Clinical and molecular characterization of 40 patients with Noonan syndrome

Noonan syndrome (NS, OMIM 163950) is an autosomal dominant disorder, with a prevalence at birth of 1:1000–1:2500 live births, characterized by short stature, facial and skeletal dysmorphisms, cardiovascular defects and haematological anomalies. Missense mutations of PTPN11 gene account for approximately 50% of NS cases, while molecular lesions of other genes of the RAS/MAPK pathway – KRAS, SOS1 and RAF1 – play a minor role in the molecular pathogenesis of the disease. Forty patients were enrolled in the study with a PTPN11 mutation detection rate of 31.5%, including a novel missense mutation, Phe285Ile, in a familial case with high intrafamilial phenotypic variability. All patients negative for PTPN11 mutations were further screened for mutations of the KRAS, SOS1, and RAF1 genes, revealing a Thr266Lys substitution in SOS1 in a single patient, a newborn with a subtle phenotype, characterized by facial dysmorphisms and a mild pulmonic stenosis.