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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.)

Purpose: Tethered spinal cord syndrome (TCS) is characterized by cutaneous attachments on the filum terminale that stretch the spinal cord, leading to musculoskeletal and urogenital sequelae. While the neurocutaneous associations with TCS remain undefined, a recent study reports a high incidence of TCS among a pediatric neurofibromatosis (NF) cohort. This present study utilizes a population-level database to estimate TCS incidence among pediatric patients with neurofibromatosis types 1 and 2 (NF1, NF2)., Methods: The TriNetX Research Network was queried to identify patients diagnosed with NF and/or TCS before the age of 21. Symptomatic TCS requiring surgical intervention was identified using corresponding procedural codes within 12 months following TCS diagnosis. Odds ratios (OR) were calculated to measure the associations of NF1/NF2 with TCS., Results: 19,426 pediatric NF patients were evaluated (NF1: 18,383, NF2: 1042). The average ages of TCS diagnosis among NF1, NF2, and non-NF patients were 12, 16, and 9 years, respectively. The incidence of TCS was 1.2% in NF1 patients and 7.3% in NF2 patients, compared to 0.074% in the general population. The associations of NF incidence with TCS were significantly increased in both NF1 (OR 16.42; 14.38-18.76) and NF2 (OR 105.58; 83.56-133.40) patients compared to the general population. Symptomatic TCS requiring surgical intervention was not significantly associated with NF1/NF2 patients compared to the general TCS population., Conclusion: This analysis demonstrates a high incidence of TCS but delayed intervention in pediatric NF patients. Considering TCS counseling, spinal MRI, and earlier intervention may be warranted for NF patients experiencing musculoskeletal symptomatology., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

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: Pediatric meningioma differs not only in its rare incidence from the adult meningioma, but also in its clinical characteristics. Many treatment approaches of pediatric meningioma are based on the study results of adult meningioma studies. The aim of this study was to explore the clinical and epidemiological characteristics of pediatric meningioma., Methods: Data on pediatric patients diagnosed between 1982 and 2021 with NF2-associated or sporadic meningioma and recruited in the trials/registries HIT-ENDO, KRANIOPHARYNGEOM 2000/2007 and KRANIOPHARYNGEOM Registry 2019 were retrospectively analyzed for clinical characteristics, etiology, histology, therapy, and outcome., Results: One hundred fifteen study participants were diagnosed with sporadic or NF2-associated meningioma at a median age of 10.6 years. There was a 1:1 sex ratio, with 14% of study participants suffering from NF2. 46% of the meningiomas were located hemispherically, 17% at the optic nerve/ intraorbital and 10% ventricularly. Multiple meningiomas were detected in 69% of NF2 patients and in 9% of sporadic meningiomas. 50% of the meningiomas were WHO grade I, 37% WHO grade II and 6% WHO grade III. Progressions or recurrences occurred after a median interval of 1.9 years. Eight patients (7%) died, 3 of them due to disease. The event-free survival was higher for WHO grade I than for WHO grade II meningioma patients (p = 0.008)., Conclusions: The major difference to the preceding literature could be found in the distribution of different WHO grades and their influence on event-free survival. Prospective studies are warranted to assess the impact of different therapeutic regimens., Clinical Trial Registration Numbers: NCT00258453; NCT01272622; NCT04158284., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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.)

The neurofibromatoses are a group of genetic disorders that cause development of nervous system tumors as well as various other tumor and systemic manifestations. Neurofibromatosis type 1 is the most prevalent of these conditions and has the most variable phenotype and highest risk of malignant tumor formation. Neurofibromatosis type 2 has no associated malignant tumors but does carry significant morbidity, including deafness, facial weakness, and physical disability. Schwannomatosis is the least prevalent of these disorders and is characterized primarily by nonvestibular schwannomas and pain., (Copyright © 2021 Elsevier Inc. All rights reserved.)

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.)

Objectives: We aimed to investigate the prevalence and cost-associated risk factors for hospital stays for Neurofibromatosis Type 2 (NF2) patients in the past decade., Patients and Methods: A multi-year cross-sectional study was performed using the National Inpatient Sample. Patients with a diagnosis code of NF2 according to the International Classification of Diseases, 9th Revision, Clinical Modification coding system were queried from 2006-2014. Sampling discharge weights were used to calculate trend estimates for national demographics, hospital characteristics, comorbidities, and surgical interventions. Regression analysis was performed to determine significant independent associations between comorbidities and admission cost., Results: From 2006-2014, there were 5,078 discharges for patients diagnosed with NF2. Patient demographics, comorbidities, and procedures performed were overall consistent over time. The most common admission diagnoses were hearing loss (28.2 %), acoustic schwannoma (14.3 %), cranial meningioma (11.8 %) and epilepsy (10.8 %). The most common procedures performed were craniotomy and meningioma resection (10.2 %) and acoustic neuroma open resection (7.9 %). The median inflation-adjusted cost of admission did not change over time, with an admission cost value of $12,387 [6,042 - 26,051]. On regression analysis, obstructive hydrocephalus, craniotomy and meningioma resection, acoustic neuroma open resection, and spine tumor resection were all independent predictors of increased cost., Conclusion: The care for NF2 patients continues to evolve over time. We report the prevalence of patient demographics, comorbidities, and treatments in the NF2 inpatient population. Further studies are warranted to better understand the risk factors for higher costs, so that patients with NF2 may continue to receive life-long quality care in a cost-effective manner., (Copyright © 2020 Elsevier B.V. All rights reserved.)

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.

Objective: NF2 patients can develop new meningiomas throughout their lifetime. Little is known about the clinical features of newly developed NF2 meningiomas. In this study, we analyzed newly developed NF2 meningiomas in a large patient population., Patients and Methods: Among 452 NF2 patients, the location patterns of 81 pediatric and 939 adult NF2 meningiomas were compared to find the predominant locations of newly developed meningiomas in adulthood. The clinical features of 39 newly developed meningiomas in 24 NF2 patients were summarized. Clinical risk factors of NF2 meningioma growth rates were analyzed., Results: Pediatric patients had significantly more intracranial meningiomas than adult patients at the skull base (except for the petrosal region) (p < 0.0063). Adult patients had significantly more cranial meningiomas than pediatric patients at the parasagittal, parafalcine (middle & posterior), and frontal/parietal/cerebellar convex surfaces (p < 0.0063). Newly developed NF2 meningiomas in adults tended to occur at different locations than the locations of NF2 meningiomas in pediatric patients. New meningiomas could develop at various ages. Ninety-five NF2 patients were imaged and followed up for at least one year. Twenty-four patients (25.3 %) developed 39 new meningiomas during the follow-up period. They usually had initial meningiomas when new meningiomas occurred. The number of newly developed meningiomas per patient and the petrosal location were significantly associated with both the absolute and relative annual growth rates (p < 0.05)., Conclusions: The number of newly developed NF2 meningiomas seems to be a clinical marker of NF2 disease severity. In adults, new NF2 meningiomas tend to occur in patients with initial meningiomas. The predominant locations of newly developed NF2 meningiomas seem to be the parasagittal, parafalcine (middle/posterior), and frontal/parietal/cerebellar convex surfaces., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: Closely paralleling previous radiologic studies, recent population-based prevalence data suggest sporadic vestibular schwannoma (VS) affects over one in 2,000 adults and up to one in 500 in those aged 70 years or older. Attributable to increased utilization of magnetic resonance imaging and screening protocols for asymmetrical sensorineural hearing loss, the increasing detection rate of sporadic VS fundamentally changes the perception of VS as a whole. The primary objective of the current study was to contextualize modern epidemiological trends in neurofibromatosis type 2 (NF2) in light of these recent advancements in the understanding of sporadic VS., Study Design: Population-based study., Setting: Olmsted County, Minnesota. Population size on January 1, 2017: 159,689 people., Patients: All patients with NF2 diagnosed between Jan 1, 1966 and Dec 31, 2016, identified using the Rochester Epidemiology Project., Main Outcome Measures: Incidence, prevalence., Results: Six incident cases were identified over the past 50 years. From 1966 to 2016, the age- and sex-adjusted incidence rate was 0.10 per 100,000 person-years. The incidence rate remained at 0.12 over the most recent decade. Five cases met disease prevalence criteria, and the age- and sex-adjusted prevalence of NF2 on Jan 1, 2017 was 3.1 per 100,000 persons. All prevalent cases were women, and the resultant prevalence among women only was 6.0 per 100,000 persons., Conclusions: The modern age- and sex-adjusted incidence rate and prevalence of NF2 is 0.10 per 100,000 person-years and 3.1 per 100,000 persons, respectively. In contrast to trends in incidence rates of sporadic VS over the last half-century, this study demonstrates that the incidence of NF2 has remained relatively stable since 1966. This divergence in epidemiological trends is likely attributed to the nature of NF2, with early clinical manifestations resulting in diagnosis regardless of modern advances, whereas the increased incidence of sporadic VS is heavily influenced by improved detection in a greater population of patients with minimally symptomatic or asymptomatic tumors.

Objectives: Schwannomatosis is a dominantly inherited condition predisposing to schwannomas of mainly spinal and peripheral nerves with some diagnostic overlap with neurofibromatosis-2 (NF2), but the underlying epidemiology is poorly understood. We present the birth incidence and prevalence allowing for overlap with NF2., Methods: Schwannomatosis and NF2 cases were ascertained from the Manchester region of England (population=4.8 million) and from across the UK. Point prevalence and birth incidence were calculated from regional birth statistics. Genetic analysis was also performed on NF2 , LZTR1 and SMARCB1 on blood and tumour DNA samples when available., Results: Regional prevalence for schwannomatosis and NF2 were 1 in 126 315 and 50 500, respectively, with calculated birth incidences of 1 in 68 956 and 1 in 27 956. Mosaic NF2 causes a substantial overlap with schwannomatosis resulting in the misdiagnosis of at least 9% of schwannomatosis cases. LZTR1 -associated schwannomatosis also causes a small number of cases that are misdiagnosed with NF2 (1%-2%), due to the occurrence of a unilateral vestibular schwannoma. Patients with schwannomatosis had lower numbers of non-vestibular cranial schwannomas, but more peripheral and spinal nerve schwannomas with pain as a predominant presenting symptom. Life expectancy was significantly better in schwannomatosis (mean age at death 76.9) compared with NF2 (mean age at death 66.2; p=0.004)., Conclusions: Within the highly ascertained North-West England population, schwannomatosis has less than half the birth incidence and prevalence of NF2., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

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.

Objective: Onset of symptoms in severe sporadic neurofibromatosis type 2 (NF2) is typically within childhood; however, there is poor awareness of presenting features in young children, potentially resulting in delayed diagnosis and poorer outcome. We have reviewed presentation of sporadic paediatric NF2 to raise awareness of early features, highlighting those requiring further investigation., Design: Patients diagnosed with NF2 at age ≤16 and seen between 2012 and 2015 were notified via the British Paediatric Neurology Surveillance Unit or identified through the English NF2 service., Results: Epidemiological data estimate that 1 in 110 611 births are affected with childhood-onset NF2. Notes of 32 patients with sporadic NF2 were reviewed. Of those presenting under the age of 5, 89% (17/19) had ocular, 74% (14/19) dermatological and 58% (11/19) neurological signs; in 84% (16/19) features were multisystemic. Sixty-six per cent (21/32) had ≥1 atypical feature, including cerebellar hypoplasia in three cases (9%) and focal cortical dysplasia in five out of seven seizure-related presentations. Five cases presented with a sometimes transient or intermittent cranial nerve mononeuropathy. The mean delay to diagnosis was 3.16 years; in eight cases (25%) this exceeded 6 years. Most significant delay occurred in mononeuropathy, ophthalmological and/or seizure presentations, with a mean delay of 3, 4.5 and 6 years, respectively. Eighty-four per cent (27/32) of cases needed intervention in childhood., Conclusions: All non-vestibular schwannoma NF2 presentations in childhood had significant diagnostic delay. We emphasise the importance of detailed assessment of skin and eyes in unusual presentations and propose an aide to prompt timely referral to specialist services., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

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.)

Objective: To characterize the clinical features of patients with neurofibromatosis type 2 (NF2) and determine prognostic risk factors for progressive disabilities., Methods: In this retrospective cohort study of the Japanese national NF2 registry between 2009 and 2013, clinical data (demographic, history, oncologic, and neurologic) of 807 patients with a diagnosis of NF2 were analyzed. The overall severity of neurologic disability was assessed using a comprehensive 25-point scoring system encompassing a wide variety of neurologic deficits. In 587 patients in whom longitudinal disability data were available, multivariate logistic regression was performed to identify risk factors for significant progression of disability., Results: The clinical characteristics of the Japanese NF2 population were heterogeneous. The median age of onset was 24 years (range, 1-80 years), the male:female ratio was 1:1.29, and the initial severity score was 4 (range, 0-22) out of 25 points. A family history of NF2 was present in 33% of the patients. Most frequent clinical features were bilateral cranial nerve VIII nerve sheath tumor (NST) in 87%, spinal NST in 80%, hearing loss in 65%, spinal dysfunction in 50%, intracranial meningioma in 49%, and facial paresis in 36%. The disability score progressed by ≥5 points in 6.1% of patients over the study period. Based on multivariate logistic regression analyses, the significant independent risk factors of progression (P value) included age of onset <25 years (P = 0.015), positive family history (P = 0.007), positive treatment history (P = 0.026), hearing loss (P = 0.014), facial paresis (P = 0.015), blindness (P = 0.011), and hemiparesis (P = 0.025)., Conclusions: The Japanese NF2 population has heterogeneous clinical features. Risk factors for progressive disability include younger age of onset, positive family history, positive treatment history, and specific neurologic deficits., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

OBJECTIVE People with neurofibromatosis Type 2 (NF2) have a genetic predisposition to nervous system tumors. NF2-associated schwannomas stabilize or decrease in size in over half of the patients while they are receiving bevacizumab. NF2 patients treated with bevacizumab for rapidly growing schwannoma were retrospectively reviewed with regard to ependymoma prevalence and response to treatment. METHODS The records of 95 NF2 patients receiving bevacizumab were retrospectively reviewed with regard to spinal ependymoma prevalence and behavior. The maximum longitudinal extent (MLE) of the ependymoma and associated intratumoral or juxtatumoral cysts were measured on serial images. Neurological changes and patient function were reviewed and correlated with radiological changes. RESULTS Forty-one of 95 patients were found to have ependymomas (median age 26 years; range 11-53 years). Thirty-two patients with a total of 71 ependymomas had scans appropriate for serial assessment with a mean follow-up of 24 months (range 3-57 months). Ependymomas without cystic components showed minimal change in MLE. Twelve patients had ependymomas with cystic components or syringes. In these patients, reductions in MLE were observed, particularly due to decreases in the cystic components of the ependymoma. Clinical improvement was seen in 7 patients, who all had cystic ependymomas. CONCLUSIONS Bevacizumab treatment in NF2 patients with spinal cord ependymomas results in a decrease in the size of intratumoral and juxtatumoral cysts as well as adjacent-cord syringes and a decrease in cord edema. This may provide clinical benefit in some patients, although the changes do not meet the current criteria for radiological tumor response.

Objective: Patients with neurofibromatosis type 2 (NF2) are prone to develop multiple intracranial neoplasms, such as schwannomas of the cranial nerves and meningiomas. The aim of our study was to investigate 1) the median growth rate per year, 2) the growth-free interval, and 3) the growth patterns of NF2-associated intracranial tumors., Methods: All available magnetic resonance (MR) images of patients from the regional neurofibromatosis center were collected. The depicted tumors' volumes were then calculated if the tumors met the following inclusion criteria: contrast enhanced T1-weighted MRI datasets had to be available from at least two investigations and tumors had to be measurable on at least two slices., Results: One-hundred and eighty-eight tumors from 52 patients (20 male, 32 female) met the inclusion criteria for volumetric analysis. Overall, the median follow-up time was 76.5 months per patient (range 13-199 months). After 5 years, the median tumor size was 196% ± 338% for vestibular schwannomas (VS), 204% ± 702% meningiomas (M), 128% ± 64.9% for non-vestibular schwannomas (NVS) and 139% ± 270% for pre-operated tumors of the cerebellopontine angle (TX), respectively. The median time to 20% tumor progression was 21 months for VS, NVS and TX, and 17 months for M. Overall, saltatory growth was the most common growth pattern (46.9%)., Conclusions: Most NF2-associated tumors display a saltatory growth pattern. Meningiomas and untreated vestibular schwannomas grow rapidly and overall at similar rates. Tumors of the CPA that have been operated on and non-vestibular schwannomas show less relative growth per year., (Copyright © 2016 Elsevier Inc. 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.