Noonan syndrome and neurofibromatosis type I in a family with a novel mutation in NF1

Abstract

Noonan syndrome (NS) and neurofibromatosis type I (NF1) belong to a group of clinically related disorders that share a common pathogenesis, dysregulation of the RAS-MAPK pathway. NS is characterized by short stature, heart defect, pectus deformity and facial dysmorphism, whereas skin manifestations, skeletal defects, Lisch nodules and neurofibromas are characteristic of NF1. Both disorders display considerable clinical variability. Features of NS have been observed in individuals with NF1 -a condition known as neurofibromatosis-Noonan syndrome (NFNS). The major gene causing NFNS is NF1. Rarely, a mutation in PTPN11 in addition to an NF1 mutation is present. We present the clinical and molecular characterization of a family displaying features of both NS and NF1, with complete absence of neurofibromas. To investigate the etiology of the phenotype, mutational analysis of NF1 was conducted, revealing a novel missense mutation in exon 24, p.L1390F, affecting the GAP-domain. Additional RAS-MAPK pathway genes were examined, but no additional mutations were identified. We confirm that NF1 mutations are involved in the etiology of NFNS. Furthermore, based on our results and previous studies we suggest that evaluation of the GAP-domain of NF1 should be prioritized in NFNS.

Increased rate of missense/in-frame mutations in individuals with NF1-related pulmonary stenosis: a novel genotype–phenotype correlation

“…The reported molecular analyses of this group was based on DNA analyses except for a single case in which combined DNA/RNA approach was utilized. 19 The disease association predictive tool (SNP &Go 24 ) suggested a disease causative prediction with maximal reliability score in all of the mutations associated with NFNS and PS. In addition, using Splice Site Finder-like, MaxEntScan, NNSPLICE, GeneSplicer and Human Splicing Finder tools no effect on splicing was predicted for these mutations.…”

“…Finally, the findings of increasing numbers of possible genotypephenotype correlations in small series of NF1 patients 19,[29][30][31] suggest the need for renewed interest in this area with further large prospective studies of well-characterized patients.…”

“…Although originally reported as a distinct condition, subsequent clinical 17 and molecular analysis has shown that the majority of NFNS patients have only NF1 gene mutations, with a significantly higher prevalence of nontruncating mutations, particularly in-frame deletions, than in typical NF1. 18,19 Two cases have been reported with both NF1 and PTPN11 mutations. In one, the patient inherited the PTPN11 gene mutation from a parent and had a de novo NF1 mutation, 20 and in the other a de novo PTPN11 gene mutation with inherited NF1.…”

Noonan Syndrome: Clinical Aspects and Molecular Pathogenesis

“…These findings support the view that NFNS is genetically distinct from NS and emphasize the extreme phenotypic variability associated with lesions in the NF1 gene. The identification of specific NF1 alleles recurring in NFNS, the evidence that these alleles cosegregate with the condition in families, and the observation of a peculiar mutational spectrum strongly suggest that the term 'NFNS' does characterize a phenotypic variant of NF1, which manifests with a lower incidence of plexiform neurofibromas, skeletal anomalies, and internal tumors, in association with hypertelorism, ptosis, low-set ears, and CHDs [Carey, 1998;Baralle et al, 2003;De Luca et al, 2005;Hüffmeier et al, 2006;Nyström et al, 2009]. It should be noted, however, that some of the mutations identified in patients with NFNS have also been reported in NF1 without any feature suggestive of NS.…”

Noonan Syndrome Eye Signs: A Case Report

“…Several genes leading to this syndrome (PTPN11, SOS1, RAF1, and KRAS) have been identified (13,14). Moreover, neurofibromatosis and NS coexistence have also been shown due to mutations in the neurofibromin gene located on the long arm of chromosome 17 (15,16).…”