Molecular and clinical characterization of 37 patients with Noonan syndrome

Noonan syndrome (NS, OMIM 163950) is an autosomal dominant disorder, with a prevalence 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 play a minor role in the molecular pathogenesis of the disease. Twenty-nine sporadic and 4 familial cases of NS, for a total of 37 patients, underwent molecular analysis of the main genes of the patwhay with a total mutation detection rate of 78.8% (26/33). In details, we found 15 sporadic and 2 familial PTPN11 (51,5%), 6 sporadic and 1 familial SOS1 (21,2%), 1 sporadic KRAS and 1 sporadic BRAF (3%) mutated cases. The two PTPN11 familial cases were characterized by a very high intrafamilal varability, with a surprisingly mild facial phenotype. Interestingly, we have observed some peculiar clinical features in SOS1 patients, in particular a prominent metopic suture in a turricephalyc cranial vault, not observed in PTPN11 mutated NS patients. The KRAS patient presented typical NS dysmorphisms not associated with congenital heart defects, while the BRAF patient, in addition to the characteristic NS phenotype, presented epilepsy, a severe mental retardation and a Chiari type I malformation, so far reported only in 4 other cases; it is possible to propose that the cervical-occipital anomaly resulting in Chiari I malformation, and its variants, can be an aspect of the skeletal dysplasia of the syndrome.