Noonan Syndrome


Noonan syndrome is a genetic disorder inherited as an autosomal trait or occurring sporadically, characterised by short stature, dysmorphic facies, webbed neck, congenital heart disease or hypertrophic cardiomyopathy, skeletal anomalies, cryptorchidism and developmental delay. Missense mutations in the PTPN11 gene, encoding the protein tyrosine phosphatase SHP2, cause approximately 50% of cases. SHP2 is a positive regulator of RAS/mitogen‐activated protein kinase (MAPK) signal transduction. Noonan syndrome‐associated PTPN11 mutations typically have gain‐of‐function effects on SHP2 and RAS/MAPK signalling. Missense mutations in other genes encoding proteins in the RAS/MAPK pathway, including SOS1, KRAS, NRAS, RAF1, BRAF and possibly MEK1, also cause Noonan syndrome. In aggregate, mutations in these seven genes account for approximately 70–75% of Noonan syndrome. Genotype–phenotype associations have been established with respect to particular genes and even mutations underlying this disorder.

Key Concepts:

  • Noonan syndrome is an autosomal dominant, pleomorphic trait characterised by short stature, typical facial dysmorphia and cardiovascular defects.

  • Noonan syndrome is a genetically heterogeneous trait, caused by missense mutations in genes encoding proteins in the RAS/mitogen‐activated protein kinase pathway.

  • Most mutations causing Noonan syndrome have gain‐of‐function effects resulting in increased RAS signalling.

  • Strong genotype–phenotype associations exist for genes and even specific alleles for Noonan syndrome.

  • The seven Noonan syndrome genes identified to date account for approximately 70–75% of cases.

Keywords: PTPN11; SHP2; KRAS; NRAS; SOS1; RAF1; BRAF; MEK1; Noonan syndrome; RAS signalling

Figure 1.

Dysmorphic facial features in Noonan syndrome. Series of one affected girl from age 2–17 years, showing the evolution of the facial features. (Kindly provided by Allanson, J.)

Figure 2.

The RAS/MAPK signal transduction pathway. Schematic diagram showing the RAS/MAPK cascade and affected disease genes in the RASopathies. The genes for which mutations are known and their associated phenotypes are indicated near the cartoon representation of the proteins they encode. Positive regulatory interactions are indicated with black arrows, and the negative regulatory interaction is indicated with a red blunted arrow. CFCS, cardiofaciocutaneous syndrome; CS, Costello syndrome; NF1, neurofibromatosis type 1; NFLS, neurofibromatosis type 1‐like syndrome (also termed Legius syndrome); NFNS, neurofibromatosis‐NS; NS/LAH, Noonan‐like syndrome with loose anagen hair; RTK, receptor tyrosine kinase; WS, Watson syndrome. Reprinted with permission from the Journal of Clinical Investigation (2011) 121(3): p. 845.



Cirstea IC, Kutsche K, Dvorsky R et al. (2010) A restricted spectrum of NRAS mutations causes Noonan syndrome. Nature Genetics 42(1): 27–29.

Gremer L, Merbitz‐Zahradnik T, Dvorsky R and Cirstea IC (2010) Germline KRAS mutations cause aberrant biochemical and physical properties leading to developmental disorders. Human Mutation 32(1): 33–43.

Hof P, Pluskey S, Dhe‐Paganon S et al. (1998) Crystal structure of the tyrosine phosphatase SHP2. Cell 92(4): 441–450.

Keilhack H, David FS, McGregor M et al. (2005) Diverse biochemical properties of Shp2 mutants. Implications for disease phenotypes. Journal of Biological Chemistry 280(35): 30984–30993.

Kratz CP, Niemeyer CM, Castleberry RP et al. (2005) The mutational spectrum of PTPN11 in juvenile myelomonocytic leukemia and Noonan syndrome/myeloproliferative disease. Blood 106(6): 2183–2185.

Lee KA, Williams B, Roza K et al. (2008) PTPN11 analysis for the prenatal diagnosis of Noonan syndrome in fetuses with abnormal ultrasound findings. Clinical Genetics 75(2): 190–194.

Lepri F, De Luca A, Stella L et al. (2011) SOS1 mutations in Noonan syndrome: molecular spectrum, structural insights on pathogenic effects, and genotype–phenotype correlations. Human Mutation 32(7): 760–772.

Martinelli S, Torreri P, Tinti M et al. (2008) Diverse driving forces underlie the invariant occurrence of the T42A, E139D, I282V and T468M SHP2 amino acid substitutions causing Noonan and LEOPARD syndromes. Human Molecular Genetics 17(13): 2018–2029.

Mitin N, Rossman KL and Der CJ (2005) Signaling interplay in Ras superfamily function. Current Biology 15(14): R563–R574.

Nava C, Hanna N, Michot C et al. (2007) Cardio‐facio‐cutaneous and Noonan syndromes due to mutations in the RAS/MAPK signalling pathway: genotype–phenotype relationships and overlap with Costello syndrome. Journal of Medical Genetics 44(12): 763–771.

Neel BG, Gu H and Pao L (2003) The ‘Shp’ing news: SH2 domain‐containing tyrosine phosphatases in cell signaling. Trends in Biochemical Sciences 28(6): 284–293.

Niemeyer CM and Kratz CP (2008) Paediatric myelodysplastic syndromes and juvenile myelomonocytic leukaemia: molecular classification and treatment options. British Journal of Haematology 140(6): 610–624.

Niihori T, Aoki Y, Narumi Y et al. (2006) Germline KRAS and BRAF mutations in cardio‐facio‐cutaneous syndrome. Nature Genetics 38(3): 294–296.

Nimnual A and Bar‐Sagi D (2002) The two hats of SOS. Science's STKE 2002(145): PE36.

Noonan JA (1968) Hypertelorism with Turner phenotype. A new syndrome with associated congenital heart disease. American Journal of Diseases of Children 116(4): 373–380.

Nystrom AM, Ekvall S, Berglund E et al. (2008) Noonan and cardio‐facio‐cutaneous syndromes: two clinically and genetically overlapping disorders. Journal of Medical Genetics 45(8): 500–506.

Pandit B, Sarkozy A, Pennacchio LA et al. (2007) Gain‐of‐function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy. Nature Genetics 39(8): 1007–1012.

Razzaque MA, Nishizawa T, Komoike Y et al. (2007) Germline gain‐of‐function mutations in RAF1 cause Noonan syndrome. Nature Genetics 39(8): 1013–1017.

Roberts AE, Araki T, Swanson KD et al. (2007) Germline gain‐of‐function mutations in SOS1 cause Noonan syndrome. Nature Genetics 39: 70–74.

Rodriguez‐Viciana P, Tetsu O, Tidyman WE et al. (2006) Germline mutations in genes within the MAPK pathway cause cardio‐facio‐cutaneous syndrome. Science 311(5765): 1287–1290.

Sarkozy A, Carta C, Moretti S et al. (2009) Germline BRAF mutations in Noonan, LEOPARD, and cardiofaciocutaneous syndromes: molecular diversity and associated phenotypic spectrum. Human Mutation 30(4): 695–702.

Schubbert S, Bollag G, Lyubynska N et al. (2007) Biochemical and functional characterization of germ line KRAS mutations. Molecular and Cellular Biology 27(22): 7765–7770.

Schubbert S, Zenker M, Rowe SL et al. (2006) Germline KRAS mutations cause Noonan syndrome. Nature Genetics 38(3): 331–336.

Tartaglia M, Kalidas K, Shaw A et al. (2002) PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype–phenotype correlation, and phenotypic heterogeneity. American Journal of Human Genetics 70(6): 1555–1563.

Tartaglia M, Martinelli S, Stella L et al. (2006) Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease. American Journal of Human Genetics 78(2): 279–290.

Tartaglia M, Mehler EL, Goldberg R et al. (2001) Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP2, cause Noonan syndrome. Nature Genetics 29(4): 465–468.

Tartaglia M, Niemeyer CM, Fragale A et al. (2003) Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia. Nature Genetics 34(2): 148–150.

Tartaglia M, Pennacchio LA, Zhao C et al. (2007) Gain‐of‐function SOS1 mutations cause a distinctive form of Noonan syndrome. Nature Genetics 39(1): 75–79.

Wellbrock C, Karasarides M and Marais R (2004) The RAF proteins take centre stage. Nature Reviews Molecular Cell Biology 5(11): 875–885.

Wennerberg K, Rossman KL and Der CJ (2005) The Ras superfamily at a glance. Journal of Cell Science 118(Pt 5): 843–846.

Zenker M, Buheitel G, Rauch R et al. (2004) Genotype–phenotype correlations in Noonan syndrome. Journal of Pediatrics 144(3): 368–374.

Zenker M, Horn D, Wieczorek D et al. (2007) SOS1 is the second most common Noonan gene but plays no major role in cardio‐facio‐cutaneous syndrome. Journal of Medical Genetics 44(10): 651–656.

Zheng CF and Guan KL (1993) Properties of MEKs, the kinases that phosphorylate and activate the extracellular signal‐regulated kinases. Journal of Biological Chemistry 268(32): 23933–23939.

Further Reading

Araki T, Mohi MG, Ismat FA et al. (2004) Mouse model of Noonan syndrome reveals cell type‐ and gene dosage‐dependent effects of Ptpn11 mutation. Natural Medicines 10(8): 849–857.

Carvajal‐Vergara X, Sevilla A, D'Souza SL et al. (2010) Patient‐specific induced pluripotent stem‐cell‐derived models of LEOPARD syndrome. Nature 465(7299): 808–812.

Chen PC, Wakimoto H, Conner D et al. (2010) Activation of multiple signaling pathways causes developmental defects in mice with a Noonan syndrome‐associated Sos1 mutation. Journal of Clinical Investigation 120(12): 4353–4365.

Cordeddu V, Di Schiavi E, Pennacchio LA et al. (2009) Mutation of SHOC2 promotes aberrant protein N‐myristoylation and causes Noonan‐like syndrome with loose anagen hair. Nature Genetics 41(9): 1022–1026.

Dhandapany PS, Fabris F, Tonk R et al. (2011) Cyclosporine attenuates cardiomyocyte hypertrophy induced by RAF1 mutants in Noonan and LEOPARD syndromes. Journal of Molecular and Cellular Cardiology 51(1): 4–15.

Martinelli S, De Luca A, Stellacci E et al. (2010) Heterozygous germline mutations in the CBL tumor‐suppressor gene cause a Noonan syndrome‐like phenotype. American Journal of Human Genetics 87(29): 250–257.

Niemeyer CM, Kang MW, Shin DH et al. (2010) Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia. Nature Genetics 42(9): 794–800.

Oishi K, Gaengel K, Krishnamoorthy S et al. (2006) Transgenic Drosophila models of Noonan syndrome causing PTPN11 gain‐of‐function mutations. Human Molecular Genetics 15(4): 543–553.

Romano AA, Allanson JE, Dahlgren J et al. (2010) Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics 126(4): 746–759.

Wu X, Simpson J, Hong JH et al. (2011) MEK–ERK pathway modulation ameliorates disease phenotypes in a mouse model of Noonan syndrome associated with the Raf1(L613V) mutation. Journal of Clinical Investigation 121(3): 1009–1025.

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How to Cite close
Tartaglia, Marco, and Gelb, Bruce D(Sep 2011) Noonan Syndrome. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0006226.pub2]