Genotype-phenotype correlations in Noonan syndrome

Noonan syndrome (NS) is an autosomal dominant disorder mainly characterized by short stature, distinct facial anomalies and congenital heart defects. The cumulative record of genotype-phenotype correlations clearly indicates that PTPN11 gene mutations, responsible for almost half of the cases, either sporadic or familial, are responsible for a wide clinical spectrum, characterized by a high prevalence of pulmonary valve stenosis, typical facial features, cryptorchidism and bleeding diathesis. Mutations in the SOS1 gene are associated with clinical features partly overlapping those found in PTPN11 mutation-positive individuals, but distinguished by a low frequency of short stature and mental retardation, and a high prevalence of macrocephaly, ptosis, and skin features similar to those of cardio-facio-cutaneous syndrome (CFCS). RAF1 gene mutations are strongly associated with hypertrophic cardiomyopathy, mental retardation, short stature, and skin features of LEOPARD syndrome. Patients with KRAS mutations are sporadic, affected by variable mental retardation and may manifest features overlapping those of Costello and CFCS, while MEK1 mutations have been found so far only in two unrelated NS individuals.