Noonan and Noonan-like syndromes are disorders of dysregulation of the rat sarcoma viral oncogene homolog (RAS)-mitogen-activated protein kinase signaling pathway. In Noonan syndrome (NS), four genes of this pathway (PTPN11, SOS1, RAF1, and KRAS) are responsible for roughly 70% of the cases. We analyzed PTPN11 and KRAS genes by bidirectional sequencing in 95 probands with NS and 29 with Noonan-like syndromes, including previously reported patients already screened for PTPN11 gene mutations. In the new patients with NS, 20/46 (43%) showed a PTPN11 gene mutation, two of them novel. In our total cohort, patients with NS and a PTPN11 mutation presented significantly higher prevalence of short stature (p = 0.03) and pulmonary valve stenosis (p = 0.01), and lower prevalence of hypertrophic cardiomyopathy (p = 0.01). Only a single gene alteration, of uncertain role, was found in the KRAS gene in an NS patient also presenting a PTPN11 gene mutation. We further analyzed the influence in clinical variability of three frequent polymorphisms found in the KRAS gene and no statistically significant difference was observed among the frequency of clinical findings regarding the studied polymorphisms.
Noonan syndrome (NS) is an autosomal dominant disorder, with variable phenotypic expression, characterized by short stature, facial dysmorphisms and heart disease. Different genes of the RAS/MAPK signaling pathway are responsible for the syndrome, the most common are: PTPN11, SOS1, RAF1, and KRAS. The objective of this study was to report a patient with Noonan syndrome presenting mutations in two genes of RAS/MAPK pathway in order to establish whether these mutations lead to a more severe expression of the phenotype. We used direct sequencing of the PTPN11, SOS1, RAF1, and KRAS genes. We have identified two described mutations in heterozygosity: p.N308D and p.R552G in the genes PTPN11 and SOS1, respectively. The patient has typical clinical features similar to the ones with NS and mutation in only one gene, even those with the same mutation identified in this patient. A more severe or atypical phenotype was not observed, suggesting that these mutations do not exhibit an additive effect.
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