growth and growth hormone therapy in children with noonan syndrome
TRANSCRIPT
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Growth and Growth Hormone therapy in Children with
Noonan SyndromeGeorge S. Jeha, MDAssistant Professor
Baylor College of Medicine
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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
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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
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Normal & Abnormal Growth
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Normal growth
http://www.cdc.gov/growthcharts Accessed 6/2/2016
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Growth velocity
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Abnormal Growth
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Perinatal GrowthNoonan Syndrome
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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.
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Birth Weight
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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.
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Postnatal Growth
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Noonan Specific Growth Charts
Witt, D.R., et al., Growth curves for height in Noonan syndrome. Clin Genet, 1986. 30(3): p. 150-3.
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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
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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
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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.
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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
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Pubertal Growth
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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
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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
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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.
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Growth Hormone Secretion
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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 )♀
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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.
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GH sensitivity
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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.
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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.
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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.
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Response to GH Therapy
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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.
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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.
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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.
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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