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Background Neurofibromatosis 2 (NF2) is an autosomal-dominant tumour predisposition syndrome characterised by bilateral vestibular schwannomas, considerable morbidity and reduced life expectancy. Although genotype–phenotype correlations are well established in NF2, little is known about effects of mutation type or location within the gene on mortality. Improvements in NF2 diagnosis and management have occurred, but their effect on patient survival is unknown. Methods We evaluated clinical and molecular predictors of mortality in 1192 patients (771 with known causal mutations) identified through the UK National NF2 Registry. Kaplan–Meier survival and Cox regression analyses were used to evaluate predictors of mortality, with jackknife adjustment of parameter SEs to account for the strong intrafamilial phenotypic correlations that occur in NF2. Results The study included 241 deaths during 10 995 patient-years of follow-up since diagnosis. Early age at diagnosis and the presence of intracranial meningiomas were associated with increased mortality, and having a mosaic, rather than non-mosaic, NF2 mutation was associated with reduced mortality. Patients with splice-site or missense mutations had lower mortality than patients with truncating mutations (OR 0.459, 95% CI 0.213 to 0.990, and OR 0.196, 95% CI 0.213 to 0.990, respectively). Patients with splice-site mutations in exons 6–15 had lower mortality than patients with splice-site mutations in exons 1–5 (OR 0.333, 95% CI 0.129 to 0.858). The mortality of patients with NF2 diagnosed in more recent decades was lower than that of patients diagnosed earlier. Conclusions Continuing advances in molecular diagnosis, imaging and treatment of NF2-associated tumours offer hope for even better survival in the future.

Background: Patients with neurofibromatosis 1 (NF1) are shorter than expected and often have low bone mineral density (BMD), but the pathogenesis of these bony problems is poorly understood. Methods: We performed an exploratory study of BMD, 18 laboratory measures of bone metabolism, and fracture history in 72 adult NF1 patients. Results: Eight of the 18 clinical biochemical measures of bone health had at least 10% of NF1 patients outside the standard reference range. Serum 25-hydroxy-vitamin D concentrations were low in 56% of the NF1 patients, serum parathyroid hormone (PTH) concentrations were high in 34%, and urine deoxypyridinoline cross-link concentrations were high in 50%. Mean serum 25-hydroxy-vitamin D concentrations were significantly lower in people with NF1 than in season matched controls in both summer (p = 0.008) and winter (p

Background: Plexiform neurofibromas are benign tumours that occur in more than half of people with neurofibromatosis 1 (NF1). These tumours can cause serious complications and can also progress to malignant peripheral nerve sheath tumours (MPNSTs), one of the leading causes of death among NF1 patients. Plexiform neurofibromas are clinically heterogeneous, and knowledge of their natural history is limited. In order to characterise the growth of plexiform neurofibromas better, we performed serial magnetic resonance imaging (MRI) in NF1 patients with such tumours. Methods: MRI was done on 44 plexiform neurofibromas in 34 NF1 patients (median age 10 years; range 1–47 years). Each tumour was measured in two dimensions from the MRI scan, and the area and growth rate were calculated. The median length of follow-up was 6 years, with an average interval of 3 years between scans. Results: 36 tumours remained stable in size throughout the period of follow-up. 8 tumours increased in size; all occurred in patients who were under 21 years of age when first studied. The single exception was a man who developed rapid tumour growth and pain in a plexiform neurofibroma that had been followed for 10 years. Biopsy showed the presence of an MPNST. Conclusion: Longitudinal MRI is a valuable means of monitoring the growth of plexiform neurofibromas in individuals with NF1.

The authors report a patient with mild mental retardation, autistic features, multiple vertebral malformations, and an unusual facial appearance who carries a de novo submicroscopic deletion of chromosome 2p16.3. The patient’s deletion is ∼320 kb in size and includes only the part of the NRXN1 gene that codes for the neurexin1α promoter and initial coding exons. The more downstream neurexin1β promoter and the region surrounding it are intact. Neurexin1β has been associated with autism in several recent studies, but this is the first reported patient with loss of only neurexin1α and not of neurexin1β. These findings suggest that neurexin1α function in correct dosage is necessary for normal neurological development.

We identified de novo submicroscopic chromosome 14q11.2 deletions in two children with idiopathic developmental delay and cognitive impairment. Vancouver patient 5566 has a approximately 200 kb deletion and Vancouver patient 8326 has a approximately 1.6 Mb deletion. The Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources (DECIPHER) revealed a third patient with idiopathic developmental delay and cognitive impairment, DECIPHER patient 126, who has a approximately 1.1 Mb deletion of 14q11.2. The deletion of patient 5566 overlaps that of patient 126 and both of these deletions lie entirely within that of patient 8326. All three children have similar dysmorphic features, including widely-spaced eyes, short nose with flat nasal bridge, long philtrum, prominent Cupid's bow of the upper lip, full lower lip and similar auricular anomalies.The minimal common deletion region on chromosome 14q11.2 is only approximately 35 kb (from 20.897 to 20.932, University of California at Santa Cruz (UCSC) Genome Browser; build hg18, March 2006) and includes only two genes, SUPT16H and CHD8, which are good candidate genes for the phenotypes. The non-recurrent breakpoints of these patients, the presence of normal copy number variants in the region and the local genomic structure support the notion that this region has reduced stability.