Growth Defects in Noonan Syndrome

  • Alexsandra C. Malaquias
  • Alexander A.L. Jorge


Noonan syndrome is one of the most common syndromes transmitted by a Mendelian mode and is mainly characterized by dysmorphic facial features, congenital heart disease, and proportionate postnatal short stature. In recent years, germline mutations that affect components of the RAS/MAPK (mitogen-activated protein kinase) pathway as PTPN11, KRAS, SOS1, and RAF1 genes were shown to be involved in the pathogenesis of Noonan syndrome as well as of four rare syndromes with phenotype overlapping with Noonan syndrome: LEOPARD syndrome, cardiofaciocutaneous syndrome, Costello syndrome, and neurofibromatosis type 1. These mutations are predicted to be gain-of-function defects increasing signaling down the RAS/MAPK pathway. Some genotype–phenotype correlation has been reported in Noonan syndrome patients, allowing screening for mutations in Noonan syndrome-related genes based on clinical signs. Several hormones act through receptors that stimulate the RAS/MAPK pathway, and therefore, Noonan syndrome and related disorders represent a remarkable opportunity to study the implication of the RAS/MAPK pathway in different endocrine systems, including the GH/IGF-1 system. Additionally, similarly to Turner syndrome, growth velocity and final height of Noonan syndrome patients can be improved by recombinant human growth hormone treatment. In this chapter, we review the diagnostic, clinical, and molecular aspects of Noonan syndrome and rhGH treatment of short stature in these patients.


Short Stature Noonan Syndrome rhGH Therapy rhGH Treatment PTPN11 Mutation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Cardiofaciocutaneous syndrome


Epidermal growth factor


Extracellular signal-regulated kinase


Fibroblast growth factor


GTPase-activating proteins


Growth hormone


Guanosine nucleotide exchange factor


Insulin-like growth factor 1




Idiopathic short stature


Janus kinase


Juvenile myelomonocytic leukemia


Kirsten rat sarcoma viral oncogene homolog


Mitogen-activated protein kinase


Mitogen-activated protein kinase kinase 1-interacting protein 1


Multiple giant cell lesions




Noonan syndrome


Online Mendelian inheritance in man


Protein tyrosine phosphatase


Protein tyrosine phosphatase, non-receptor type 11


Murine leukemia viral oncogene homolog 1


Recombinant human growth hormone


Src homology


Src homology region 2-domain phosphatase 2


Son of sevenless, drosophila, homolog 1


Signal transducers and activators of transcription


Tumor necrosis factor 1


Turner syndrome



This work was supported by grants from Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) (05/04726-0 and 07/59555-0 to A.C.M.) and from Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) (307951/06-5 to A.A.L.J).


  1. Allanson JE. Noonan syndrome. J Med Genet. 1987;24(1):9–13.PubMedCrossRefGoogle Scholar
  2. 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(9):5377–81.PubMedCrossRefGoogle Scholar
  3. Carpenter LR, Farruggella TJ, Symes A, Karow ML, Yancopoulos GD, Stahl N. Enhancing leptin response by preventing SH2-containing phosphatase 2 interaction with Ob receptor. Proc Natl Acad Sci USA. 1998;95(11):6061–6.PubMedCrossRefGoogle Scholar
  4. Cirstea IC, Kutsche K, Dvorsky R, Gremer L, Carta C, Horn D, Roberts AE, Lepri F, Merbitz-Zahradnik T, Konig R, Kratz CP, Pantaleoni F, Dentici ML, Joshi VA, Kucherlapati RS, Mazzanti L, Mundlos S, Patton MA, Silengo MC, Rossi C, Zampino G, Digilio C, Stuppia L, Seemanova E, Pennacchio LA, Gelb BD, Dallapiccola B, Wittinghofer A, Ahmadian MR, Tartaglia M, Zenker M. A restricted spectrum of NRAS mutations causes Noonan syndrome. Nat Genet. 2010;42(1):27–9.PubMedCrossRefGoogle Scholar
  5. Cordeddu V, Di Schiavi E, Pennacchio LA, Ma’ayan A, Sarkozy A, Fodale V, Cecchetti S, Cardinale A, Martin J, Schackwitz W, Lipzen A, Zampino G, Mazzanti L, Digilio MC, Martinelli S, Flex E, Lepri F, Bartholdi D, Kutsche K, Ferrero GB, Anichini C, Selicorni A, Rossi C, Tenconi R, Zenker M, Merlo D, Dallapiccola B, Iyengar R, Bazzicalupo P, Gelb BD, Tartaglia M. Mutation of SHOC2 promotes aberrant protein N-myristoylation and causes Noonan-like syndrome with loose anagen hair. Nat Genet. 2009;41(9):1022–6.PubMedCrossRefGoogle Scholar
  6. Cotterill AM, McKenna WJ, Brady AF, Sharland M, Elsawi M, Yamada M, Camacho-Hubner C, Kelnar CJ, Dunger DB, Patton MA, Savage MO. 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(6):2291–7.PubMedCrossRefGoogle Scholar
  7. Duncan WJ, Fowler RS, Farkas LG, Ross RB, Wright AW, Bloom KR, Huot DJ, Sondheimer HM, Rowe RD. A comprehensive scoring system for evaluating Noonan syndrome. Am J Med Genet. 1981;10(1):37–50.PubMedCrossRefGoogle Scholar
  8. Ferreira LV, Souza SA, Arnhold IJ, Mendonca BB, Jorge AA. 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):5156–60.PubMedCrossRefGoogle Scholar
  9. Ferreira LV, Souza SC, Montenegro LR, Malaquias AC, Arnhold IJ, Mendonca BB, Jorge AA. Analysis of the PTPN11 gene in idiopathic short stature children and Noonan syndrome patients. Clin Endocrinol (Oxford). 2008;69(3):426–31.CrossRefGoogle Scholar
  10. 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(11–12):999–1006.PubMedCrossRefGoogle Scholar
  11. Limal JM, Parfait B, Cabrol S, Bonnet D, Leheup B, Lyonnet S, Vidaud M, Le Bouc Y. Noonan syndrome: relationships between genotype, growth, and growth factors. J Clin Endocrinol Metab. 2006;91(1):300–6.PubMedCrossRefGoogle Scholar
  12. MacFarlane CE, Brown DC, Johnston LB, Patton MA, Dunger DB, Savage MO, McKenna WJ, Kelnar CJ. Growth hormone therapy and growth in children with Noonan’s syndrome: results of 3 years’ follow-up. J Clin Endocrinol Metab. 2001;86(5):1953–6.PubMedCrossRefGoogle Scholar
  13. Maile LA, Clemmons DR. Regulation of insulin-like growth factor I receptor dephosphorylation by SHPS-1 and the tyrosine phosphatase SHP-2. J Biol Chem. 2002;277(11):8955–60.PubMedCrossRefGoogle Scholar
  14. Martinelli S, De Luca A, Stellacci E, Rossi C, Checquolo S, Lepri F, Caputo V, Silvano M, Buscherini F, Consoli F, Ferrara G, Digilio MC, Cavaliere ML, van Hagen JM, Zampino G, van der Burgt I, Ferrero GB, Mazzanti L, Screpanti I, Yntema HG, Nillesen WM, Savarirayan R, Zenker M, Dallapiccola B, Gelb BD, Tartaglia M. Heterozygous germline mutations in the CBL tumor-suppressor gene cause a Noonan syndrome-like phenotype. Am J Hum Genet. 2010;87(2):250–7.PubMedCrossRefGoogle Scholar
  15. Mendez HM, Opitz JM. Noonan syndrome: a review. Am J Med Genet. 1985;21(3):493–506.PubMedCrossRefGoogle Scholar
  16. Nava C, Hanna N, Michot C, Pereira S, Pouvreau N, Niihori T, Aoki Y, Matsubara Y, Arveiler B, Lacombe D, Pasmant E, Parfait B, Baumann C, Heron D, Sigaudy S, Toutain A, Rio M, Goldenberg A, Leheup B, Verloes A, Cave H. Cardio-facio-cutaneous and Noonan syndromes due to mutations in the RAS/MAPK signalling pathway: genotype phenotype relationships and overlap with Costello syndrome. J Med Genet. 2007;44(12):763–71.PubMedCrossRefGoogle Scholar
  17. Neumann TE, Allanson J, Kavamura I, Kerr B, Neri G, Noonan J, Cordeddu V, Gibson K, Tzschach A, Kruger G, Hoeltzenbein M, Goecke TO, Kehl HG, Albrecht B, Luczak K, Sasiadek MM, Musante L, Laurie R, Peters H, Tartaglia M, Zenker M, Kalscheuer V. Multiple giant cell lesions in patients with Noonan syndrome and cardio-facio-cutaneous syndrome. Eur J Hum Genet. 2009;17(4):420–5.PubMedCrossRefGoogle Scholar
  18. Noonan JA. Noonan syndrome and related disorders: alterations in growth and puberty. Rev Endocr Metab Disord. 2006;7(4):251–5.PubMedCrossRefGoogle Scholar
  19. Noordam C, van der Burgt I, Sweep CG, Delemarre-van de Waal HA, Sengers RC, Otten BJ. 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):53–9.CrossRefGoogle Scholar
  20. Padidela R, Camacho-Hubner C, Attie KM, Savage MO. Abnormal growth in noonan syndrome: genetic and endocrine features and optimal treatment. Horm Res. 2008;70(3):129–36.PubMedCrossRefGoogle Scholar
  21. Pandit B, Sarkozy A, Pennacchio LA, Carta C, Oishi K, Martinelli S, Pogna EA, Schackwitz W, Ustaszewska A, Landstrom A, Bos JM, Ommen SR, Esposito G, Lepri F, Faul C, Mundel P, Lopez Siguero JP, Tenconi R, Selicorni A, Rossi C, Mazzanti L, Torrente I, Marino B, Digilio MC, Zampino G, Ackerman MJ, Dallapiccola B, Tartaglia M, Gelb BD. Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy. Nat Genet. 2007;39(8):1007–12.PubMedCrossRefGoogle Scholar
  22. Ranke MB, Heidemann P, Knupfer C, Enders H, Schmaltz AA, Bierich JR. Noonan syndrome: growth and clinical manifestations in 144 cases. Eur J Pediatr. 1988;148(3):220–7.PubMedCrossRefGoogle Scholar
  23. Razzaque MA, Nishizawa T, Komoike Y, Yagi H, Furutani M, Amo R, Kamisago M, Momma K, Katayama H, Nakagawa M, Fujiwara Y, Matsushima M, Mizuno K, Tokuyama M, Hirota H, Muneuchi J, Higashinakagawa T, Matsuoka R. Germline gain-of-function mutations in RAF1 cause Noonan syndrome. Nat Genet. 2007;39(8):1013–7.PubMedCrossRefGoogle Scholar
  24. Roberts AE, Araki T, Swanson KD, Montgomery KT, Schiripo TA, Joshi VA, Li L, Yassin Y, Tamburino AM, Neel BG, Kucherlapati RS. Germline gain-of-function mutations in SOS1 cause Noonan syndrome. Nat Genet. 2007;39(1):70–4.PubMedCrossRefGoogle Scholar
  25. Romano AA, Dana K, Bakker B, Davis DA, Hunold JJ, Jacobs J, Lippe B. 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):2338–44.PubMedCrossRefGoogle Scholar
  26. Schubbert S, Zenker M, Rowe SL, Boll S, Klein C, Bollag G, van der Burgt I, Musante L, Kalscheuer V, Wehner LE, Nguyen H, West B, Zhang KY, Sistermans E, Rauch A, Niemeyer CM, Shannon K, Kratz CP. Germline KRAS mutations cause Noonan syndrome. Nat Genet. 2006;38(3):331–6.PubMedCrossRefGoogle Scholar
  27. Schubbert S, Shannon K, Bollag G. Hyperactive Ras in developmental disorders and cancer. Nat Rev Cancer. 2007;7(4):295–308.PubMedCrossRefGoogle Scholar
  28. Sharland M, Morgan M, Smith G, Burch M, Patton MA. Genetic counselling in Noonan syndrome. Am J Med Genet. 1993;45(4):437–40.PubMedCrossRefGoogle Scholar
  29. Stofega MR, Herrington J, Billestrup N, Carter-Su C. Mutation of the SHP-2 binding site in growth hormone (GH) receptor prolongs GH-promoted tyrosyl phosphorylation of GH receptor, JAK2, and STAT5B. Mol Endocrinol. 2000;14(9):1338–50.PubMedCrossRefGoogle Scholar
  30. Tartaglia M, Gelb BD. Noonan syndrome and related disorders: genetics and pathogenesis. Annu Rev Genomics Hum Genet. 2005;6:45–68.PubMedCrossRefGoogle Scholar
  31. Tartaglia M, Gelb BD, Zenker M. Noonan syndrome and clinically related disorders. Best Pract Res Clin Endocrinol Metab. 2011;25(1):161–79.PubMedCrossRefGoogle Scholar
  32. Tartaglia M, Pennacchio LA, Zhao C, Yadav KK, Fodale V, Sarkozy A, Pandit B, Oishi K, Martinelli S, Schackwitz W, Ustaszewska A, Martin J, Bristow J, Carta C, Lepri F, Neri C, Vasta I, Gibson K, Curry CJ, Siguero JP, Digilio MC, Zampino G, Dallapiccola B, Bar-Sagi D, Gelb BD. Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome. Nat Genet. 2007;39(1):75–9.PubMedCrossRefGoogle Scholar
  33. Tidyman WE, Rauen KA. Expert Rev Mol Med. Noonan, Costello and cardio-facio-cutaneous syndromes: dysregulation of the Ras-MAPK pathway. 2008;10:e37.PubMedCrossRefGoogle Scholar
  34. 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(2):187–91.PubMedCrossRefGoogle Scholar
  35. Van Vactor D, O’Reilly AM, Neel BG. Genetic analysis of protein tyrosine phosphatases. Curr Opin Genet Dev. 1998;8(1):112–26.PubMedCrossRefGoogle Scholar
  36. Weismann CG, Hager A, Kaemmerer H, Maslen CL, Morris CD, Schranz D, Kreuder J, Gelb BD. PTPN11 mutations play a minor role in isolated congenital heart disease. Am J Med Genet A. 2005;136(2):146–51.PubMedGoogle Scholar
  37. Zenker M, Buheitel G, Rauch R, Koenig R, Bosse K, Kress W, Tietze HU, Doerr HG, Hofbeck M, Singer H, Reis A, Rauch A. Genotype-phenotype correlations in Noonan syndrome. J Pediatr. 2004;144(3):368–74.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Alexsandra C. Malaquias
    • 1
  • Alexander A.L. Jorge
    • 2
    • 3
  1. 1.Hospital das Clínicas, Labaratório de Hormonios e Genetica MolecularSao PauloBrazil
  2. 2.Unidade de Endocrinologia Genetica, Laboratorio de Endocrinologia Celular e Molecular LIM/25São PauloBrazil
  3. 3.Disciplina de Endocrinologia da, Faculdade de Medicina da, Universidade de São PauloSão PauloBrazil

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