Noonan Syndrome

Marco Tartaglia, Istituto Superiore di Sanità, Rome, Italy
Bruce D Gelb, Mount Sinai School of Medicine, New York, USA

Published online: September 2011

DOI: 10.1002/9780470015902.a0006226.pub2

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.
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    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.

Related Sub-Topics:

Developmental Disorders | Specific Genetic Disorders | Mutational Mechanisms of Genetic Disease
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Article Title: Noonan Syndrome
 
How to Cite close
Tartaglia, Marco, and Gelb, Bruce D(Sep 2011) Noonan Syndrome. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0006226.pub2]