Discussion of the efficacy of growth hormone therapy in children with Noonan Syndrome and short stature

1. Growth and Growth Hormone
therapy in Children with Noonan
Syndrome
George S. Jeha, MD
Assistant Professor
Baylor College of Medicine

2. Goals
• Discuss limitations of current understanding
• Discuss normal growth and the value of growth charts
• In utero growth for Noonan Syndrome
• Postnatal growth for Noonan Syndrome
• Pre-pubertal growth
• Puberty & final adult height
• Growth hormone secretion in children with Noonan Syndrome
• Response to GH/IGF-1 generation (GH sensitivity)
• Outcomes from GH therapy in children with Noonan syndrome
• Summary

3. Disclaimer
• Most studies tackling growth and growth hormone therapy in
children with Noonan syndrome are affected by:
• Small Sample size
• Mostly retrospective
• Lacking randomization and controls
• Overextended conclusions unsupported by the data

4. Normal & Abnormal Growth

5. Normal growth
http://www.cdc.gov/growthcharts Accessed 6/2/2016

6. Growth velocity

7. Abnormal Growth

8. Perinatal Growth
Noonan Syndrome

9. Prenatal Growth
• 151 individuals (83 M, 68 F) 1
• Mean Gestational Age 39 Weeks/Mean Birth Weight 3450g (510)
• Gestational age 38-42 week of gestation2:
• BWT were 3182±1052g for (n=55 ♂) and 3219±745 g for (n = 37 ♀)
• Length 51.0±1.9cm (n=44 ♂) and (n = 39 ♀)51.1±2.4cm
• Delivery mode:
• Spontaneous vaginal delivery 69%
• Forceps delivery in 9%
• Caesarian section in 21%
1.Sharland, M., et al., A clinical study of Noonan syndrome. Arch Dis Child, 1992. 67(2): p. 178-83.
2.Ranke, M.B., et al., Noonan syndrome: growth and clinical manifestations in 144 cases. Eur J Pediatr, 1988. 148(3): p. 220-7.

10. Birth Weight

11. Immediate Postnatal Growth
• Edema at birth and weight loss in the first week are common
• Feeding problems are common:
• 76% with feeding difficulties
• 15% mild (poor suck,>1hr per feed)
• 38% moderate (very poor suck, slow feeding, recurrent vomiting)
• 24% severe (requiring >2 wks. of tube feeds)
Sharland, M., et al., A clinical study of Noonan syndrome. Arch Dis Child, 1992. 67(2): p. 178-83.

12. Postnatal Growth

13. Noonan Specific Growth Charts
Witt, D.R., et al., Growth curves for height in Noonan syndrome. Clin Genet, 1986. 30(3): p. 150-3.

14. Noonan Specific Growth Charts
Witt, D.R., et al., Growth curves for height in Noonan syndrome. Clin Genet, 1986. 30(3): p. 150-3.
Males
n=64
Females
n=48

15. Noonan Specific Growth Charts
Ranke, M.B., et al., Noonan syndrome: growth and clinical manifestations in 144 cases. Eur J Pediatr, 1988. 148(3): p. 220-7.
Male
89
Female
55

16. Head Circumference
Male Female
Ranke, M.B., et al., Noonan syndrome: growth and clinical manifestations in 144 cases. Eur J Pediatr, 1988. 148(3): p. 220-7.

17. Weight for Height
Ranke, M.B., et al., Noonan syndrome: growth and clinical manifestations in 144 cases. Eur J Pediatr, 1988. 148(3): p. 220-7.
Male Female

18. Pubertal Growth

19. Growth Velocity
Ranke, M.B., et al., Noonan syndrome: growth and clinical manifestations in 144 cases. Eur J Pediatr, 1988. 148(3): p. 220-7.
Male Female

20. Skeletal Maturation
Ranke, M.B., et al., Noonan syndrome: growth and clinical manifestations in 144 cases. Eur J Pediatr, 1988. 148(3): p. 220-7.
Male Female
Chronological age
Boneage
Boneage Chronological age

21. Puberty/Fertility
• Average age at onset of puberty:
• 14yrs in female (10.5yrs normal)
• 14.5yrs in males (11.5yrs normal)
• 6% (6/97) received sex hormones to induce puberty
• 77% of boys had cryptorchidism
• 16% had had or were trying to have children
• 2/3 had no problem
Shaw, A.C., et al., The natural history of Noonan syndrome: a long-term follow-up study. Arch Dis Child, 2007. 92(2): p. 128-32.

24. Growth Hormone Secretion

25. Spontaneous and Stimulated GH secretion
Noordam, C., et al., Growth hormone (GH) secretion in children with Noonan syndrome: frequently abnormal without consequences for growth or response to GH
treatment. Clin Endocrinol (Oxf), 2001. 54(1): p. 53-9.
Parameter Mean Range
12-h overnight GH profile
*mean GH level (mU/l) 7 5 2.4-14.8
mean GH level (SDS) -1.7 -4.2±0.7
Peak max (mU/l) 33 12.1-89.5
Number of Peaks 6 6-8
*calculated baseline (mU/l) 2.1 0 4-5 5
area over baseline (mU/l) 63.7 17.6-133.7
area over 0-line (mU/l) 88.1 24.1-161.3
Provocative test
maximum GH on glucagon (mU/l) 38.6 16.0-70.5
Urinary GH
*urinary GH excretion (mU/24 h) 2.7 0.2-8.4
*IGF-1 (SDS) -0.4 -1±0.5
IGFBP-3 (SDS) -0.4 -1.8±1.0
N=17 (4♀)

26. 24-hr GH secretion
Noordam, C., et al., Growth hormone (GH) secretion in children with Noonan syndrome: frequently abnormal without consequences for growth or response to GH
treatment. Clin Endocrinol (Oxf), 2001. 54(1): p. 53-9.

27. GH sensitivity

28. GH response to arginine in Noonan with
PTPN11 mutation
● Noonan n=12
○ SS n=12
Bertelloni, S., et al., IGF-I generation test in prepubertal children with Noonan syndrome due to mutations in the PTPN11 gene. Hormones (Athens), 2013. 12(1): p. 86-
92.

29. IGF-1 Generation
Bertelloni, S., et al., IGF-I generation test in prepubertal children with Noonan syndrome due to mutations in the PTPN11 gene. Hormones (Athens), 2013. 12(1): p. 86-
92.

30. Response to GH by Genotype
Ferreira, L.V., et al., PTPN11 (protein tyrosine phosphatase, nonreceptor type 11) mutations and response to growth hormone therapy in children with Noonan
syndrome. J Clin Endocrinol Metab, 2005. 90(9): p. 5156-60.

31. Response to GH Therapy

32. Raynal, P., Growth hormone and noonan syndrome: update in dysfunctional signaling aspects and in therapy for short stature. Horm Stud, 2014. 2: p. 2-10.
Reference
Number of
patients n (n ♀)
Baseline
age year
Baseline
height SDS
GH dose
mg/kg/week
(mcg/kg/day)
Duration of
therapy year
Δ height SDS
after therapy
Height gain at
adult age cm
Kirk, 2001 10 (4) 12 -3.1 0.3 (43) 5.3 0.8 3.1
Mcfarlane , 2001
Controlled
23 (7) 9.3 -2.7 0.33(47) 3 0.8 N.A.
Ogawa, 2004 15 (7) 7.5 -2.8 0.17(24) 2 0.6 N.A.
Binder, 2005
Mut+
Mut-
8 (N.A.)
3 (N.A.)
7.4
6.3
-3.46
-3.8
0.29(41)
0.35(50)
1
1
0.66
1.26
N.A.
N.A.
Osio, 2005 (NAH) 18 (11) 8.7 -2.9 0.23(33)-0.46(66) 9.8 1.7 13(♂) 9.8(♀)
Limal, 2006
Mut+
Mut-
15 (N.A.)
10 (N.A.)
10.4
10.3
-3.5
-3
0.3(43) or 0.46(66)
0.3(43) or 0.46(66)
2
2
0.4
1
N.A.
N.A.
Noordam, 2008 (NAH)
Mut+
Mut-
29 (8)
22(6)
5(0)
11 -2.8 0.35(50) 6.4 1.3 N.A.
Raaijmakers, 2008 (NAH)
(median)
KIGS
24 (N.A.) 10.2 -3.24 0.17(24)-0.77(110) 7.59 0.87 N.A.
Romano, 2009, (NAH)
NCGS
65 (30) 11.6 -3.5 0.33(47) 5.6 1.4 10.9(♂) 9.2(♀)
Lee, 2012
120 (30) 9.2 -2.65 0.33(47)-0.41(58) 4 1.33 N.A.

33. Near Adult Height
Romano, A.A., et al., Growth response, near-adult height, and patterns of growth and puberty in patients with noonan syndrome treated with growth hormone. J Clin
Endocrinol Metab, 2009. 94(7): p. 2338-44.

34. Predictors of response to GH
Romano, A.A., et al., Growth response, near-adult height, and patterns of growth and puberty in patients with noonan syndrome treated with growth hormone. J Clin
Endocrinol Metab, 2009. 94(7): p. 2338-44.

35. GH Therapy
• Consistent findings:
• Increase in height SDS by a total of 1-1.7 SDS
• Most of the improvement occurs in year 1 (0.5-1.26 SDS)
• Studies reporting near adult height report a change of 0.6-2.1 SDS
• 2/3 of treated patients reached a height within 1SDS of mid-parental height
• Jury is out on whether PTPN mutations lead to GH resistance
• Therapy initiated from 6-12 yrs of age
• Earlier initiation of therapy associated with a better response
• Longer puberty associated with a better response
• No change in BMI
• Therapy well tolerated with low incidence of side effects (cardiac & metabolic)
• Large RCT with earlier initiation and F/U to NAH required