Ann Pediatr Endocrinol Metab.  2016 Mar;21(1):26-30. 10.6065/apem.2016.21.1.26.

Long-term efficacy of recombinant human growth hormone therapy in short-statured patients with Noonan syndrome

• Jeong I
• Kang E
• Cho JH
• Kim GH
• Lee BH
• Choi JH
• Yoo HW

• KMID: 2161303
• DOI: http://doi.org/10.6065/apem.2016.21.1.26

Abstract

PURPOSE
Noonan syndrome (NS) is characterized by short stature, heart anomalies, developmental delays, dysmorphic features, cryptorchidism, and coagulation defects. Several studies reported the short-term effects of recombinant human growth hormone (rhGH) treatment on the improvement of height. This study was performed to evaluate the long-term efficacy of rhGH in children with NS in Korea.
METHODS
This study included 15 prepubertal NS children who received rhGH subcutaneously at a dose of 50-75 µg/kg/day for 6 days a week for at least >3 years. Preand posttreatment data, such as height, weight, bone age, insulin-like growth factor 1 (IGF-1), and IGF binding protein 3 (IGFBP-3) levels, were collected every 6 months.
RESULTS
Chronologic age and bone age at the start of treatment were 7.97±1.81 and 5.09±2.12 years, respectively. Height standard deviation score (SDS) was increased from -2.64±0.64 to -1.54±1.24 years after 3 years (P<0.001). Serum IGF-1 SDS levels were elevated from -1.28±1.03 to -0.10±0.94 (P<0.001). Height SDS was more increased in subjects without PTPN11 mutations compared to those with mutations after 3 years (P=0.012). However, the other parameters, including bone age, IGF-1 SDS, and IGFBP-3 SDS, were not significantly different between patients with and without PTPN11 mutations.
CONCLUSION
Although this study included a relatively small number of patients, long-term rhGH therapy in NS patients was safe and effective at improving height, growth velocity, and serum IGF-1 levels, in accordance with previous studies. However, the meticulous monitoring of potential adverse events is still needed because of high dose of rhGH and preexisting hyperactivity of RAS-MAPK pathway. Patients with PTPN11 mutations demonstrated a decreased response to rhGH therapy compared to those without mutations.

Keyword

Noonan syndrome; Growth hormone; PTPN11

MeSH Terms

Child
Cryptorchidism
Growth Hormone
Heart
Human Growth Hormone*
Humans*
Insulin-Like Growth Factor Binding Protein 3
Insulin-Like Growth Factor I
Korea
Male
Noonan Syndrome*
Growth Hormone
Human Growth Hormone
Insulin-Like Growth Factor Binding Protein 3
Insulin-Like Growth Factor I

Figure

• 

  Fig. 1 Sequential changes of height SDS (A), GV (B), and IGF-1 SDS (C) during rhGH treatment in patients with Noonan syndrome with or without PTPN11 mutations. Mann-Whitney U-test was used to compare the response to rhGH therapy according to genotypes. P-values less than 0.05 were considered to be statistically significant. SDS, standard deviation score; GV, growth velocity; IGF-1, insulin-like growth factor 1; rhGH, recombinant human growth hormone.

Reference

1. Mendez HM, Opitz JM. Noonan syndrome: a review. Am J Med Genet. 1985; 21:493–506. PMID: 3895929.

2. Sharland M, Burch M, McKenna WM, Paton MA. A clini cal study of Noonan syndrome. Arch Dis Child. 1992; 67:178–183. PMID: 1543375.

3. Tartaglia M, Mehler EL, Goldberg R, Zampino G, Brunner HG, Kremer H, et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet. 2001; 29:465–468. PMID: 11704759.

4. Roberts AE, Araki T, Swanson KD, Montgomery KT, Schiripo TA, Joshi VA, et al. Germline gain-of-function mutations in SOS1 cause Noonan syndrome. Nat Genet. 2007; 39:70–74. PMID: 17143285.

5. Tartaglia M, Pennacchio LA, Zhao C, Yadav KK, Fodale V, Sarkozy A, et al. Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome. Nat Genet. 2007; 39:75–79. PMID: 17143282.

6. Kobayashi T, Aoki Y, Niihori T, Cave H, Verloes A, Okamoto N, et al. Molecular and clinical analysis of RAF1 in Noonan syndrome and related disorders: dephosphorylation of serine 259 as the essential mechanism for mutant activation. Hum Mutat. 2010; 31:284–294. PMID: 20052757.

7. Lepri FR, Scavelli R, Digilio MC, Gnazzo M, Grotta S, Dentici ML, et al. Diagnosis of Noonan syndrome and related disorders using target next generation sequencing. BMC Med Genet. 2014; 15:14. PMID: 24451042.

8. Ko JM, Kim JM, Kim GH, Yoo HW. PTPN11, SOS1, KRAS, and RAF1 gene analysis, and genotype-phenotype correlation in Korean patients with Noonan syndrome. J Hum Genet. 2008; 53:999–1006. PMID: 19020799.

9. Lee BH, Kim JM, Jin HY, Kim GH, Choi JH, Yoo HW. Spectrum of mutations in Noonan syndrome and their correlation with phenotypes. J Pediatr. 2011; 159:1029–1035. PMID: 21784453.

10. Flex E, Jaiswal M, Pantaleoni F, Martinelli S, Strullu M, Fansa EK, et al. Activating mutations in RRAS underlie a phenotype within the RASopathy spectrum and contribute to leukaemogenesis. Hum Mol Genet. 2014; 23:4315–4327. PMID: 24705357.

11. Choi JH, Oh MY, Yum MS, Lee BH, Kim GH, Yoo HW. Moyamoya syndrome in a patient with Noonan-like syndrome with loose anagen hair. Pediatr Neurol. 2015; 52:352–355. PMID: 25563136.

12. Gelb BD, Tartaglia M. Noonan syndrome and related disorders: dysregulated RAS-mitogen activated protein kinase signal transduction. Hum Mol Genet. 2006; 15(Spec No 2):R220–R226. PMID: 16987887.

13. Noonan JA. Noonan syndrome and related disorders: alterations in growth and puberty. Rev Endocr Metab Disord. 2006; 7:251–255. PMID: 17177115.

14. Otten BJ, Noordam C. Growth in Noonan syndrome. Horm Res. 2009; 72(Suppl 2):31–35. PMID: 20029234.

15. Noonan JA, Kappelgaard AM. The efficacy and safety of growth hormone therapy in children with noonan syndrome: a review of the evidence. Horm Res Paediatr. 2015; 83:157–166. PMID: 25503994.

16. Noordam C, Peer PG, Francois I, De Schepper J, van den Burgt I, Otten BJ. Long-term GH treatment improves adult height in children with Noonan syndrome with and without mutations in protein tyrosine phosphatase, nonreceptor-type 11. Eur J Endocrinol. 2008; 159:203–208. PMID: 18562489.

17. Osio D, Dahlgren J, Wikland KA, Westphal O. Improved final height with long-term growth hormone treatment in Noonan syndrome. Acta Paediatr. 2005; 94:1232–1237. PMID: 16203673.

18. Choi JH, Lee BH, Jung CW, Kim YM, Jin HY, Kim JM, et al. Response to growth hormone therapy in children with Noonan syndrome: correlation with or without PTPN11 gene mutation. Horm Res Paediatr. 2012; 77:388–393. PMID: 22777296.

19. van der Burgt I, Berends E, Lommen E, van Beersum S, Hamel B, Mariman E. Clinical and molecular studies in a large Dutch family with Noonan syndrome. Am J Med Genet. 1994; 53:187–191. PMID: 7856646.

20. Korea Centers for Disease Control and Prevention, Division of Chronic Disease Surveillance, Committee for the Development of Growth Standard for Korean Children and Adolescents. Korean Pediatric Society, Committee for School Health and Public Health Statistics. 2007 Korean children and adolescents growth standard (commentary for the development of 2007 growth chart). Cheongju: Korea Centers for Disease Control and Prevention, Division of Chronic Disease Surveillance;2007.

21. Hyun SE, Lee BC, Suh BK, Chung SC, Ko CW, Kim HS, et al. Reference values for serum levels of insulin-like growth factor-I and insulin-like growth factor binding protein-3 in Korean children and adolescents. Clin Biochem. 2012; 45:16–21. PMID: 22032863.

22. Greulich WW, Pyle SI. Radiographic atlas of skeletal development of the hand and wrist. 2nd ed. Stanford: Stanford University Press;1959.

23. Cotterill AM, McKenna WJ, Brady AF, Sharland M, Elsawi M, Yamada M, et al. The short-term effects of growth hormone therapy on height velocity and cardiac ventricular wall thickness in children with Noonan's syndrome. J Clin Endocrinol Metab. 1996; 81:2291–2297. PMID: 8964866.

24. MacFarlane CE, Brown DC, Johnston LB, Patton MA, Dunger DB, Savage MO, et al. Growth hormone therapy and growth in children with Noonan's syndrome: results of 3 years' follow-up. J Clin Endocrinol Metab. 2001; 86:1953–1956. PMID: 11344190.

25. Binder G, Neuer K, Ranke MB, Wittekindt NE. PTPN11 mutations are associated with mild growth hormone resistance in individuals with Noonan syndrome. J Clin Endocrinol Metab. 2005; 90:5377–5381. PMID: 15985475.

26. Limal JM, Parfait B, Cabrol S, Bonnet D, Leheup B, Lyonnet S, et al. Noonan syndrome: relationships between genotype, growth, and growth factors. J Clin Endocrinol Metab. 2006; 91:300–306. PMID: 16263833.

27. De Rocca Serra-Nedelec A, Edouard T, Treguer K, Tajan M, Araki T, Dance M, et al. Noonan syndrome-causing SHP2 mutants inhibit insulin-like growth factor 1 release via growth hormone-induced ERK hyperactivation, which contributes to short stature. Proc Natl Acad Sci U S A. 2012; 109:4257–4262. PMID: 22371576.

28. Burch M, Sharland M, Shinebourne E, Smith G, Patton M, McKenna W. Cardiologic abnormalities in Noonan syndrome: phenotypic diagnosis and echocardiographic assessment of 118 patients. J Am Coll Cardiol. 1993; 22:1189–1192. PMID: 8409059.

29. Marino B, Digilio MC, Toscano A, Giannotti A, Dallapiccola B. Congenital heart diseases in children with Noonan syndrome: An expanded cardiac spectrum with high prevalence of atrioventricular canal. J Pediatr. 1999; 135:703–706. PMID: 10586172.

30. Noordam C, Draaisma JM, van den Nieuwenhof J, van der Burgt I, Otten BJ, Daniels O. Effects of growth hormone treatment on left ventricular dimensions in children with Noonan's syndrome. Horm Res. 2001; 56:110–113. PMID: 11847472.