Growth and Growth Hormone therapy in Children with

Noonan SyndromeGeorge S. Jeha, MDAssistant Professor

Baylor College of Medicine

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

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

Normal & Abnormal Growth

Normal growth

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

Growth velocity

Abnormal Growth

Perinatal GrowthNoonan Syndrome

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.

Birth Weight

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.

Postnatal Growth

Noonan Specific Growth Charts

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

Noonan Specific Growth Charts

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

Malesn=64

Femalesn=48

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.

Male89

Female55

Head CircumferenceMale Female

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

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

Pubertal Growth

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

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

Bone

age

Bone

age

Chronological age

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.

Growth Hormone Secretion

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 Range12-h overnight GH profile

*mean GH level (mU/l) 7 5 2.4-14.8mean GH level (SDS) -1.7 -4.2±0.7

Peak max (mU/l) 33 12.1-89.5Number of Peaks 6 6-8

*calculated baseline (mU/l) 2.1 0 4-5 5area over baseline (mU/l) 63.7 17.6-133.7area over 0-line (mU/l) 88.1 24.1-161.3

Provocative testmaximum 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±0.5IGFBP-3 (SDS) -0.4 -1.8±1.0

N=17 (4 )♀

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.

GH sensitivity

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.

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.

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.

Response to GH Therapy

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 ofpatients n (n )♀

Baselineage year

Baselineheight SDS

GH dosemg/kg/week(mcg/kg/day)

Duration oftherapy year

Δ height SDSafter therapy

Height gain atadult age cm

Kirk, 2001 10 (4) 12 -3.1 0.3 (43) 5.3 0.8 3.1

Mcfarlane , 2001Controlled 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, 2005Mut+Mut-

8 (N.A.)3 (N.A.)

7.46.3

-3.46-3.8

0.29(41)0.35(50)

11

0.661.26

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.)

10.410.3

-3.5-3

0.3(43) or 0.46(66)0.3(43) or 0.46(66)

22

0.41

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)

KIGS24 (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, 2012ANSWER 120 (30) 9.2 -2.65 0.33(47)-0.41(58) 4 1.33 N.A.

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.

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.

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