaluation, treatment, and prevention of
[31] Hafez M, Youssry I, El-Hamed FA, Ibrahim A. Abnormal glucose tolerance in vitamin D deficiency: an endocrine society clinical practice guideline. J Clin
beta thalassemia: assessment of risk factors. Hemoglobin 2009;33:101e8. Endocrinol Metabol 2011 Jul;96(7):1911e30.
[32] Kattamis C, Ladis V, Tsoussis D, Kaloumenou I, Theodoridis C. Evolution of [60] Skordis N, Loannou YS, Kyriakou A, Savva SC, Efstathiou E, Savvides I, et al.
glucose intolerance and diabetes in transfused patients with thalassemia. Effect of bisphosphonate treatment on bone mineral density in patients with
Pediatr Endocrinol Rev 2004;2(Suppl 2):267e71. thalassaemia major. Pediatr Endocrinol Rev 2008;6:144e8.
[33] Soliman A, De Sanctis V, Yassin M, Elalaily R, Eldarsy NE. Continuous glucose [61] De Sanctis V, Elawwa A, Angastiniotis M, Eleftheriou A, Kattamis C, Karimi M,
monitoring system and new era of early diagnosis of diabetes in high risk et al. Highlights from the first Thalassaemia forum on growth and endocrine
groups. Indian J Endocrinol Metabol 2014;18:274e82. complications in Thalassemia Doha, (October 2-3, 2011). Pediatr Endocrinol
[34] Merkel PA, Simonson DC, Amiel SA, Plewe G, Sherwin RS, Pearson HA, et al. Rev 2012 Mar;9(3):672e9.
Insulin resistance and hyperinsulinemia in patients with thalassemia major [62] Pasqualetti P, Colantonio D, Collacciani A, Casale R, Natali G. Circadian pattern
treated by hypertransfusion. N Engl J Med 1988;318:809e14. of circulating plasma ACTH, cortisol, and aldosterone in patients with beta-
[35] Dmochowski K, Finegood DT, Francombe W, Tyler B, Zinman B. Factor's thalassemia. Acta Endocrinol (Copenh) 1990;123:174e8.
determining glucose tolerance in patients with thalassemia major. J Clin [63] Elsedfy HH, El Kholy M, Tarif R, Hamed A, Elalfy M. Adrenal function in
106 P. Singh, A. Seth / Pediatric Hematology Oncology Journal 2 (2017) 98e106
thalassemia major adolescents. Pediatr Endocrinol Rev 2011;8:295e9. [65] Chirico V, Lacquaniti A, Salpietro V, Luca N, Ferraù V, Piraino B, et al. Thyroid
[64] De Sanctis V, Tanas R, Gamberini MR, Sprocati M, Govoni MR, Marsella M. Dysfunction in thalassemic patients: ferritin as prognostic marker and com-
Exaggerated TSH Response to TRH (‘Sub-Biochemical’ Hypothyroidism) in bined iron chelators as ideal therapy. Eur J Endocrinol 2013 Oct 21;169(6):
prepubertal and adolescent thalassaemic patients with iron overload: prev- 785e93.
alence and 20-year natural history. Pediatr Endocrinol Rev 2008;6(1):170e3.