Clinical features and disease severity in patients with mosaic neurofibromatosis type 1: a single-center study and literature review.

BACKGROUND: The mosaic form of neurofibromatosis type 1 (NF1) is called mosaic NF1 (MNF1). No specific MNF1 follow-up guidelines exist. It is debatable if patients with MNF1 should be clinically examined and undergo follow-up in accordance with the standard NF1 guidelines, as MNF1 patients more often may develop more benign phenotypes and thereby less disease-associated complications including cognitive impairment. We discussed the need for a specific MNF1 follow-up guideline with focus on frequency of plexiform neurofibromas and NF1-associated complications. METHOD: A systematic retrospective data collection in a MNF1 cohort from one of two Danish national centers of NF1 Expertise was completed. Data collected included demographics, clinical features including NF1 diagnostic criteria and NF1-associated complications. Recent literature in the field was reviewed. RESULTS: We identified 17 patients with MNF1 with a median age of 37 years [4; 66]. Eleven (65%) were females. Five patients (30%) had a plexiform neurofibroma. The median age at detection of plexiform neurofibroma was 30 years [14; 60]. Nine (53%) had at least one NF1-related complication; scoliosis, hypertension, ADHD, learning disability, language delay, autism and delay in gross and fine motor function development. We reviewed nine articles. In total, 126 cases were described within three case-series. Nineteen (15%) had a plexiform neurofibroma and in total, 23 NF1-associated complications were reported including language delay, learning disability and skeletal abnormalities. Furthermore, from the literature it was evident that the diagnosing of MNF1 varies among physicians and across countries. CONCLUSION: Patients with MNF1 present with plexiform neurofibromas and other NF1-related complications with a frequency requiring that follow-up of MNF1 patients should be in accordance with the standard NF1 guideline in both childhood and adulthood. Physicians should be aware of cognitive impairment as a complication to MNF1. To develop a specific MNF1 follow-up guideline, there is a need for an international consensus on the diagnostic criteria for MNF1 and a follow-up study conducted in a larger MNF1 cohort.

A founder synonymous COL7A1 mutation in three Danish families with dominant dystrophic epidermolysis bullosa pruriginosa identifies exonic regulatory sequences required for exon 87 splicing.

Dystrophic epidermolysis bullosa pruriginosa (DEB-Pr) (OMIM 604129) represents a distinct variant within the DEB clinical spectrum. It is characterized by intense pruritus and distinctive nodular prurigo-like and/or hypertrophic lichenoid lesions mainly localized on the arms, legs and upper shoulders. DEB-Pr is caused by either dominant (DDEB-Pr) or recessive mutations in the COL7A1 gene encoding type VII collagen (COLVII). The full spectrum of COL7A1 mutations in DEB-Pr remains elusive and the genotype-phenotype correlation is largely incomplete. Here, we report and functionally characterize a previously unrecognized translationally silent exonic COL7A1 mutation that results in skipping of exon 87 and is associated with DDEB-Pr phenotypes in several members of three apparently unrelated Danish families. A haplotype segregation study suggested a common ancestor in these kindred. Functional splicing analysis of the mutant exon by a COL7A1 minigene construct and computational prediction for splicing regulatory cis-sequences prove that the mutation alters the activity of an exonic splicing enhancer (ESE) critical for exon inclusion. These findings substantiate for the first time the involvement of an ESE mutation in the pathogenesis of DEB and have implications for genetic counselling of Danish families with DDEB.