NS is typically inherited in an autosomal dominant pattern with variable expression. Recurrence in siblings and apparent transmission from parent to child has long suggested a genetic defect with autosomal dominant inheritance and variable expression. Mutations in the Ras/mitogen activated protein kinase signaling pathways are known to be responsible for about 70% of NS cases. Persons with NS have up to a 50% chance of transmitting it to their offspring. The fact that an affected parent is not always identified for children with NS suggests several possibilities: # Manifestations could be so subtle as to go unrecognized (variable expressivity) # NS is heterogeneous, comprising more than one similar condition of differing causes, and some of these may not be inherited. # A high proportion of cases may represent new, sporadic mutations. Type Online Mendelian Inheritance in Man database Gene Year found Locus % of cases Description Refs. NS1 PTPN11 2001 12q24.1 50% The PTPN11 gene encodes the protein tyrosine phosphatase SHP-2. This protein is a component of several intracellular signal transduction pathways involved in embryonic development that modulate cell division, differentiation, and migration, including one mediated by the epidermal growth factor receptor, which is important in the formation of the semilunar heart valves. Duplication of the chromosome region containing PTPN11 can also result in NS. NS2 Unknown; autosomal recessive NS3 KRAS 2006 12p12.1 <5% NS4 SOS1 2006 2p22 10% Activating mutations in SOS1 can give rise to NS. SHP-2 and SOS1 positively regulate the Ras/MAP kinase pathway, suggesting that its dysregulation mediates NS development. NS5 RAF1 2007 3p25 3–17% Heterozygous mutations in NRAS, HRAS, BRAF, SHOC2, MAP2K1, MAP2K2, and CBL have also been associated with a smaller percentage of NS and related phenotypes. A condition known as "neurofibromatosis–Noonan syndrome" is associated with neurofibromin.
Noonan syndrome
Growth hormone deficiency
Avellis syndrome
Williams syndrome
Muenke syndrome
Christianson syndrome
GRACILE syndrome
Sugarman syndrome