Incidence of mosaicism in 1055 de novo NF2 cases: much higher than previous estimates with high utility of next-generation sequencing.

PURPOSE: To evaluate the incidence of mosaicism in de novo neurofibromatosis 2 (NF2). METHODS: Patients fulfilling NF2 criteria, but with no known affected family member from a previous generation (n = 1055), were tested for NF2 variants in lymphocyte DNA and where available tumor DNA. The proportion of individuals with a proven or presumed mosaic NF2 variant was assessed and allele frequencies of identified variants evaluated using next-generation sequencing. RESULTS: The rate of proven/presumed mosaicism was 232/1055 (22.0%). However, nonmosaic heterozygous pathogenic variants were only identified in 387/1055 (36.7%). When variant detection rates in second generation nonmosaics were applied to de novo cases, we assessed the overall probable mosaicism rate to be 59.7%. This rate differed by age from 21.7% in those presenting with bilateral vestibular schwannoma <20 years to 80.7% in those aged ≥60 years. A mosaic variant was detected in all parents of affected children with a single-nucleotide pathogenic NF2 variant. CONCLUSION: This study has identified a very high probable mosaicism rate in de novo NF2, probably making NF2 the condition with the highest expressed rate of mosaicism in de novo dominant disease that is nonlethal in heterozygote form. Risks to offspring are small and probably correlate with variant allele frequency detected in blood.

Identifying the deficiencies of current diagnostic criteria for neurofibromatosis 2 using databases of 2777 individuals with molecular testing.

PURPOSE: We have evaluated deficiencies in existing diagnostic criteria for neurofibromatosis 2 (NF2). METHODS: Two large databases of individuals fulfilling NF2 criteria (n = 1361) and those tested for NF2 variants with criteria short of diagnosis (n = 1416) were interrogated. We assessed the proportions meeting each diagnostic criterion with constitutional or mosaic NF2 variants and the positive predictive value (PPV) with regard to definite diagnosis. RESULTS: There was no evidence for usefulness of old criteria "glioma" or "neurofibroma." "Ependymoma" had 100% PPV and high levels of confirmed NF2 diagnosis (67.7%). Those with bilateral vestibular schwannoma (VS) alone aged ≥60 years had the lowest confirmation rate (6.6%) and reduced PPV (80%). Siblings as a first-degree relative, without an affected parent, had 0% PPV. All three individuals with unilateral VS and an affected sibling were proven not to have NF2. The biggest overlap was with LZTR1-associated schwannomatosis. In this category, seven individuals with unilateral VS plus ≥2 nondermal schwannomas reduced PPV to 67%. CONCLUSIONS: The present study confirms important deficiencies in NF2 diagnostic criteria. The term "glioma" should be dropped and replaced by "ependymoma." Similarly "neurofibroma" should be removed. Dropping "sibling" from first-degree relatives should be considered and testing of LZTR1 should be recommended for unilateral VS.

The experience of auditory implant recipients undergoing magnetic resonance imaging: Factors associated with pain.

OBJECTIVE: Many patients with cochlear implants (CI) and auditory brainstem implants (ABI) require magnetic resonance imaging (MRI) following implantation. This study explores the patient experience of MRI, identifying factors associated with pain, and the effect of interventions designed to enhance comfort and safety. METHODS: A prospective observational case series from a tertiary referral unit. Tight head bandaging ± local anaesthetic injection (devices with non-MRI-compatible magnets) or observation alone (implants with MRI-compatible magnets) were employed for 1.5 T MRI of consecutive adult patients with CI or ABI without magnet removal. Pain was recorded via visual analogue scale (1 = no pain, 5 = extreme pain) at three time points; (1) baseline, (2) head bandage applied (3) during scanning. Patient age, device type, body area imaged and total scan time were recorded as variables, alongside adverse events. RESULTS: Data were collected for 227 MRI scans (34 patients with ABI, 32 with CI). In patients managed with bandaging, pain score after bandaging but prior to scanning (median 2.2) did not differ from pain during scanning (2.1), but both were significantly higher than baseline (1.4, both P ≤ 0.001). Scanning areas other than the head/cervical spine was associated with higher pain scores (P = 0.036). Pain during MRI differed between different manufacturers implants (P ≤ 0.001). Adverse events occurred in 8/227 scans (3.5%), none occurring with devices containing an MRI-compatible magnet. CONCLUSION: MRI scanning with auditory implant magnets in situ is safe and well tolerated by patients.