Noonan syndrome is a heterogeneous genetic disorder characterized by craniofacial features, heart defects and short stature. Furthermore, affected individuals often present skeletal defects, delayed psychomotor development, intellectual impairment, increased bleeding tendency and cryptorchidism. Noonan syndrome is inherited in an autosomal dominant manner, whereas in around 60% of cases the mutations arise de novo. At present, genetic diagnosis can be made in approximately 70% of suspected cases. Germline mutations in genes of proteins involved in the RAS/mitogen-activated protein kinase (MAPK) signaling pathway have been described in Noonan syndrome.
This pathway is essential for the regulation of cell proliferation, differentiation and survival. Approximately 50% of the known mutations are located in the PTPN11 gene. Other genes known to be involved in the pathogenesis of Noonan syndrome include RAF1, SOS1, KRAS, BRAF, NRAS, MAP2K and SHOC. Recent investigations suggest that mutations in the RIT1 gene might also be causal for Noonan syndrome.