1. Ashraf T Soliman MD PhD FRCP Professor of Pediatrics and Endocrinology
Linear Growth and PUBERTAL ABNORMALITIES IN CHILDREN AND ADOLESCENTS WITH Beta Thalassemia
Ashraf T Soliman MD PhD FRCP
Professor of Pediatrics and Endocrinology

2. I-CET-A Course - Countries

5. Farag Talaat. http://ambassadors

6. INDIA

7. Musallam K M et al. Haematologica 2013;98:833-844

8. Clinical complications profile of regularly transfused β-thalassemia major patients.
Growth failure
Differences in common clinical complications profile between non-transfusion-dependent thalassemias compared to regularly transfused β-thalassemia major patients. The figure illustrates those complications that are often observed at a higher prevalence in one group over the other in available studies and clinical settings, although all mentioned complications can exist in both entities at varying rates.
©2013 by Ferrata Storti Foundation
Musallam K M et al. Haematologica 2013;98:

9. What is the Magnitude of these problems?
Do Patients with Thalassemia have significant Growth and Pubertal Disorder?
What is the Magnitude of these problems?

13. Nutrition
Genes T4
GH – IGF-I
Nutrition
Genes T4
Sex Steroids
Nutrition
GH-IGF-I
Genes T4

16. How to Assess Growth Axis
GHRH test
GH Stimulation test
History
Nutrition
Physical exam
Anthropometry
Measure IGF-I
Measure Growth and bone age

22. How to Assess Gonadal Axis
GnRH test
FSH- LH Basal
+ Pulsatile properties
Basal Testosterone and
T after HCG
Basal Estradiol & Progesterone
History
Tanner stage
Growth
Physical Exam
Growth- Tanner Staging
Testicle size, US ovary -uterus
Bone age

33. How to Investigate Short Patient

34. What is the Magnitude of these problems?
Do Patients with Thalassemia have significant Growth and Pubertal Disorder?
What is the Magnitude of these problems?

35. Prevalence of Growth & Pubertal Abnormalities
SURVEYS
Prevalence of Growth & Pubertal Abnormalities
in Patients with Thalassaemia Major

36. I. Growth and Pubertal Survey Qatar Egypt Iran Italy Cyprus Romania

37. Growth and Pubertal Surveys
Country survey
Growth Delay
Hypogonadism
Cyprus
35%
32%
Greece
42%
Italy
---
49%
Egypt
62%
73% males,
42% females
Qatar
46%
Romania
54%
77% males
41% females
N. America
----
TIF
30.8%
40.5%
Pediatr Endocrinol Rev Dec;5(2): ,& Clin Endocrinol (Oxf) Jun;42(6):581-6.
Acta Endocrinologica (Buc), vol. I, no. 2, p , 2005

38. QATAR SURVEY

39. Alexandria Survey ( n = 120)
HtSDS
49% < -2
83% < -1
17 % > -1

40. GVSDS < -1 in patients and controls

41. Thalassaemia (males) 73 % had test. vol < 3 ml
n = 45 , all > 14 yr
Age = /- 3.5 yr
73 % had test. vol < 3 ml

42. Age of Thelarche

43. Thal: Breast Development
All >14 y
Age = /- 3.2 yr
42 % --No breast development

44. Age of Menarche (years)

45. Qatar- Growth and Endocrine Complications in Thalassemic Children and Adolescents (6-18 years)

46. CONCLUSIONS Thalassaemia 49% had HtSDS <-2 and 83% <-1
73% of boys (>14 y) lack pubescent changes
42% of girls ( >14) lack pubescent changes

48. What is the Growth Pattern of these Patients ?
Which Stage of Growth is more affected ?

50. Anita Saxena, Int J Hum Genet, 3(4): 237-246 (2003)

51. Disturbed Upper /Lower segement
because of short trunk due to vertebral pathology
Anita Saxena, Int J Hum Genet, 3(4): (2003)

52. Thalassemics Vs Normal
Weight Curves for
Thalassemics Vs Normal
Anita Saxena, Int J Hum Genet, 3(4): (2003)

53. Time of Growth Abnormalities
1. Late Childhood
(Nutrition, GH-IGF-I, T4)
2. Pubertal Growth Spurt (attenuated)
(Sex steroids, GH-IGF-I, Nutrition, T4, Insulin)

54. Summary Thalassemic patients are short Slow rate of linear growth
+/- low body weight and BMI
Delayed or absent pubertal spurt
Growth faltering sets in earlier but becomes obvious after the age of 8 years

55. High Prevalence of short stature
(Soliman et al., 1999;
Low et al., 1998;
Theodoridis et al., 1998;
Caruso-Nicoletti, 1998;
Roth et al., 1997;
Kwan et al., 1995;
Grundy et al., 1994).
Truncal shortening:
Rodda et al., 1995;
Hamidah et al., 2001).

56. Why patients with TM do not grow well ???

57. What is the effect of Intensive Chelation Therapy on Growth ?
Started early-Positive effect on linear growth.
80% attained normal adult height
( Garcia-Mayor et al, Horm Res 1993; 40, 5.)

58. ??? Effectiveness of Different Transfusion Treatment Regimes
Growth impairment and pubertal abnormalities in thalassemia major, has persisted despite major treatment advances.
Chelation therapy may not always prevent or ameliorate late growth failure and/or delayed or absent puberty.
(Chan et al. 2000; De Sanctis et al. 2000).

59. POSSIBLE FACTORS AFFECTING GROWTH AND PUBERTY IN THALASSAEMIA

60. Reported Endocrine abnormalities:
Thalassaemia:
GH/IGF-I abnormalities
Hypogonadism(1ry, 2ry)
Thyroid dysfunction
IGT, IDDM
PTH deficiency

64. GH-IGF-I Growth Axis In Thalassemia Major

65. Studies / questions on GH /IGF-I in TM
GH response to provocation ?
Spontaneous GH secretion ?
IGF-I / BP3 secretion ?
IGF-I/BP3 generation in response to exogenous GH in these patients ?
GH-IGF-I response to blood transfusion
Effect of GH treatment on linear growth ?

66. Studies on GH-IGF-I axis
Effect of associated hypogonadism, hypothyroidism, DM ?
Nutrition effect on IGF-I secretion ?
Anatomy (MRI) of the hypothalamic/pituitary area in these patients ?

68. 1. Do patients with Thalassemia have GH deficiency ?

69. Prevalence of GH deficincy in thalassemia
Country
Prevalence %
Qatar –Doha ( n =81)
45%
Egypt – Alexandria ( n = 120)
40%
Egypt – Cairo ( n = 30)
33%
Greece- Athens
38%
Turkey-Izmir
Iran-Shiraz (n= 138)
(53.5% ) boys, (46.5%) girls
Italy - Ferrara ( adults)
8% males, 9% females
Italy – Rome (adults)
32 %
Italy- Milan (adults)
22% (severe) 19% (partial)
J Endocrinol Invest Sep;33(8): Epub 2010 Feb 15.
Clin Endocrinol (Oxf) Nov;67(5): Epub 2007 Jul 3.
IJMS . Vol 27, No. 2, June 2002
Arch Med Sci 2010; 6, 1: 90-95
J Trop Pediatr (1999) 45 (1):
J Trop Pediatr Feb;48(1):50-4.

70. Thal : GH after stimulation
40% of patients had peak GH < 7 Ug/L

72. Short Thalassemic With Normal GH response to provocation
2. Do they secrete normal GH spontaneously at night ??

73. Thal : Nocturnal GH (patient-1) and age-matched control30
Patient 1
Control 25 20 15 GH 10 5 8 9 10 11 12 13 14 15 16 17 18 19 20 73 73

74. Thal: Nocturnal GH secretion (patient -2) vs control74 74

75. Tha: Nocturnal GH secretion (patient-4) vs control75

76. Thal: Nocturnal GH secretion (patient -5) vs control76 76

77. Thal: Nocturnal GH secretion (patient-6) vs control77 77

78. Thal: Nocturnal GH secretion (patient -7) vs control78 78

79. Thal: Nocturnal GH secretion (patient -8) vs control79 79

80. Thal: Nocturnal GH secretion (patient -9) vs control80 80

81. Thal: Nocturnal GH secretion (patient-10) vs control81 81

82. GH Neuro-secretory Dysfunction
High incidence of
GH Neuro-secretory Dysfunction
(40% of short patients)

84. 3. Do They Secrete Normal IGF-I ??

85. IGF-I in TM vs GHD vs CDGP85 85

86. Low IGF-I High Prevalence (50-85%) with
Defective GH secretion
Normal GH response
Neurosecretory dysfunction
Soliman et al., 1999)
(Shamshirsaz A A et al) 2003)
Vannasaeng.S et al , 1980
Roth C et al., 1997
Soliman et al., 1999
Spoliotis BE; 1996
Pasqualetti et al 1992

87. What is the pattern of IGF-I throughout childhood ?
The age-related levels in serum total IGF-I in thalassemic males were significantly decreased from early childhood to 18 years of age compared to normal subjects.

89. IGF-I Generation in GHD vs GHS
Thalassemic males with GHD did not show any significant peak of IGF-I levels until 18 years of age.
Thalassemic males with normal GH response to provocation (GHS) achieved a significant peak level of IGF-I that was attenuated and late compared to normal males.

91. IGF-I Secretion
The basal serum IGF-I concentrations at different ages did not differ between the GHD and GHS groups until the age of 12 years.
After 12 years of age, IGF-I levels were significantly higher in thalassemic children with GHS.

92. Comparison between Growth and IGF-I secretion throughout childhood and puberty
Soliman AT, PER, 2010
Anita Saxena, Int J Hum Genet, 3(4): (2003)

94. Short Patients with Thalassemia
4. Do They Generate Enough IGF-I in Response To GH ??
Partial GH Resistance ?

95. Thal: IGF-I generation

96. IGF-BP3 in Thalassemia

97. IGFBP3 after GH injection

98. Thal: GH/IGF-I/BP3 axis
Children with thalassemia:
High incidence of GHD and GH-NSD
Low IGF-I
Lower IGFBP3
Decreased IGF-I synthesis after GH vs CDGD and GHD

100. Does correction of anemia increase secretion of IGF-I in T children with low IGF-I ? and /or
Does it improve the response of IGF-I to exogenous stimulation by GH?

101. 5. What is the effect of anemia on IGF-I Secretion ?

102. Correction of anemia significantly increased IGF-I Secretion

105. IGF-I levels increased significantly with correction of anemia.
GH injections increased IGF-I significantly in TM.
The peak IGF-I response to GH injections did not differ before vs after blood transfusion.

106. 7. What is the Effect of Pubertal Delay /Failure on Growth and IGF-I ?
8. What is the effect of defective GH-IGF-I axis on puberty ?

107. Thalassaemic Boys
Have high incidence pubertal delay/failure and short stature
1. Gonadotropin deficiency (pituitary)
2. Defective sex-steroid secretion (testes) have been described
3. Defective growth spurt

108. Deprivation of GH and IGF-I:
1) Delays the timely onset of puberty
2) Slows the pace of pubertal maturation (all species);
3) Attenuates phallic growth (human);
4) Reduces adult testicular size (rodent);
but does not affect fertility in the mature individual (all species)
Zachmann M, J Clin Endocrinol Metab 30:85–92
Young IR1989 J Endocrinol 121:563–570
Ernst M, 1991 Mol Endocrinol 5:1081–1089
Slootweg MC, 1997, J Endocrinol 155:159–164

110. PUBERTAL ASSESSMENT IN THALASSEMIA MAJOR

111. Pubertal Surveys In BTM
Country survey
Hypogonadism
Cyprus
32%
Greece
42%
Italy
49%
Egypt
73% males,
42% females
Qatar
46%
Romania
77% males
41% females
N. America
35%
TIF
40.5%
Pediatr Endocrinol Rev Dec;5(2): ,& Clin Endocrinol (Oxf) Jun;42(6):581-6.
Acta Endocrinologica (Buc), vol. I, no. 2, p , 2005

112. Thalassaemia (males) 73 % had test. vol < 3 ml
n = 45 , all > 14 yr
Age = /- 3.5 yr
73 % had test. vol < 3 ml
Ashraf T Soliman
12/22/2017
112
112

113. Testicular Volume
Ashraf T Soliman
12/22/2017
113
113

114. Age of Thelarche
Ashraf T Soliman
12/22/2017
114
114

115. Thal: Breast Development
All >14 y
Age = /- 3.2 yr
42 % --No breast development
Ashraf T Soliman
12/22/2017
115
115

116. Age of Menarche (years)
Ashraf T Soliman
12/22/2017
116
116

117. CONCLUSIONS Thalassaemia
40-70% of boys (>14 y) lack pubescent changes
40-60% of girls ( >14y) lack pubescent changes
117
117

118. Hypogonadism Effect on Growth in TM
Deprivation of sex-steroids at or after the time of expected puberty :
Loss or attenuation of pubertal growth spurt
predisposes to reduced peak bone mass (osteopenia, osteoporosis)
Testosterone, GH, IGF-I concentrations correlate with bone mass in some analyses
Ongphiphadhanakul B, Clin Endocrinol (Oxf) 1998; 49:803–809
van den Beld AW, J Clin Endocrinol Metab 2000; 85:3276–3282
Seeman E, Am J Physiol 1996; 270:E320–E327

119. Puberty : Thalassemic Patients
1. Delayed puberty
2. Hypo gonadotropic hypogonadism
3. Defective testosterone secretion
4. Defective spermatogenesis
5. Delayed onset of menstruation
6. Primary Amenorrhea
7. Secondary Amenorrhea

120. Basal Investigations 1. Low Sex steroid (testosterone- Estradiol)
2. low Gonadotropin (LH and FSH)
(Hypogonadotrophic hypogonadism)

122. LH Secretion patient vs controls

126. Pubertal Induction
And Growth

127. Testosterone replacement in HH males
The anabolic effects of testosterone are associated with :
1) Increased pulsatile GH secretion
2) Increased IGF-I synthesis in liver and bone cells
3) Increased GI absorption and skeletal retention of calcium and magnesium
4) Increased mass, mechanical loading and energy expendature.
Cicognani A, Acta Endocrinol (Copenh) 1989; 121:777–783
Hansen TB, J Clin Endocrinol Metab 1996; 81:3352–3359

130. What is the effect of Nutrition on Growth and IGF-I in TM ?

131. Nutrition is an important factor in growth and development
Protein/Calorie Defect due to hyper-catabolism (BM, Cardiac and Resp )
Zinc deficiency exists as a growth-limiting factor in thalassemia major : Short stature, low weight, anorexia, and hypogonadism found in the zinc deficiency, has been found in most of the patients (Arcasoy and Cavadar 1981; Arcasoy et al. 1983).
Vitamin D Deficiency

132. Wt, BMI and IGF-I Before vs after Nutritional Supplementation

133. Vitamin D Deficiency
Vitamin D deficiency was detected in % of thalassemic adolescents.
An IM injection of a mega dose of cholecalciferol is an effective therapy for treatment for 3 months.
Correction of VDD --- Increased Linear Growth and IGF-I level
Pediatric Endocrinology Reviews (PER), 6 Supp 1, 2008 NAPOLI N.
Bone ISSN, 2006; 
Br J Haematol Jun;141(6):891-4

134. Zinc Deficiency and Treatment
Biochemical evidence of Zn deficiency in 40% of Thalassemic patients
Those who received Zn for 1-7 years had higher growth velocity and HTSDS.
Arcasoy A et al. Am J Hematol 1987, 24:127

136. PATHOLOGY
Pituitary
Liver
Pancreas

137. MRI studies in patients with defective GH secretion (n = 9)
Evidence of iron deposition in the pituitary gland and midbrain (n = 7)
Marked diminution of the pituitary size (n = 4)
Thinning of the pituitary stalk (n = 3) with its posterior displacement (n = 2),

138. T T2
A T Soliman J Trop Pediatr Dec;45(6):

139. A T Soliman J Trop Pediatr. 1999 Dec;45(6):327-37.

140. Pituitary Siderosis Pediatr Radiol. 2007 December; 37(12): 1191–1200.
patient
Control
A 12-year-old β-thalassaemia major. Midsagittal T1-weighted (TR/TE 500/20 ms) scan shows low-signal intensity of the anterior pituitary lobe (arrow) and the bone marrow (asterisks) suggesting iron overload. The pituitary gland is small measuring 3.5 mm. This patient developed hypogonadotropic hypogonadism.
b An 11-year-old male with β-thalassaemia major. Mid-sagittal T1-weighted (TR/TE 500/20 ms) shows normal signal intensity of the anterior pituitary lobe (arrow) along with normal pituitary gland height (6 mm). The bone marrow (asterisk) shows low-signal intensity suggesting iron overload

141. Siderosis of Liver and Pancreas Pediatr Radiol
Siderosis of Liver and Pancreas Pediatr Radiol December; 37(12): 1191–1200
A 17-year-old male with β-thalassaemia major. Axial scan, fourth echo of a multiecho spin-echo
sequence (TR/TE: 2000/20, 40, 60, 80, 100, 120, 140, 160 ms),
shows low-signal intensity in the liver, bone marrow of the spinal body and the pancreas
suggesting iron overload.

142. The photomicrograph (iron stain; magnification,
500) of undecalcified bone section illustrates the thick linear deposition of iron (blue line) along the mineralization front (thick arrows).
The unmineralized zone is also stained blue, but with lighter intensity (areas between thin arrows). Active osteoblasts (arrowheads) are
also present along the osteoid surface.

143. Iron deposition in Kupffer cells and spilling into parenchymal cells in late stages of hemosiderosis

145. What is the Effect of GH therapy on Growth and IGF-I in TM ??

146. Thal: Growth on GH therapy

147. Thal: IGF-I & GV after GH therapy

148. Short term (one year) GH Therapy Studies
Demonstrated that treatment for one year resulted in significant increase in the growth velocity without increase in rate of skeletal maturation.
The growth rate on GH therapy was significantly slower in TM and their IGF-I were lower vs non-thalassemic children with GHD or ISS on same GH doses.

149. Short term (> 2 years) GH Therapy Studies
A positive growth response to GH was demonstrated in the second year of treatment in the report by( Wu et al )
And for 3 to 4 years with improvement in the height SDS for both bone age and chronological age in other studies
(Kwan EYW, J Pediatr Endocrinol Metab 2000; 13 :

150. (Final adult height) after GH Therapy for 2-9 years
Before Treatment
Final adult Ht
Boys
-3.7
-1.75
Girls
-2.8
-1.58
Theodoridis et al. J Pediatr Endocrinol Metab 1998; 11 (Suppl 3) :
HtSDS
Before
Treatment
Final Adult
Height SDS
Improvement compared to mid-parental Ht
N= 10
Started -age 11 y
-2.63
-0.6
1.6
Low LC, Ind J Ped 2005, 159, 64

152. What is the effect of Bone Marrow Transplantation on Growth ?

153. BMD after bone marrow transplantation in TM (n = 32) F/U > 2 yr
The HtSDS increased by 0.6 SD ( from -1.6 to 1) 5 years after BMT.
Before BMT 40% had HtSDS < % were < -2
5 Years after BMT only 15% had HtSDS < -2.
Pediatr Hematol Oncol. ;21 (5):411-9

154. TM – Effect of bone marrow transplantation (BMT) ( n= 47)
A strict correlation between age at time of transplant and final adult height.
T M who were <7 years had a less impaired growth rate than did patients who were >7 years.
The greatest loss in height was observed with High Ferritin and ALT.
Subjects who received BMT before 7 years had normal adult Ht in relation to the genetic target height .
Subjects who received BMT after 7 years of age, failed to achieve their full genetic potential.
A close effect of the age at time of transplant on subsequent growth rate.
Bone Marrow Transplantation (2001) 28,

155. Bone Marrow Transplant. 1997 Oct;20(7):567-73.
GH therapy (2y): effect On TM patients after BMT (IGF-I secretion & growth)
Responders
Increased GV
Increased IGF-I secetion
Decreased Ferritin
Decreased ALT and AST
Non-responders
Decreased GV
No change in IGF-I
Increased Ferritin
Higher ALT and AST
There was a significant correlation between IGF-I, ALT, AST & ferritin in all patients before and after therapy.
Bone Marrow Transplant Oct;20(7):

157. Thalassaemia (Summary)
Slow linear growth (HtSDS, GV)
High prevalence of impaired spontaneous and provoked GH secretion
Low IGF-I and BP3 secretion
Low of IGF-I after GH injection and therapy.
GV improved on GH therapy but < those for ISS and GHD
Partial improvement of final adult ht with GH therapy.

160. RECOMMENDATIONS

161. Increasing IGF-I : Proper transfusion and Chelation
Improving nutritional status ( Protein-Calorie, Vitamin D, Zn, Carnitine)
Correcting GHD (GH / IGF-I therapy)
Inducing puberty at proper time,
Prevention of hepatitis
Bone marrow transplantation (before 7 y)
Might improve growth and BMD

162. IGF-I therapy with or without GH is on small trials now ????
TM patients with and without GHD have low IGF-I secretion.
Their Growth and IGF-I response to GH is suboptimal (GH resistance)
They need bigger GH doses for accelerating growth.
Final adult height after GH treatment is still short
IGF-I has growth promoting as well as insulin-like activities while GH is lipolytic.
IGF-I therapy with or without GH is on small trials now ????

163. Algorithm If the patient is GH deficient ---Start GH therapy early
If he responds to normal dose ( mg/kg/day) with proper increase of IGF-I--- continue
If GV is slow and/or IGF-I low - Increase GH dose
At or after (13 (F) and 14 (M) years slowly induce puberty simulating the normal physiology
At all stages supplement nutrition +/- Zinc +/- vit D therapy to increase IGF-I --- growth.
Correct any Thyroid hormone deficiency

164. Puberty Guidelines (6-months Intervals)
Tanner staging should be recorded every six months.
Girls without evidence of an advancing pubertal stage by years and boys by 14 years require screening with LH/ FSH, and se steroid.
If LH and FSH levels are low for the patient’s age, suspect hypogonadism.
GnRH stimulation may help to dx HH.
(This should to be done prior to a blood transfusion on a different day than the oral glucose tolerance test.)

165. BTM: Male Hypogonadism
Testosterone level should be checked annually in boys, starting in the early adolescent years (at approximately 13 years old).
If testosterone level is low--- endocrine consultation --- start monthly Testosterone vs HCG treatment.
The starting dose is usually 50 mg, given monthly as an intramuscular shot.
The dose needs to be adjusted periodically for the patient’s age and pubertal status, as well as for a sexually active man.

166. BTM: Female Hypogonadism
Estrogen replacement is recommended for amenorrheic adolescent girls and adult women:
2.5-5ug Ethinyl Estradiol with increasing doses q 6mon
Afterward, an oral contraceptive pill may replace Premarin.
A gynecological consultation and fertility evaluation is recommended for women on estrogen therapy.

167. Thank You