NF1 Gene Mutations are the Major Molecular Event in Neurofibromatosis-Noonan Syndrome

Abstract

Neurofibromatosis–Noonan syndrome is a rare autosomal dominant disorder which combines neurofibromatosis type 1 (NF1) features with Noonan syndrome. Noonan syndrome (NS) and the clinically overlapping disorders and Neurofibromatosis-Noonan syndrome (NFNS) share the some common clinical features. It is now known that all these disorders are caused by mutations in components of the RAS-MAPK signaling pathway which is important in tumorigenesis. NF1 gene mutations are reported in the majority of these patients. There are some data in the literature about the NF1 mutant allele which can lead to manifestations of Noonan syndrome. We have studied four NFNS cases which all fit the NFNS criteria. We evaluated these patients one with Watson syndrome (WS) and the other one with Rhabdomyosarcoma. Although WS and NFNS were described as distinct disorders, detailed clinical examination of these families revealed that not only pulmonic stenosis, borderline intelligence, and multiple cafe´-au-lait spots, but also multiple Lisch nodules, neurofibromas in one third of patients, and short stature were present. The only distinction between WS and NFNS would be that NFNS patients show a more classical phenotype of both NS and NF, whereas WS patients show only a mild expression of NF. Recently, there is increasing evidence for WS and NFNS being allelic to NF1 in the majority of patients. We analyzed 4 NFNS patients by PCR based techniques. Genomic DNA was extracted from peripheral blood samples. PCR was performed with intronic primers for all exons of the NF1. DNA samples were sequenced to detect variations in each exon. This study supports that the major gene causing NFNS is NF1. Therefore inclusion of NF1 in the genetic screening of patients with clinically suspected NS, preferentially when café-au-lait spots are present. As a result, the present study provides the molecular evidence of the role of NF1 mutations in NFNS.