Study of PTPN11 and KRAS genes in patients with Noonan and Noonan-like syndromes / Estudo dos genes PTPN11 e KRAS em pacientes afetados pela síndrome de Noonan e pelas síndromes Noonan-like

AUTOR(ES)
DATA DE PUBLICAÇÃO

2009

RESUMO

INTRODUCTION: Noonan syndrome shows autosomal dominant inheritance, and is a relatively frequent disease in the population, with an estimated incidence between 1/1000 and 1/2500 live births. The main clinical features are: facial dysmorphisms, short stature, cryptorchidism and cardiac abnormalities. The differential diagnosis between Noonan syndrome and Noonan-like syndromes is not always easy, due to the overlap of the their clinicla findings. The Noonan-like syndromes, more rare that the Noonan syndrome, include the LEOPARD syndrome, neurofibromatosis-Noonan, cardiofaciocutaneous and Costello. Currently it is known that Noonan syndrome and Noonan-like syndromes involve mutations in genes belonging to the RAS-MAPK signaling pathway. In Noonan syndrome, at least four genes of this pathway are responsible for the phenotype: PTPN11, SOS1, RAF1 and KRAS. Mutations in PTPN11, the first gene described in association with this syndrome, are found in approximately 40% of cases. The second gene described, the KRAS gene, is responsible for about 2% of the cases that dont have mutations in the PTPN11 gene. Mutations in the KRAS gene are present in patients with Noonan syndrome with mental retardation and/or developmental delay more pronounced and in patients with cardiofaciocutaneous syndrome whose ectodermal involvement is more subtle. OBJECTIVE: Due to the recent association of the KRAS gene with Noonan and Noonan-like syndromes is important: (1) to test the frequency of mutation in this gene in patients with or without mutations in PTPN11 and (2) to estabilish a more precise genotype-phenotype correlation, allowing the realization of a more appropriate genetic counseling. METHODS: 95 probands with Noonan syndrome and 30 with Noonan-like syndromes were evaluated. The molecular analysis was performed by the polymerase chain reaction, followed by purification and bidirectional sequencing. RESULTS: PTPN11 gene mutation was found in 20/46 (43%) patients with Noonan syndrome, two of them not previously described. By correlating the clinical features of patients with Noonan syndrome in this study, with or without mutations in the PTPN11 gene, it was noted that patients with mutations have significantly higher incidence of short stature, pulmonary stenosis and lower incidence of hypertrophic cardiomyopathy. Mutations in KRAS gene were found in two patients a patient with Noonan syndrome ant the other with Costello syndrome. Gene alterations in more than one gene at the RASMAPK patway were observed in two patients, but one of the mutations in each patient didnt predict a significant phenotypic effect. Were also foud three polymorphisms in the KRAS gene, but with the same frequency in the control group. To check the influence of these polymorphisms, the main features of Noonan syndrome were related among patients with this syndrome who had mutations in the PTPN11 gene and compared of the presence or absence of these polymorphisms. No statistically significant difference was found. CONCLUSION: Patients with Noonan syndrome and PTPN11 gene mutation had a higher incidence of short stature and pulmonary valve stenosis and a lower incidence of hypertrophic cardiomyopathy. The KRAS gene, previously related to Noonan and cardiofaciocutaneous syndrome, was also responsible for Costello syndrome. Gene alterations considered as nonpathogenic and polymorphisms found in the KRAS gene seem to have a not great influence on the phenotypic variability in Noonan syndrome. However, it is not possible to completely rule out that these changes have a subtle effect and that, together with other genetic variations and/or environmental factors, may have a modulating effect

ASSUNTO(S)

mutation síndrome de noonan mutação noonan syndrome polimorfismo genético polymorphism genetic

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