NF1 exon 22 analysis of individuals with the clinical diagnosis of neurofibromatosis type 1.

Café-au-lait macules are frequently seen in Ras-MAPK pathway disorders and are a cardinal feature of neurofibromatosis type 1 (NF1). Most NF1 individuals develop age-related tumorigenic manifestations (e.g., neurofibromas), although individuals with a specific 3-bp deletion in exon 22 of NF1 (c.2970_2972delAAT) have an attenuated phenotype with primarily pigmentary manifestations. Previous reports identify this deletion c.2970_2972delAAT in exon 17 of NF1 using NF Consortium nomenclature. For this report, we elected to use standard NCBI nomenclature, which places this identical deletion within exon 22. SPRED1 mutations cause Legius syndrome, which clinically overlaps with this attenuated NF1 phenotype. In an unselected cohort of 50 individuals who fulfilled NIH clinical diagnostic criteria from an NF Clinic and did not have SPRED1 mutations, we sequenced NF1 exon 22 in order to identify children and adolescents with multiple café-au-lait spots who could be projected to have lower likelihood to develop tumors. Two individuals with NF1 exon 22 mutations were identified: an 11-year-old boy with the c.2970_2972delAAT in-frame deletion and a 4-year-old boy with c.2866dupA. The father of the second patient had an attenuated form of NF1 and showed 24% germline mosaicism of the c.2866dupA mutation in whole blood. These individuals emphasize the need for mutation analysis in some individuals with the clinical diagnosis of NF1 who lack the tumorigenic or classic skeletal abnormalities of NF1. Specifically, with the identification of Legius syndrome, the need to recognize the attenuated phenotype of NF1 mosaicism and confirmation by mutation analysis is increasingly important for appropriate medical management and family counseling.

SPRED 1 mutations in a neurofibromatosis clinic.

Legius syndrome, caused by SPRED1 mutations, has phenotypic overlap with neurofibromatosis type 1 (NF1) without tumorigenic manifestations. Patients fulfilling the National Institutes of Health (NIH) diagnostic criteria for NF1 were enrolled at the University of Utah NF Clinic, and SPRED1 mutation analysis was performed to identify the frequency of Legius syndrome within an NF1 clinic population. SPRED1 sequencing was performed on 151 individuals with the clinical diagnosis of NF1, and 2 individuals (1.3%) were found to have novel SPRED1 mutations, p.R18X and p.Q194X. The phenotypes for the 2 individuals with SPRED1 mutations included altered pigmentation without tumorigenesis. A specific SPRED1 haplotype allele was identified in 27 individuals. The frequency of SPRED1 mutations in patients meeting diagnostic criteria for NF1 in a hospital-based clinic is 1% to 2%. The likelihood an individual is harboring a SPRED1 mutation increases with age if multiple, nonpigmentary NF1 findings are absent. Legius syndrome patients may benefit from altered medical surveillance.