Noonan Syndrome

Abstract

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.