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Objectives: New diagnostic criteria for NF2-related schwannomatosis (NF2) were published in 2022. An updated UK prevalence was generated in accordance with these, with an emphasis on the rate of de novo NF2 (a 50% frequency is widely quoted in genetic counselling). The distribution of variant types among de novo and familial NF2 cases was also assessed., Methods: The UK National NF2 database identifies patients meeting updated NF2 criteria from a highly ascertained population cared for by England's specialised service. Diagnostic prevalence was assessed on 1 February 2023. Molecular analysis of blood and, where possible, tumour specimens for NF2, LZTR1 and SMARCB1 was performed., Results: 1084 living NF2 patients were identified on prevalence day (equivalent to 1 in 61 332). The proportion with NF2 inherited from an affected parent was only 23% in England. If people without a confirmed molecular diagnosis or bilateral vestibular schwannoma are excluded, the frequency of de novo NF2 remains high (72%). Of the identified de novo cases, almost half were mosaic. The most common variant type was nonsense variants, accounting for 173/697 (24.8%) of people with an established variant, but only 18/235 (7.7%) with an inherited NF2 pathogenic variant (p<0.0001). Missense variants had the highest proportion of familial association (56%). The prevalence of LZTR1 -related schwannomatosis and SMARCB1 -related schwannomatosis was 1 in 527 000 and 1 in 1.1M, respectively, 8.4-18.4 times lower than NF2., Conclusions: This work confirms a much higher rate of de novo NF2 than previously reported and highlights the benefits of maintaining patient databases for accurate counselling., Competing Interests: Competing interests: DGE has received consultancy fees from AstraZeneca, Springworks and Everything Genetic Ltd., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: This study examined the association between neurological symptoms and quality of life (QoL) in patients with neurofibromatosis type 2 (NF2) using a national database of all patients who newly claimed for medical expense subsidies in Japan from 2015 to 2019., Methods: The Japanese Ministry of Health, Labour and Welfare provided access to the "National Database of Designated Intractable Diseases of Japan" containing the "Medical Certificates of Designated Intractable Diseases" of all patients with NF2. The database included information on five items of QoL: "mobility," "self-care," "usual activities," "pain/discomfort," and "anxiety/depression." To examine the association between the presence/absence of neurological symptoms and QoL, multivariable logistic regression analyses were performed, adjusted for potential confounders., Results: Data from 187 patients (97 females and 90 males; mean (standard deviation) age, 43.1 (17.9) years) were analyzed. Overall, 31% to 55% of patients were recorded as having moderate/severe impairment of QoL. Spinal dysfunction was significantly associated with deterioration of all components of QoL, whereas speech dysfunction and hemiparesis were specifically associated with physical health-related components of QoL. Spinal dysfunction, facial nerve palsy, and age 25-64 years were significantly associated with "anxiety/depression.", Conclusions: In the present epidemiological study using a national database of NF2 in Japan, spinal dysfunction was significantly associated with deterioration of all components of QoL, including subjective and mental health-related components of QoL, whereas speech dysfunction and hemiparesis were specifically associated with physical health-related components of QoL.

Purpose: People with pre-existing conditions may be more susceptible to severe COVID-19 when infected by SARS-CoV-2. The relative risk and severity of SARS-CoV-2 infection in people with rare diseases such as neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), or schwannomatosis (SWN) is unknown., Methods: We investigated the proportions of people with NF1, NF2, or SWN in the National COVID Cohort Collaborative (N3C) electronic health record data set who had a positive test result for SARS-CoV-2 or COVID-19., Results: The cohort sizes in N3C were 2501 (NF1), 665 (NF2), and 762 (SWN). We compared these with N3C cohorts of patients with other rare diseases (98-9844 individuals) and the general non-NF population of 5.6 million. The site- and age-adjusted proportion of people with NF1, NF2, or SWN who had a positive test result for SARS-CoV-2 or COVID-19 (collectively termed positive cases) was not significantly higher than in individuals without NF or other selected rare diseases. There were no severe outcomes reported in the NF2 or SWN cohorts. The proportion of patients experiencing severe outcomes was no greater for people with NF1 than in cohorts with other rare diseases or the general population., Conclusion: Having NF1, NF2, or SWN does not appear to increase the risk of being SARS-CoV-2 positive or of being a patient with COVID-19 or of developing severe complications from SARS-CoV-2., Competing Interests: Conflict of Interest J.T.J. is a recipient of royalties from Elsevier and consulting fees from Navio Theragnostics, Inc; CereXis; and Recursion. S.P. is a cofounder of NFlection Therapeutics and NF2 Therapeutics, Inc; consults for Akouos; and serves on the Scientific Advisory Board of and holds stock in SonALAsense. All other authors declare no conflicts of interest., (Copyright © 2022. Published by Elsevier Inc.)

This study explores the natural history of vestibular, trigeminal and lower cranial nerve schwannomas (VS, TS, LCNS) in patients with Neurofibromatosis type 2 (NF2), to understand how pathogenic variants (PVs) of the NF2 gene affect tumour burden and growth rate, via a retrospective analysis of a UK NF2 centre database and imaging. VS, TS and LCNS location and size were measured in accordance with a standardised protocol. PVs were categorised in accordance with the UK NF2 Genetic Severity Score (GSS). 153 patients (age 5-82) had 458 schwannomas, of which 362 were previously untreated comprising: 204 VS, 93 TS, and 65 LCNS (IX, X, XI). 322 schwannomas had sequential imaging allowing growth rate analysis with a mean follow-up of 45 months. VS were universally present, and bilateral in 146/153 cases. 65% of tumours grew >2 mm during the study period at mean rate 2.0 mm/year. Significant association was found between increasing GSS and growth rate. TS occurred in 66/153 patients (bilateral in 27/153); 31% of tumours showed growth (mean 1.8 mm/yr). Significant increase in tumour prevalence was noted with increasing GSS. LCNS were found in 47/153 patients (bilateral in 19/153); 27% of tumours showed growth (mean 1.9 mm/yr). The trend for increased prevalence with increasing GSS did not reach significance. VS growth rate was significantly influenced by GSS and they were much more likely to grow than TS and LCNS. TS prevalence also correlated with increasing GSS., (© 2022. The Author(s), under exclusive licence to European Society of Human Genetics.)

Background: Limited data exist on the disease course of neurofibromatosis type 2 (NF2) to guide clinical trial design., Methods: A prospective database of patients meeting NF2 diagnostic criteria, reviewed between 1990 and 2020, was evaluated. Follow-up to first vestibular schwannoma (VS) intervention and death was assessed by univariate analysis and stratified by age at onset, era referred, and inheritance type. Interventions for NF2-related tumors were assessed. Cox regression was performed to determine the relationship between individual factors from time of diagnosis to NF2-related death., Results: Three hundred and fifty-three patients were evaluated. During 4643.1 follow-up years from diagnosis to censoring, 60 patients (17.0%) died. The annual mean number of patients undergoing VS surgery or radiotherapy declined, from 4.66 and 1.65, respectively, per 100 NF2 patients in 1990-1999 to 2.11 and 1.01 in 2010-2020, as the number receiving bevacizumab increased (2.51 per 100 NF2 patients in 2010-2020). Five patients stopped bevacizumab to remove growing meningioma or spinal schwannoma. 153/353 (43.3%) had at least one neurosurgical intervention/radiation treatment within 5 years of diagnosis. Patients asymptomatic at diagnosis had longer time to intervention and better survival compared to those presenting with symptoms. Those symptomatically presenting <16 and >40 years had poorer overall survival than those presenting at 26-39 years (P = .03 and P = .02, respectively) but those presenting between 16 and 39 had shorter time to VS intervention. Individuals with de novo constitutional variants had worse survival than those with de novo mosaic or inherited disease (P = .004)., Conclusion: Understanding disease course improves prognostication, allowing for better-informed decisions about care., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: Cases of sporadic vestibular schwannoma (sVS) have a low rate of association with germline pathogenic variants. However, some individuals with sVS can represent undetected cases of neurofibromatosis type 2 (NF2) or schwannomatosis. Earlier identification of patients with these syndromes can facilitate more accurate familial risk prediction and prognosis., Methods: Cases of sVS were ascertained from a local register at the Manchester Centre for Genomic Medicine. Genetic analysis was conducted in NF2 on blood samples for all patients, and tumour DNA samples when available. LZTR1 and SMARCB1 screening was also performed in patient subgroups., Results: Age at genetic testing for vestibular schwannoma (VS) presentation was younger in comparison with previous literature, a bias resulting from updated genetic testing recommendations. Mosaic or constitutional germline NF2 variants were confirmed in 2% of patients. Pathogenic germline variants in LZTR1 were found in 3% of all tested patients, with a higher rate of 5% in patients <30 years. No pathogenic SMARCB1 variants were identified within the cohort. Considering all individuals who received tumour DNA analysis, 69% of patients were found to possess two somatic pathogenic NF2 variants, including those with germline LZTR1 pathogenic variants., Conclusions: Undiagnosed schwannoma predisposition may account for a significant minority of apparently sVS cases, especially at lower presentation ages. Loss of NF2 function is a common event in VS tumours and may represent a targetable common pathway in VS tumourigenesis. These data also support the multi-hit mechanism of LZTR1 -associated VS tumourigenesis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Neurofibromatosis type 2 (NF2) is a genetic disorder characterized by mutations of the NF2 tumor suppressor gene that predisposes patients to develop multiple tumors in the peripheral and central nervous system. The most common neoplasms associated with the disease are schwannomas and meningiomas. Both have been shown to contain abnormalities in chromosome 22 and the NF2 gene, suggesting a genetic component to their pathogenesis. Perineuriomas are rare benign tumors arising from the perineural cells. They are commonly classified as intraneural and soft tissue perineuriomas. Several studies have reported mutations in genes on chromosome 22 in both types of perineuriomas, and there are reports of soft tissue perineuriomas associated with NF2 gene mutations. Despite this, perineuriomas are not considered as part of the NF2 constellation of tumors., Method: The electronic medical records were searched for patients with a radiologic or pathologic diagnosis of intraneural perineurioma. Patients with clinical signs and genetic testing consistent with a diagnosis of NF2 were further evaluated., Results: Of 112 patients meeting inclusion criteria, there were two cases of intraneural perineurioma in patients with NF2 treated at our institution (1.8%). We include a third patient treated at another facility for whom we performed a virtual consultation., Conclusions: The rarity of both NF2 and perineuriomas could explain the rarity of perineuriomas in the setting of NF2. Furthermore, there is divergent intraneural and soft tissue perineurioma somatic mutation pathogenesis, and there may be cytogenetic overlap between perineuriomas and multiple tumor syndromes. Our observed occurrence of intraneural perineurioma in the setting of NF2 in several patients provides further evidence of a potential link between the NF2 gene and the development of intraneural perineurioma.

Objectives: Neurofibromatoses (type 1: NF1; type 2: NF2) are autosomal dominant tumor predisposition syndromes mostly caused by loss-of-function mutations in the tumor suppressor genes NF1 and NF2, respectively. Genotyping is important for correct diagnosis of these diseases. The authors aimed to characterize NF1 and NF2 variants in patients from Southern Brazil., Methods: Ninety-three unrelated probands with NF1 and 7 unrelated probands with NF2 features were recruited from an Oncogenetics center in Southern Brazil. Two next generation sequencing panels were customized to identify point mutations: NF1 (NF1, RNF135, and SUZ12 genes) and NF2 (NF2 and SMARCB1 genes). Large rearrangements were assessed by Multiplex Ligation-dependent Probe Amplification., Results: Sixty-eight heterozygous NF1 variants were identified in 75/93 probands (80%) and 3 heterozygous NF2 variants were identified in 3/7 probands (43%). In NF1, 59 (87%) variants were pathogenic (4 large rearrangements - 6%), 6 (9%) were likely pathogenic, 3 (4%) were variants of uncertain significance and 28 (41%) were novel. In NF2, all variants were pathogenic. No novel genotype-phenotype correlations were observed; however, previously described correlations were confirmed in our cohort., Conclusion: The clinical and molecular characterization of neurofibromatoses in different populations is very important to provide further insights into the pathogenesis of these diseases.

Background/aim: Individuals with type 2 Neurofibromatosis are predisposed for the appearance of schwannomas. In the present study we analyzed the loss of heterozygosity and mutations in the NF2 gene in patients with sporadic Schwannoma without Neurofibromatosis type 2., Materials and Methods: We analyzed 39 patients with sporadic spinal schwannoma. We quantified the number of alleles by FISH and sequenced the NF2 gene., Results: We identified 16/39 patients with point mutations and/or LOHs in the tumor samples analyzed. The LOHs were found in 7/39 patients. Two homozygous mutations were detected in 4/39 tumors, and the presence of the mutation in heterozygosis was revealed in 3/39 patients. In two tumors, we detected the loss of one allele of the NF2 gene, with no mutation., Conclusion: The genetic alterations observed in the NF2 gene indicated that spinal schwannomas are associated with genetic alterations also found in other schwannomas and type 2 Neurofibromatosis, which reinforces the etiological role of this gene., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: To date, few studies have been published about the growth dynamics of tumors associated with neurofibromatosis type-2 (NF2), none of which evaluated gender-specific differences. Our aim was to compare radiographic data of female and male patients with NF2., Methods: MR images of 40 patients (20 female, 20 male) from the regional NF2 referral center were included in this analysis. Tumor sizes were determined by semi-automated volumetric measurement. Intracranial tumors were measured on post-contrast T1-weighted MRI datasets and volumes of intramedullary spinal tumors were determined from sagittal T2-weighted MRI datasets., Results: The median follow-up time was 91 months (range, 16-199 months) per patient. Intracranial tumors: On average, female patients had 13.4 neoplasms, while male patients had 6.75 (p = 0.042). The overall median time to tumor progression of ≥20 % was 20 months for females and 18 months for males. Tumors of the cerebellopontine angle (CPA) that had undergone previous surgery had shorter progression-free intervals in females than in males (16 and 24 months, respectively; p = 0.012). The median 1-year growth rate was 17.5 ± 44.6 % in females compared to 12.5 ± 44.9 % in males (p = 0.625). Intramedullary spinal tumors: On average, females had 2.05 tumors and males had 1.75 tumors (p = 0.721). Median time to tumor progression was 21 months in females and 44 months in males (p = 0.204). After 2 years, the median growth rate was 24.4 ± 56.8 % in female and 13.5 ± 40.4 % in male patients (p = 0.813)., Conclusions: The radiographic data in this study suggest that female patients are affected by a greater number of tumors than male patients and that post-surgery tumors of the CPA grow faster in females than in males.

Purpose: Four sets of clinical diagnostic criteria have been proposed for neurofibromatosis 2, but all have low sensitivity at the time of initial clinical assessment for the disease among patients with a negative family history who do not present with bilateral vestibular schwannomas. We have empirically developed and tested an improved set of diagnostic criteria that uses current understanding of the natural history and genetic characteristics of neurofibromatosis 2 to increase sensitivity while maintaining very high specificity., Methods: We used data from the UK Neurofibromatosis 2 Registry and Kaplan-Meier curves to estimate frequencies of clinical features at various ages among patients with or without unequivocal neurofibromatosis 2. On the basis of this analysis, we developed the Baser criteria, a new diagnostic system that incorporates genetic testing and gives more weight to the most characteristic features and to those that occur before 30 years of age., Results: In an independent validation subset of patients with unequivocal neurofibromatosis 2, the Baser criteria increased diagnostic sensitivity to 79% (9-15% greater than previous sets of criteria) while maintaining 100% specificity at the age at onset of the first characteristic sign of neurofibromatosis 2., Conclusion: The Baser criteria permit early diagnosis in a greater proportion of patients with neurofibromatosis 2 than previous sets of diagnostic criteria.

Point mutation and loss of heterozygosity (LOH) analyses were performed in 12 Polish patients with a classic symptom of NF2 - bilateral vestibular schwannomas (BVS). In 5 patients (41.7%), germline mutations were found in the NF2 gene: 2 previously reported substitutions (c.592C>T and c.52C>T) and 3 novel mutations (c.1001&#95;1002insG, c.1029&#95;1030insCC, c.774&#95;778dupGAATG). In addition, LOH analysis of 30 tumour samples from 10 patients revealed a molecular basis of NF2 in 3 patients (25%) that did not have any germline mutation. The molecular defects in sporadic cases of NF2 are still being discussed.

Neurofibromatosis type 2 (NF2) is a rare autosomal dominant disorder characterized by the occurrence of bilateral vestibular schwannomas, various brain and spinal tumours as well as peripheral nerve tumours, cutaneous tumours and juvenile posterior lenticular opacity. NF2 is caused by mutations in both alleles of a tumour suppressor gene coding for a protein called schwannomin or merlin. It is suggested that the development of NF2 tumours is caused by complete inactivation of the merlin/schwannomin gene. Interestingly, in a NF2 mouse model, peripheral nerve pathology was more frequently described than schwannomas. However, review of the literature shows that patients suffering from NF2 seldom have unexplained clinical features of peripheral nerve lesion unrelated to tumour masses. Single case reports describe sural nerve biopsies, which histologically show onion-bulb-like formations, seemingly originating from Schwann cells. We have conducted a systematic investigation to determine the occurrence and aetiology of peripheral nerve involvement in NF2 patients. We investigated 15 patients with definite NF2 and in 10 of these found electrophysiological evidence of neuropathy. In this study we present the classification of neuropathy, correlation to clinical findings, and histological findings of a sural nerve biopsy. We conclude that peripheral neuropathy, mostly of axonal type, is a common clinical finding in NF2. We hypothesize that the aetiology of this frequent peripheral neuropathy syndrome in NF2 is caused by compression effects of multiple tumourlets, originating along the length of the peripheral nerves on adjacent nerve fibres, by local influences of the endoneurial pathological cells on adjacent nerve fibres and/or the inability of these cells to properly adhere to, or ensheath, the axon.

Neurofibromatosis type 2 is an often devastating autosomal dominant disorder which, until relatively recently, was confused with its more common namesake neurofibromatosis type 1. Subjects who inherit a mutated allele of the NF2 gene inevitably develop schwannomas, affecting particularly the superior vestibular branch of the 8th cranial nerve, usually bilaterally. Meningiomas and other benign central nervous system tumours such as ependymomas are other common features. Much of the morbidity from these tumours results from their treatment. It is now possible to identify the NF2 mutation in most families, although about 20% of apparently sporadic cases are actually mosaic for their mutation. As a classical tumour suppressor, inactivation of the NF2 gene product, merlin/schwannomin, leads to the development of both NF2 associated and sporadic tumours. Merlin/schwannomin associates with proteins at the cell cytoskeleton near the plasma membrane and it inhibits cell proliferation, adhesion, and migration.

A clinical and genetic study of type 2 neurofibromatosis (NF2) has been carried out in the United Kingdom. Virtually complete ascertainment of cases in the north-west of England was achieved and suggests a population incidence of 1 in 33,000 to 40,000. In the UK as a whole, 150 cases have been identified and been used to study the clinical and genetic features of NF2. The autosomal dominant inheritance of NF2 was confirmed, 49% of cases were assessed as representing new mutations, and the mutation rate was estimated to be 6.5 x 10(-6). Evidence to support a maternal gene effect was found in that age at onset was 18.17 years in 36 maternally inherited cases and 24.5 in 20 paternally inherited cases (p = 0.027). The preponderance of maternally inherited cases was also significant (p = 0.03). Data are presented which suggest that there are two types of NF2, one with later onset and bilateral vestibular schwannomas as the only usual feature, and the other with earlier onset and multiple other tumours. A considerable number of cases did not fall easily into one or other group and other factors such as maternal effect on severity and anticipation need to be considered.