Noonan syndrome (NS) is an autosomal-dominant disease characterized by distinctive facial features, webbed neck, cardiac anomalies, short stature and cryptorchidism. NS exhibits phenotypic overlap with Costello syndrome and cardio-facio-cutaneous (CFC) syndrome. Germline mutations of genes encoding proteins in the RAS/mitogen-activated protein kinase (MAPK) pathway cause NS and related disorders. Germline mutations in PTPN11, KRAS, SOS1, RAF1, and NRAS have been identified in 60-80 % of NS patients. Germline mutations in HRAS have been identified in patients with Costello syndrome and mutations in KRAS, BRAF, and MAP2K1/2 (MEK1/2) have been identified in patients with CFC syndrome. Recently, mutations in SHOC2 and CBL have been identified in patients with Noonan-like syndrome. It has been suggested that these syndromes be comprehensively termed RAS/MAPK syndromes, or RASopathies. Molecular analysis is beneficial for the confirmation of clinical diagnoses and follow-up with patients using a tumor-screening protocol, as patients with NS and related disorders have an increased risk of developing tumors. In this review, we summarize the genetic mutations, clinical manifestations, associations with malignant tumors, and possible therapeutic approaches for these disorders.
- RAS/MAPK signaling pathway
ASJC Scopus subject areas