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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.

Type 2 neurofibromatosis (NF2) is an autosomal dominant disorder caused by mutations in the NF2 tumor suppressor gene NF2 on chromosome 22. Around 1 in 33000 people are born with an NF2 mutation although more than one-third of the 60% of de novo cases are not conceived with the mutation but this develops later in embryogenesis (mosaics). NF2 has a substantial effect on life expectancy and individuals with a constitutional truncating mutation have the worst prognosis. The vast majority of people with NF2 will develop bilateral vestibular schwannomas with many developing schwannomas on other cranial, spinal and peripheral nerves. Cranial and spinal meningiomas and intraspinal low grade indolent ependymomas are the other major tumor features. Cutaneous features can be subtle with only 70% having evidence of intracutaneous plaque-like schwannomas or subcutaneous lesions on peripheral nerves. Café-au-lait patches are more frequent than in the general population but in only around 1% will meet NIH criteria for NF1., (© 2015 Elsevier B.V. All rights reserved.)

Advances in molecular biology have resulted in novel therapy for neurofibromatosis 2-related (NF2) tumours, highlighting the need for robust outcome measures. The disease-focused NF2 impact on quality of life (NFTI-QOL) patient questionnaire was assessed as an outcome measure for treatment in a multi-centre study. NFTI-QOL was related to clinician-rated severity (ClinSev) and genetic severity (GenSev) over repeated visits. Data were evaluated for 288 NF2 patients (n = 464 visits) attending the English national NF2 clinics from 2010 to 2012. The male-to-female ratio was equal and the mean age was 42.2 (SD 17.8) years. The analysis included NFTI-QOL eight-item score, ClinSev graded as mild, moderate, or severe, and GenSev as a rank order of the number of NF2 mutations (graded as mild, moderate, severe). The mean (SD) 8.7 (5.4) score for NFTI-QOL for either a first visit or all visits 9.2 (5.4) was similar to the published norm of 9.4 (5.5), with no significant relationships with age or gender. NFTI-QOL internal reliability was good, with a Cronbach's alpha score of 0.85 and test re-test reliability r = 0.84. NFTI related to ClinSev (r = 0.41, p < 0.001; r = 0.46 for all visits), but weakly to GenSev (r = 0.16, p < 0.05; r = 0.15 for all visits). ClinSev related to GenSev (r = 0.41, p < 0.001; r = 0.42 for all visits). NFTI-QOL showed a good reliability and ability to detect significant longitudinal changes in the QOL of individuals. The moderate relationships of NFTI-QOL with clinician- and genetic-rated severity suggest that NFTI-QOL taps into NF2 patient experiences that are not encompassed by ClinSev rating or genotype.

Neurofibromatosis type 2 (NF2) is an autosomal dominant multiple neoplasia syndrome of the central nervous system. The aim of the present study was to characterize the clinical course of early onset NF2. The specific Japanese disease registry for NF2 in 2010 was analyzed retrospectively. The male:female ratio for the 312 patients identified in the database was 1:1.29. The median age at onset was 25years (range 2-76years), with 31.3% of patients exhibiting symptoms at <20years of age. Patients with an age at onset of <20years were found to have more frequent spinal cord and extravestibular cranial nerve involvement, cutaneous signs, and convulsions than patients with a later age at onset. Of patients younger than 18years of age, half did not exhibit hearing problems; in contrast, they frequently had other cranial nerve schwannomas, cranial meningioma, spinal cord tumors, and subcutaneous schwannoma. There were weak but significant positive correlations between symptomatic periods and disability scores in patients with an age of onset of ⩾20years (R=0.225; P<0.01) and those with an earlier age of onset (R=0.306; P<0.01). Although there were no significant differences in disability scores between genders or patients with an age at onset of <20 versus ⩾20years, patients with an earlier age at onset had significantly higher disability scores for spinal symptoms than patients with an age at onset of ⩾20years. Atypical extravestibular presentation is common in early onset NF2, with more prominent spinal symptoms., (Copyright © 2013 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Objective: It is widely accepted that stereotactic radiosurgery (SRS) is less effective in controlling NF2-related vestibular schwannomas (VS-NF2), than sporadic VS. Concerns persist regarding the risks of malignant transformation and the development of secondary tumours. In recent years there has been an increase in the number of centres offering SRS and fractionated stereotactic radiotherapy (SRT) services for VS. The NF2 National Commissioning Group service framework has recommended limiting radiation therapies for VS-NF2 to SRS (Gamma Knife) provided in Sheffield. The aims of this review were to: 1) Establish the current provision of SRT and SRS services in England. 2) Determine the radiation therapies employed for NF2 patients since 2000. 3) Determine the feasibility of identifying a national cohort of NF2 patients in England who have received radiation therapy since 2000., Methods: The lead clinicians managing VS patients in the major regional neurosurgical units in England, and those providing SRS services to NF2 patients were contacted and when possible, databases were examined., Results: A total of 18 NHS centres and 2 private centres were included. This included the four NF2 'hub centres' (Cambridge, London, Oxford and Manchester). Their NF2 databases identified 4, 8, 23 and 42 VS-NF2 treatments with SRS or SRT, respectively since 2000. Eleven centres reported that they had referred VS-NF2 patients exclusively to Sheffield. Each estimated that they had referred no more than one patient per year. The survey identified four Gamma Knife Centres and six Linac SRS/SRT centres with the capacity to treat VS and VS-NF2 patients. Of these, four centres confirmed that they had treated VS-NF2 patients., Conclusion: Since 2000 fewer than 100 SRS and SRT treatments have been undertaken for VS-NF2 patients. Approximately 60% of these have been performed in Sheffield. There is considerable uncertainty regarding the role of radiation therapy in the management of VS-NF2 and consequently a range of views and practice.

The purpose of this paper is to study acoustic neuroma diagnostic process, describe tumor's molecular basis and its magnetic resonance imaging characterization, which is considered to be the gold standard diagnostic tool to study this disease.

Objective: Schwannomas are typically benign tumors that occur sporadically, in neurofibromatosis type 2 (NF2), or in an entity called "schwannomatosis." Schwannomatosis patients develop multiple schwannomas without involvement of the vestibular apparatus. Geneticists, neurologists, and pathologists have recognized that schwannomatosis is distinct from NF2, but schwannomatosis remains unfamiliar to many radiologists. This article reviews the current medical literature, highlighting the similarities and differences between the schwannomatosis and NF2 phenotypes, genotypes, clinical manifestations, management considerations, and imaging findings., Conclusion: Imaging plays a critical role in diagnosing schwannomatosis, and a basic understanding of this syndrome is of interest to diagnostic radiologists. Moreover, it is imperative that radiologists be able to differentiate schwannomatosis from NF2 on imaging because there are significant differences in the management of these two diseases and clinical outcomes for affected patients.

Neurofibromatosis type 2 (NF2) is rare genetic disorder characterized by the development of multiple benign tumors of the nervous system. The majority of people with NF2 are diagnosed in the second or third decade of life with bilateral vestibular schwannomas. Among NF2 patients followed up in our NF2 clinic, seven patients have been diagnosed with NF2 after the age of 70 years. Bilateral vestibular schwannomas were present in 4/7 patients. No NF2 mutation was identified by blood screening, suggesting a high prevalence of NF2 somatic mosaicism. During a mean follow-up of 96 months, 8/11 vestibular schwannomas demonstrated no tumor growth, and only one patient required treatment. Other tumors, including meningiomas and other schwannomas, remained stable. One patient required shunting for secondary normal-pressure hydrocephalus. Thus, NF2 can occasionally be diagnosed in people aged 70 and older, and is characterized by a high prevalence of atypical forms and a low growth potential of tumors, arguing in favor of a wait-and-scan policy as initial management., (Copyright © 2013 Wiley Periodicals, Inc.)

A comprehensive discussion of neurofibromatosis 2 (NF2) is presented, including clinical characteristics, symptoms, diagnosis, tumor types, prevalence and incidence, genetic testing, imaging, treatment options, and follow-up management of NF2., (Copyright © 2012 Elsevier Inc. All rights reserved.)

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.

Neurofibromatosis type 2 is an autosomal-dominant multiple neoplasia syndrome that results from mutations in the NF2 tumour suppressor gene located on chromosome 22q. It has a frequency of one in 25,000 livebirths and nearly 100% penetrance by 60 years of age. Half of patients inherit a germline mutation from an affected parent and the remainder acquire a de novo mutation for neurofibromatosis type 2. Patients develop nervous system tumours (schwannomas, meningiomas, ependymomas, astrocytomas, and neurofibromas), peripheral neuropathy, ophthalmological lesions (cataracts, epiretinal membranes, and retinal hamartomas), and cutaneous lesions (skin tumours). Optimum treatment is multidisciplinary because of the complexities associated with management of the multiple, progressive, and protean lesions associated with the disorder. We review the molecular pathogenesis, genetics, clinical findings, and management strategies for neurofibromatosis type 2.

Background: Neurofibromatosis 2 (NF2) is an autosomal dominant disease that is characterized by nervous system tumors and ocular abnormalities., Objective: To investigate genotype-phenotype correlations demonstrated for NF2-associated nervous system tumors, cataracts, and retinal lesions., Methods: Forty-eight patients with NF2 from a tertiary neurological referral center underwent screening for constitutional NF2 mutations with multiple screening methods. Each patient underwent a complete ophthalmic examination, including fluorescein angiography to detect retinal vascular lesions., Results: Retinal abnormalities (epiretinal membranes or retinal microaneurysms) were present in 25 of the 48 patients (52%). The occurrence of epiretinal membranes and retinal microaneurysms was highly correlated, but retinal abnormalities were not significantly correlated with cataracts (present in 39 of 47 patients [83%]). Logistic regression with full constitutional nonsense or frameshift mutations as the reference group demonstrated that somatic mosaicism was associated with a significantly lower likelihood of retinal abnormalities (odds ratio, 0.05; 95% confidence interval, 0.01-0.49)., Conclusions: To our knowledge, this is the first genetic, clinical, and angiographic characterization of retinal abnormalities in NF2. Severe mutations are correlated with a more severe retinal involvement. Clinical Relevance Retinal abnormalities, which can be revealed by means of fluorescein angiography, are more common in patients with NF2 who have nonsense or frameshift mutations.

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.

Conclusions: The precise risk factors for neurological complications after acoustic neurinoma radiosurgery were identified on long-term follow-up. Type 2 neurofibromatosis was found to be a risk factor for hearing loss and peripheral tumor dose was a risk factor for seventh and fifth cranial nerve injuries. These risk factors corresponded to those reported at other institutions. At the present time, controversy exists regarding history of prior surgical resection and tumor size as risk factors for cranial nerve complications., Objectives: To identify more precisely the risk factors for neurological complications after stereotactic radiosurgery (SRS) based on long-term follow-up., Patients and Methods: Between June 1990 and September 1998, 138 patients with acoustic neurinomas had SRS at Tokyo University Hospital. Of these, the 125 patients who were followed up for at least 6 months were entered into the present study. The patients' ages ranged from 13 to 77 years (median 53 years). The average tumor diameter ranged from 6.7 to 25.4 mm (mean 13.9 mm). The maximum tumor doses ranged from 20 to 40 Gy (mean 29.8 Gy), and the peripheral doses ranged from 12 to 25 Gy (mean 15.4 Gy). One to 12 isocenters were used (median 4). The follow-up period ranged from 6 to 191 months (median 60 months). The potential risk factors for neurological complications were analyzed using two univariate actuarial analyses. The neurological complications studied included hearing loss, facial palsy, and trigeminal nerve dysfunction. The variables analyzed were age, gender, prior operation, neurofibromatosis type 2 (NF2), tumor diameter, maximum tumor dose, peripheral tumor irradiation dose, and the number of isocenters. Variables with significant p values (<0.05) on both actuarial analyses were considered risk factors., Results: NF2 was significantly correlated with both total hearing loss and pure tone threshold (PTA) elevation; a history of prior surgical resection, tumor size, and the peripheral tumor dose were significantly correlated with facial palsy; and the peripheral tumor dose was significantly correlated with trigeminal neuropathy.

Introduction: Germline mutations in the NF2 gene are responsible for 80 p.cent of neurofibromatosis type 2 typical cases. Mutations are mainly truncating mutations or deletions, missense mutations having been reported in few cases. An important phenotypic variability is observed among gene carriers. To assess whether the phenotypic variability of neurofibromatosis 2 could be linked to genotype, clinical data of 154 patients whose NF2 germline alteration had been identified in our laboratory have been collected., Methods: A retrospective questionnaire was sent to the physicians in charge of these patients. Statistical analyses regarding genotypic and phenotypic data were performed by comparisons of average values and correlation tests., Results: In French patients, type of mutation was correlated neither with patients' sex, nor with disease occurrence mode (de novo or inherited mutation). Disease associated with missense mutations occurred later, with a less severe symptomatology. Patients with nonsense or frameshift mutations were more frequently affected with meningiomas and spinal tumours, in addition to VIII nerve schwannomas, an observation that underlies the genetic determination of the number and type of NF2-related tumours., Conclusion: Results from the literature as well as from our study tend to show that only few correlations exist between genotype and phenotype in the NF2 disease. It also recognizes that missense mutations have a lower level of evolution, severity and mortality risk. Nonsense and frameshift mutations seem to be associated with a higher number of meningiomas and spinal tumours. Therefore, NF2 gene screening keeps its indications in both typical and moderate forms of the disease. Mutations are responsible of 80 p.cent of typical forms; in moderate forms, identification of a missense mutation seems linked to a lower disease evolution. In any case, assessment and supervision should be identical. Finally, in a small number of cases, the NF2 gene appears to be implicated in clinical forms different from those defined by NIH and it might be of interest to enlarge the clinical features suggestive of the disease.

Introduction: Neurofibromatosis 2 (NF2) is a rare autosomal dominant disease whose hallmark is the development of bilateral vestibular schwannomas., State of the Art: Other features of NF2 include schwannomas, meningiomas, ependymomas, localized along the central nervous system, schwannomas of the peripheral nerves, cutaneous and ophthalmological manifestations. NF2 can be diagnosed in patients without bilateral vestibular schwannoma with sets of diagnostic criteria. Disease phenotype is variable among patients. Main negative prognostic factors are a young age at onset of symptoms and a high number of tumors at diagnosis. NF2 tumor suppressor gene encodes Merlin/Schwannomin, and is also involved in most sporadic schwannomas and meningiomas. Its functions remains largely unknown., Perspectives and Conclusions: Treatment and follow of NF2 patients up require oto-neurosurgical teams experienced in NF2. Yearly and life time surveillance is mandatory. A clinical screening protocol is suggested. Classically, only symptomatic lesions are to be treated. Some authors advocate an early proactive strategy against vestibular schwannoma in order to preserve hearing. When a treatment is advisable, surgery remains the treatment of choice for tumors. Auditory brainstem implant must be taken into account in hearing rehabilitation.

Medical decision-making is based on benefit-to-cost analysis. Optimally, treatment obtains a high degree of benefit while minimizing the physical, social, and financial costs. The goals of the treatment of acoustic schwannomas are prohibiting tumor growth and alleviation of symptoms caused by damage to local structures. These symptoms-tinnitus, ataxia, and hearing loss--secondary to eighth nerve dysfunction, as well as symptoms arising from damage to adjacent structures such as the facial nerve, trigeminal nerve, or pons, can be caused by tumor growth or treatment. Determination of optimal therapy must also take into account an understanding of the natural history of the disease, because acoustic schwannomas are slow-growing benign tumors that when left untreated, usually enlarge over time and cause problems.

Objective: To assess the risk of radiosurgery inducing malignancy in neurofibromatosis-2 (NF2) and von Hippel-Lindau disease., Methods: A retrospective cohort study of 118 NF2 and 19 von Hippel-Lindau disease patients, totalling 906 and 62 patient-years of follow-up data, respectively., Results: Two cases of intracranial malignancy were identified, both of which occurred in NF2 patients. One of these was thought to have arisen before the radiosurgery; the other was a glioblastoma diagnosed 3 years after radiosurgery., Conclusion: Because gliomas may occur in as many as 4% of NF2 patients, this may not represent an increased risk. We continue to offer radiosurgery treatment to selected NF2 and von Hippel-Lindau disease patients and consider that the late risk of malignancy arising after irradiation must be put in the context of the condition being treated, the treatment options available to these individuals, and their life expectancy.

Objective: Vestibular schwannomas present significant management challenges in patients with neurofibromatosis Type 2 (NF2). We evaluated the results of gamma knife radiosurgery for the management of these tumors, focusing on tumor response, hearing preservation, and other factors affecting outcomes., Methods: Stereotactic radiosurgery was performed to manage 74 schwannomas in 62 patients. Ipsilateral serviceable hearing was present in 35% of tumors before the procedure. The mean tumor volume was 5.7 cm3. The mean margin and maximum dose used were 14 and 27.5 Gy, respectively. Cox regression analyses were performed to identify factors affecting outcomes., Results: The median follow-up period was 53 months, and two patients were lost to follow-up. Actuarial local control rates at were 85, 81, and 81% at 5, 10, and 15 years, respectively. Tumor volume was significant as a predictor of local control. Since 1992, using current radiosurgery techniques (magnetic resonance imaging scan targeting and reduced margin dose to 14 Gy or less), the actuarial serviceable hearing preservation rate is 73% at 1 year, 59% at 2 years, and 48% at 5 years after radiosurgery. Facial neuropathy occurred in 8% of tumors, trigeminal neuropathy occurred in 4%, and vestibular dysfunction occurred in 4%. Radiation dose and tumor volume were predictive of development of new deficits. No radiosurgery-associated secondary tumors or atypical or malignant changes were noted., Conclusion: Stereotactic radiosurgery is a safe and effective management modality for neurofibromatosis Type 2 vestibular schwannomas. Although results do not seem to be as good as for patients with sporadic unilateral tumors, gamma knife radiosurgery results seem favorable and indicate that radiosurgery should be strongly considered for primary tumor management in selected patients.

Neurofibromatosis is a disease caused by a chromosomal defect that can occur spontaneously or be inherited. The disease is grossly disfiguring and carries with it significant psychological sequelae. It is characterized by tumors on nerve sheaths that can arise anywhere in the body. The rate and frequency of occurrence is unpredictable. More than nine different types of neurofibromatosis have been identified, but other than types 1 and 2, they are quite rare. All types of neurofibromatosis persist for a lifetime, so nurses from different backgrounds may encounter such a patient for various reasons. Nursing care should focus not only on the medical issues the patient presents with, but also on the psychosocial needs that may arise.

Object: The authors conducted a study to examine the incidence, classification, and progression of spinal tumors in patients with neurofibromatosis Type 2 (NF2) treated at a single center, and to examine relationships with the known mutational subtypes of NF2., Methods: They performed a retrospective review of clinical records, neuroimaging studies, and genetic data obtained in 61 patients with NF2. Forty-one (67%) of 61 patients harbored one or more spinal tumors. Thirty-four patients had undergone serial spinal magnetic resonance imaging during a mean follow-up period of 52 months (range 10-103 months; median 53 months). In 16 patients there were multiple extramedullary tumors smaller than 5 mm, which did not progress. Fourteen patients harbored at least one extramedullary tumor that was greater than 5 mm; of these, radiological progression was demonstrated or spinal tumor excision was performed during the follow-up period in eight cases (57%). Eleven patients harbored intramedullary cord tumors in addition to small and large extramedullary tumors, three (27%) of which exhibited radiological progression. In cases in which genotypes were known, protein-truncating mutations were significantly more likely to be associated with the presence of spinal tumors than in other types (p = 0.03, Fisher exact test). No associations between clinical behavior of spinal tumors and genotype, however, could be demonstrated., Conclusions: Spinal tumors in cases involving NF2 are heterogeneous in type, distribution, and behavior but larger-size tumors are more likely to progress significantly. Intramedullary tumors usually accompany multiple extramedullary tumors. In the authors' experience subtyping of the NF2 mutation has not yet influenced management. Protein-truncating mutations are associated with an increased prevalence of spinal tumors.

Objective: Spinal nerve sheath tumors arise from the spinal nerve root and grow along it. There are two sites at which the growth of a tumor is restricted: the dural aperture for the spinal nerve root and the intervertebral foramen. This article describes the growth pattern of a spinal nerve sheath tumor along the spinal nerve root at various spinal levels., Methods: We retrospectively reviewed the records for 149 patients with spinal nerve sheath tumors who were treated between 1980 and 2001. Of these, 176 resected tumors were classified into five groups according to the relationship to the dura mater and/or the intervertebral foramen., Results: Strictly intradural tumors compose 8% of nerve sheath tumors of the first two cervical nerve roots. The percentage of these tumors increased gradually from the high cervical region to the thoracolumbar region, where it was more than 80%. In contrast, the percentage of strictly extradural tumors gradually decreased from the rostral portion to the caudal portion. Similarly, a percentage of tumors extending outside the spinal canal decreased from the rostral portion to the caudal portion. These changes of the growth pattern may be explained by the anatomic features of the spinal nerve roots, which have a longer intradural component at the more caudal portion of the spinal axis., Conclusion: The anatomic relationship of a nerve sheath tumor with the dura mater and the intervertebral foramen varies depending on the level of the tumor. This knowledge may help us to create a strategy for total resection of a nerve sheath tumor.

The "phakomatosis" concept was formulated early in the twentieth century by the ophthalmologist van der Hoeve. He included 3 disorders in the group-neurofibromatosis, tuberous sclerosis complex, and von Hippel-Lindau syndrome--on the basis of the occurrence of patchy ophthalmologic manifestations in each disorder. Since the name was coined, much has been learned about the pathogenesis of these 3 disorders. It is clear that 2 of them--neurofibromatosis and tuberous sclerosis--are collective terms for multiple disorders. Each of the conditions is caused by distinct genetic defects, with little commonality in terms of protein function. Yet, in some respects, the disorders share a pathogenetic mechanism, that of the tumor suppressor gene. This review will briefly describe these disorders in light of what has been learned about underlying molecular pathogenesis. In each case, genetic testing is beginning to be available; principles of the use of genetic tests will be described.

Objective: To determine the incidence of vestibular schwannoma (VS) in sporadic, neurofibromatosis type 2 (NF2) germ-line and mosaic form in a 10-year period., Study Design: Review of all incident cases of VS presenting to the four main neurosurgical centers for a population of 4.1 million from 1990 to 1999 and cross-referencing with the regional cancer registry., Setting: Population based., Patients: All patients presenting with VS detected on magnetic resonance imaging scan., Results: A total of 419 sporadic and 64 NF2-related VS were identified over the study period. This represented an incidence of 10.4 per million per year for sporadic VS and 11.8 per million per year including NF2-related tumors. The incidence rose to 14 per million per year in the latter 5 years. The NF2 patient diagnoses represent an estimated birth incidence of 1 in 25,000, and 7% of the patients with VS had NF2, which is higher than previous estimates., Conclusions: The incidence of VS is rising almost certainly due to increasing diagnosis in the magnetic resonance imaging era. At current rates, 1 per 1,000 individuals will be diagnosed with VS in their lifetime. More VS than previously thought are due to NF2, which may be because of recognition of mosaic forms of the disease.

To evaluate the results of Gamma Knife radiosurgery treating vestibular schwannomas (VS) secondary to type 2 neurofibromatosis (NF2) we reviewed our clinical experience. Among the VS that have been treated between July 1992 and January 2002, we could analyze retrospectively the data of 50 VS from 37 patients. Fourteen patients had the mild phenotype while 23 were affected by the severe form. Before radiosurgery, one or two microsurgery attempts had been undertaken in 16 VS. Tumor Volume ranged from 120 to 14405 mm3 (mean: 3468 mm3) at the time of treatment; 12 tumors were Koos stade 4. Median clinical and radiological follow-up was 62 Months and ranged from 27 to 123 Months. The 5-Year and 10-Year actuarial survival rates without failure justifying tumor removal were 90 and 85% respectively. The 5-Year actuarial survival rate without hearing decreasing was 36% when selecting the cases of useful hearing (Gardner I & II) at the time of treatment. Severe phenotype (p=0.05) and dose (>12 Gy) delivered at the tumor margin (p=0.032) were correlated to hearing deterioration at univariated analysis. Permanent facial neuropathy occurred in 2%. Even though the level of tumor control and hearing preservation is not the same as for sporadic VS, these results show that Gamma Knife radiosurgery is a valuable alternative treatment for VS in NF2 patients. Future orientation of early proactive radiosurgical treatment of intracanalicular VS will probably improve these results.