NF2-related schwannomatosis and other schwannomatosis: an updated genetic and epidemiological study.

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.

Stereotactic Radiosurgery and Radiotherapy for Vestibular Schwannoma in NF2-Related Schwannomatosis.

OBJECTIVES: To determine the long-term control rates and hearing outcomes for growing vestibular schwannoma in NF2-related schwannomatosis (NF2) treated with stereotactic radiosurgery (SRS) and fractionated radiotherapy (FRT). METHODS: Retrospective review of all patients treated with SRS/FRT between 1986 and2021 from a tertiary NF2 unit. Overall tumor control was defined as: (1) growth control (growth failure was defined as growth in any dimension of 3 millimetres or more from baseline post-SRS/FRT), and (2) treatment control (no need for further intervention). Loss of serviceable hearing was defined as a drop in speech discrimination score below 50% after SRS/FRT. RESULTS: There were 81 cases, with a mean duration of follow-up of 125 months. Overall control rate was 72% (58/81), with 80% (65/81) growth control and 74% (60/81) treatment control. There was a 5-year actuarial survival of 77% and 10-year survival of 71%. Forty-three percent (30/69) of cases did not have serviceable hearing at baseline. Of those remaining, 49% (19/39) preserved serviceable hearing during follow-up at a mean of 106 months. Actuarial survival for preservation of serviceable hearing at 5 and 10 years was 69% and 53%. There were poorer outcomes with increasing genetic severity, and with baseline tumor size >3 cm. No cases of SRS/FRT-related malignancy were identified at a mean follow-up of 10 years. CONCLUSION: Stereotactic radiosurgery/fractionated radiotherapy are an effective option to treat growing vestibular schwannoma in patients with NF2 with the potential for hearing preservation in a proportion of patients. LEVEL OF EVIDENCE: 4-Case Series Laryngoscope, 134:2364-2371, 2024.

Radiation treatment of benign tumors in NF2-related-schwannomatosis: A national study of 266 irradiated patients showing a significant increase in malignancy/malignant progression.

Background: Radiation treatment of benign tumors in tumor predisposition syndromes is controversial, but short-term studies from treatment centers suggest safety despite apparent radiation-associated malignancy being reported. We determined whether radiation treatment in NF2-related schwannomatosis patients is associated with increased rates of subsequent malignancy (M)/malignant progression (MP). Methods: All UK patients with NF2 were eligible if they had a clinical/molecular diagnosis. Cases were NF2 patients treated with radiation for benign tumors. Controls were matched for treatment location with surgical/medical treatments based on age and year of treatment. Prospective data collection began in 1990 with addition of retrospective cases in 1969. Kaplan-Meier analysis was performed for malignancy incidence and survival. Outcomes were central nervous system (CNS) M/MP (2cm annualized diameter growth) and survival from index tumor treatment. Results: In total, 1345 NF2 patients, 266 (133-Male) underwent radiation treatments between 1969 and 2021 with median first radiotherapy age of 32.9 (IQR = 22.4-46.0). Nine subsequent CNS malignancies/MPs were identified in cases with only 4 in 1079 untreated (P < .001). Lifetime and 20-year CNS M/MP was ~6% in all irradiated patients-(4.9% for vestibular schwannomas [VS] radiotherapy) versus <1% in the non-irradiated population (P < .001/.01). Controls were well matched for age at NF2 diagnosis and treatment (Males = 133%-50%) and had no M/MP in the CNS post-index tumor treatment (P = .0016). Thirty-year survival from index tumor treatment was 45.62% (95% CI = 34.0-56.5) for cases and 66.4% (57.3-74.0) for controls (P = .02), but was nonsignificantly worse for VS radiotherapy. Conclusion: NF2 patients should not be offered radiotherapy as first-line treatment of benign tumors and should be given a frank discussion of the potential 5% excess absolute risk of M/MP.

Updated protocol for genetic testing, screening and clinical management of individuals at risk of NF2-related schwannomatosis.

Genetic testing and management of individuals at risk for NF2-related schwannomatosis is complicated by the high rate of mosaicism resulting in a milder, later onset, more asymmetrical disease and the phenotypic overlap with the related schwannomatosis conditions. This updated protocol has been devised for the English NF2-related schwannomatosis service. It provides those affected with mosaic NF2-related schwannomatosis estimated risks of having an affected child; and management guidelines both for individuals at risk of NF2-related schwannomatosis, or with potential disease, due to having features that fall short of consensus diagnostic criteria. Risks of mosaicism and inferred transmission risks were derived from genetic testing of over 1000 individuals through the Manchester NF2 genetic testing service. This updated protocol, reflects the lower transmission risks now inferred in mosaic NF2-related schwannomatosis, informed by the greater sensitivity of Next Generation Sequencing in detecting low levels of mosaicism in blood, along with improved ability to analyse tumour DNA. Screening for features of NF2-related schwannomatosis is proposed until the risk of having the condition falls below a pragmatic threshold of 1%. Using these revised transmission figures, this threshold can now be reached at a younger age in many of those at risk, with earlier reassurance and discharge.

A Prospective Audit Comparing Optos Widefield Imaging to Fundus Examination for Von Hippel-Lindau Retinal Screening.

Background Von Hippel-Lindau (VHL) disease is an autosomal dominant multisystem disorder caused by germline mutations at chromosome 3p25-26 in the VHLtumour suppressor gene. Retinal manifestations include capillary haemangiomas that develop in up to 80% of gene carriers. Lifelong retinal surveillance involves yearly assessment usually by fundoscopy and often as part of a VHL multidisciplinary clinic. Optos ultra-widefield retinal imaging is now becoming more widely used in virtual retinal screening clinics. We aimed to assess discrepancies in the pickup rate of angioma and angiomatous-associated disease between slit-lamp fundoscopy and Optos ultra-widefield imaging. Methodology A total of 49 patients had both Optos ultra-widefield retinal imaging and slit-lamp fundoscopy over 16 months in VHL retinal surveillance clinics at the John Radcliffe Hospital, Oxford, UK. Optos images were analysed for image quality and presence of angioma(s) by a Consultant Ophthalmologist who was masked to the fundoscopy findings. The pickup rate was compared between slit-lamp fundoscopy and Optos imaging. Results In total, data on 94 eyes were collected. Of the total Optos retinal images, 12.8% were positive for angiomas compared to 11.7% from the slit-lamp examination. There was a discrepancy of 1.1% (one value) where the Optos image analysis suggested a possible angioma, which was not identified on slit-lamp examination. Optos imaging identified all angiomas in this cohort. Conclusions Optos imaging was non-inferior to slit-lamp examination in this sample of 94 eyes. In the current COVID-19 climate, reducing clinician-patient interaction is important. This research supports providing retinal imaging as an acceptable alternative to the yearly slit-lamp fundus examination.

A Case for Genetic Testing in Isolated Tympanic Paragangliomas.

OBJECTIVE: The aim of this study is to describe two clinical cases, which we believe highlight the need to consider routine genetic testing of all patients with new diagnosis of a tympanic paraganglioma (PGL). PATIENTS: Two patients seen in the ENT clinic at a tertiary center with a diagnosis of isolated tympanic PGL, without family history. INTERVENTION: Since 2016, all patients with newly diagnosed isolated tympanic PGL (glomus tympanicum) are offered review by the clinical genetic team and genetic testing of a panel of paraganglioma/phaeochromocytoma predisposition genes. Previously only those with multiple PGL or a family history were tested. MAIN OUTCOME MEASURES: We describe the results of genetic testing, the clinical course and discuss the ongoing implications for management. RESULTS: Both cases were identified to have a pathogenic variant in the SDHB gene after initial surgery. The clinical course for both cases was complicated by disease recurrence, as well as metastatic and secretory disease in one case. Knowledge of genetic status has influenced ongoing management, with annual MRI surveillance for other SDH-related tumors. CONCLUSION: These two cases reinforce the importance of offering genetic testing for all cases of isolated tympanic PGL. The discovery of a significant underlying genetic variant may affect management decisions and subsequent follow-up.

Evaluation of tumour surveillance protocols and outcomes in von Hippel-Lindau disease in a national health service.

BACKGROUND: Von Hippel-Lindau (VHL) disease is an inherited tumour predisposition syndrome and a paradigm for the importance of early diagnosis and surveillance. However, there is limited information on the "real world" management of VHL disease. METHODS: A national audit of VHL disease in the United Kingdom. RESULTS: VHL disease was managed mostly via specialist clinics coordinated through regional clinical genetics services (but frequently involving additional specialties). Over the study period, 19 genetic centres saw 842 individuals (393 males, 449 females) with a clinical and/or molecular diagnosis of VHL disease and 74 individuals (35 male, 39 female) with a prior risk of 50% (affected parent). All centres offered retinal, central nervous system and abdominal surveillance to affected individuals and at-risk relatives though surveillance details differed between centres (but complied with international recommendations). Renal lesions detected on the first surveillance scan were, on average, larger than those detected during subsequent scans and the larger the diameter at detection the greater the likelihood of early intervention. CONCLUSIONS: In a state-funded health care system individuals with a rare inherited cancer predisposition syndrome are generally able to access appropriate surveillance and patient management is improved compared to historical data. The "real world" data from this study will inform the future development of VHL management protocols.

Structural Abnormalities of the Central Retina in Neurofibromatosis Type 2.

INTRODUCTION: This case-control study seeks to systematically characterize the central retinal findings in a large cohort of patients with neurofibromatosis type 2 (NF2) using spectral domain optical coherence tomography (SD-OCT) as well as the examination of the potential use of this technique as a diagnostic tool in NF2. METHODS: Fifty-four patients with an NF2 diagnosis seen in a quaternary national service were age- and gender-matched to 55 controls from the normal population. Two masked assessors categorized SD-OCT images using predefined abnormalities: retinal tufts, epiretinal membrane (ERM) appearance, retinal hamartoma, and foveal contour. Specificity, sensitivity, and positive and negative predictive values were calculated for each retinal abnormality. Trends of retinal abnormalities with NF2 genetic severity groups (1. tissue mosaic; 2A. mild classic; 2B. moderate classic; and 3. severe) were investigated. RESULTS: We found retinal abnormalities in 26 patients with NF2 (48%) and 2 control patients (4%); retinal tufts were the most common abnormality therein (43%) and were not seen in controls. The specificity and sensitivity of the graded abnormalities on OCT scans in NF2 were 96% and 48%, respectively, with a positive predictive value of 93%. In our cohort, retinal tufts had a specificity of 100%, a sensitivity of 43%, and a positive predictive value of 100%. Retinal hamartomas were seen only in NF2 patients (35% sensitivity and 100% specificity). ERMs had 96% specificity and 13% sensitivity. The proportion of patients with retinal abnormalities increased statistically significantly with NF2 genetic severity; all patients within the 3. severe genetic severity had an abnormal SD-OCT. DISCUSSION/CONCLUSION: We present a systematic study of central retinal abnormalities in an NF2 population as seen on SD-OCT imaging. Our results show a high frequency of retinal abnormalities that are readily detected by SD-OCT imaging. The presence of retinal tufts may be a novel marker of NF2 with both high specificity and a positive predictive value for NF2, compared to other well-known ocular features of NF2, and may have a place in the NF2 diagnostic criteria.

A prospective prostate cancer screening programme for men with pathogenic variants in mismatch repair genes (IMPACT): initial results from an international prospective study.

BACKGROUND: Lynch syndrome is a rare familial cancer syndrome caused by pathogenic variants in the mismatch repair genes MLH1, MSH2, MSH6, or PMS2, that cause predisposition to various cancers, predominantly colorectal and endometrial cancer. Data are emerging that pathogenic variants in mismatch repair genes increase the risk of early-onset aggressive prostate cancer. The IMPACT study is prospectively assessing prostate-specific antigen (PSA) screening in men with germline mismatch repair pathogenic variants. Here, we report the usefulness of PSA screening, prostate cancer incidence, and tumour characteristics after the first screening round in men with and without these germline pathogenic variants. METHODS: The IMPACT study is an international, prospective study. Men aged 40-69 years without a previous prostate cancer diagnosis and with a known germline pathogenic variant in the MLH1, MSH2, or MSH6 gene, and age-matched male controls who tested negative for a familial pathogenic variant in these genes were recruited from 34 genetic and urology clinics in eight countries, and underwent a baseline PSA screening. Men who had a PSA level higher than 3·0 ng/mL were offered a transrectal, ultrasound-guided, prostate biopsy and a histopathological analysis was done. All participants are undergoing a minimum of 5 years' annual screening. The primary endpoint was to determine the incidence, stage, and pathology of screening-detected prostate cancer in carriers of pathogenic variants compared with non-carrier controls. We used Fisher's exact test to compare the number of cases, cancer incidence, and positive predictive values of the PSA cutoff and biopsy between carriers and non-carriers and the differences between disease types (ie, cancer vs no cancer, clinically significant cancer vs no cancer). We assessed screening outcomes and tumour characteristics by pathogenic variant status. Here we present results from the first round of PSA screening in the IMPACT study. This study is registered with ClinicalTrials.gov, NCT00261456, and is now closed to accrual. FINDINGS: Between Sept 28, 2012, and March 1, 2020, 828 men were recruited (644 carriers of mismatch repair pathogenic variants [204 carriers of MLH1, 305 carriers of MSH2, and 135 carriers of MSH6] and 184 non-carrier controls [65 non-carriers of MLH1, 76 non-carriers of MSH2, and 43 non-carriers of MSH6]), and in order to boost the sample size for the non-carrier control groups, we randomly selected 134 non-carriers from the BRCA1 and BRCA2 cohort of the IMPACT study, who were included in all three non-carrier cohorts. Men were predominantly of European ancestry (899 [93%] of 953 with available data), with a mean age of 52·8 years (SD 8·3). Within the first screening round, 56 (6%) men had a PSA concentration of more than 3·0 ng/mL and 35 (4%) biopsies were done. The overall incidence of prostate cancer was 1·9% (18 of 962; 95% CI 1·1-2·9). The incidence among MSH2 carriers was 4·3% (13 of 305; 95% CI 2·3-7·2), MSH2 non-carrier controls was 0·5% (one of 210; 0·0-2·6), MSH6 carriers was 3·0% (four of 135; 0·8-7·4), and none were detected among the MLH1 carriers, MLH1 non-carrier controls, and MSH6 non-carrier controls. Prostate cancer incidence, using a PSA threshold of higher than 3·0 ng/mL, was higher in MSH2 carriers than in MSH2 non-carrier controls (4·3% vs 0·5%; p=0·011) and MSH6 carriers than MSH6 non-carrier controls (3·0% vs 0%; p=0·034). The overall positive predictive value of biopsy using a PSA threshold of 3·0 ng/mL was 51·4% (95% CI 34·0-68·6), and the overall positive predictive value of a PSA threshold of 3·0 ng/mL was 32·1% (20·3-46·0). INTERPRETATION: After the first screening round, carriers of MSH2 and MSH6 pathogenic variants had a higher incidence of prostate cancer compared with age-matched non-carrier controls. These findings support the use of targeted PSA screening in these men to identify those with clinically significant prostate cancer. Further annual screening rounds will need to confirm these findings. FUNDING: Cancer Research UK, The Ronald and Rita McAulay Foundation, the National Institute for Health Research support to Biomedical Research Centres (The Institute of Cancer Research and Royal Marsden NHS Foundation Trust; Oxford; Manchester and the Cambridge Clinical Research Centre), Mr and Mrs Jack Baker, the Cancer Council of Tasmania, Cancer Australia, Prostate Cancer Foundation of Australia, Cancer Council of Victoria, Cancer Council of South Australia, the Victorian Cancer Agency, Cancer Australia, Prostate Cancer Foundation of Australia, Asociación Española Contra el Cáncer (AECC), the Instituto de Salud Carlos III, Fondo Europeo de Desarrollo Regional (FEDER), the Institut Català de la Salut, Autonomous Government of Catalonia, Fundação para a Ciência e a Tecnologia, National Institutes of Health National Cancer Institute, Swedish Cancer Society, General Hospital in Malmö Foundation for Combating Cancer.

Investigation and Management of Apparently Sporadic Central Nervous System Haemangioblastoma for Evidence of Von Hippel-Lindau Disease.

Haemangioblastomas are rare, highly vascularised tumours that typically occur in the cerebellum, brain stem and spinal cord. Up to a third of individuals with a haemangioblastoma will have von Hippel-Lindau (VHL) disease. Individuals with haemangioblastoma and underlying VHL disease present, on average, at a younger age and frequently have a personal or family history of VHL disease-related tumours (e.g., retinal or central nervous system (CNS) haemangioblastomas, renal cell carcinoma, phaeochromocytoma). However, a subset present an apparently sporadic haemangioblastoma without other features of VHL disease. To detect such individuals, it has been recommended that genetic testing and clinical/radiological assessment for VHL disease should be offered to patients with a haemangioblastoma. To assess "real-world" clinical practice, we undertook a national survey of clinical genetics centres. All participating centres responded that they would offer genetic testing and a comprehensive assessment (ophthalmological examination and CNS and abdominal imaging) to a patient presenting with a CNS haemangioblastoma. However, for individuals who tested negative, there was variability in practice with regard to the need for continued follow-up. We then reviewed the results of follow-up surveillance in 91 such individuals seen at four centres. The risk of developing a potential VHL-related tumour (haemangioblastoma or RCC) was estimated at 10.8% at 10 years follow-up. The risks of developing a recurrent haemangioblastoma were higher in those who presented <40 years of age. In the light of these and previous findings, we propose an age-stratified protocol for surveillance of VHL-related tumours in individuals with apparently isolated haemangioblastoma.

Sporadic vestibular schwannoma: a molecular testing summary.

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.

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

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

Neurofibromatosis type 2 and related disorders.

PURPOSE OF REVIEW: Neurofibromatosis type 2 (NF2) is a schwannoma predisposition syndrome, alongside schwannomatosis related to germline LZTR1 and SMARCB1 pathogenic variants. This review highlights their overlapping phenotypes, new insight into NF2 phenotype and treatment outcomes. RECENT FINDINGS: Mosaic NF2 is more prevalent than previously thought. Use of next-generation sequencing and tumour testing is needed to differentiate mosaic NF2 and schwannomatosis. Developing NF2 phenotypic insights include vasculopathy with brainstem infarction and vessel stenosis; focal cortical dysplasia in severe phenotypes; swallowing/speech difficulties and continued debate into malignancy in NF2. Proposed are: use of visual evoked potentials to monitor optic nerve sheath meningioma; potential routine magnetic resonance angiogram in adolescence and a genetic score to cohort patients with similar pathogenic_variants, for natural history/treatment outcome studies. Cohort studies found survival analysis to hearing loss and unilateral visual loss in severe mutation groups was 32 and 38 years; active management gave better outcomes than surveillance in spinal ependymoma; gamma knife, bevacizumab and hearing preservation surgery maintained or improved short-term hearing in selected patients, and gamma knife had a good long-term tumour control in mild patients with small tumours. SUMMARY: Further long-term outcome studies are needed comparing similar severity patients to allow informed decision making.

Trends in phenotype in the English paediatric neurofibromatosis type 2 cohort stratified by genetic severity.

Childhood onset neurofibromatosis type 2 can be severe and genotype dependent. We present a retrospective phenotypic analysis of all ascertained children in England 1.0). Focal cortical dysplasia occurred in 26% group 3 and 4% 2A. A total of 48% of group 3 underwent ≥1 major intervention (intracranial/spinal surgery/Bevacizumab/radiotherapy) compared to 35% of 2A; with 23% group 3 undergoing spinal surgery (schwannoma/ependymoma/meningioma resection) compared to 4% of 2A. Mean age starting Bevacizumab was 12.7 in group 3 and 14.9 years in 2A. In conclusion, group 3 phenotype manifests earlier with greater tumour load, poorer visual outcomes and more intervention.

First report of the efficacy of vestibular rehabilitation in improving function in patients with Neurofibromatosis type 2: an observational cohort study in a clinical setting.

PURPOSE: Patients with Neurofibromatosis type 2 often experience debilitating neuro-otological problems which affect their mobility and balance. This study examined the efficacy of a personalised program of vestibular rehabilitation for patients with Neurofibromatosis type 2. MATERIALS AND METHODS: An observational cohort study analysing routinely collected data for 21 patients in a highly specialised Neurofibromatosis type 2 service. Vestibular rehabilitation comprised an initial one-hour assessment followed by a patient-specific exercise program reviewed in person and by email consultations. Patients were subsequently followed-up at 9 months. The vestibular rehabilitation efficacy was assessed using the Dynamic Gait Index score. RESULTS: Nineteen of 21 patients were assessed as impaired and at risk of falls pre-rehabilitation (Dynamic Gait Index <19/24), of which 79% showed clinical improvement post-rehabilitation. There was a significant improvement in the Dynamic Gait Index scores pre-rehabilitation to post-rehabilitation (p < 0.001) and outcomes were subsequently maintained at the 9-month follow-up assessment. Whilst the pre-rehabilitation Dynamic Gait Index scores of patients with more severe genotype were lower compared to other patients, the beneficial effect of vestibular rehabilitation was similar amongst genetic severity groups. CONCLUSIONS: Personalised vestibular rehabilitation significantly improves function in Neurofibromatosis type 2, sustaining benefits for 9 months, irrespective of patients' age or genetic severity. Implications for rehabilitation Patients with Neurofibromatosis type 2 experience debilitating neuro-otological problems which affect their mobility and balance. A patient-tailored program of vestibular rehabilitation was offered in a highly specialised clinic for six months with a follow-up assessment at 9 months post-treatment. All patients improved from baseline, with 79% of them achieving clinically significant improvement in function and with statistically significant benefits sustained for 9 months. The beneficial effect of vestibular rehabilitation was similar for all patients, regardless of age or genetic severity, suggesting vestibular rehabilitation could be incorporated in routine clinical care in Neurofibromatosis type 2 clinics internationally.

Neurofibromatosis Type 2-Related Eye Disease Correlated With Genetic Severity Type.

OBJECTIVE: Neurofibromatosis type 2 (NF2) is an uncommon but well-recognized disorder characterized by multiple schwannomas and meningiomas. Adults typically present with hearing loss and balance disturbance, and children with ocular, dermatological, and neurological signs. Clinical diagnosis is confirmed by neuroimaging and genetic testing. Although ophthalmic features are present in patients with NF2, there are no reports correlating genetic severity subtypes with ophthalmic involvement. METHODS: We retrospectively reviewed longitudinal ophthalmological data of 83 patients with NF2, with known genetic severity subtype, to determine visual function over time. We created a scoring system (Oxford NF2 Ophthalmic Score [ONOS]) to quantify visually debilitating pathology. RESULTS: The prevalence of optic atrophy, combined hamartomas, cataract, and epiretinal membranes significantly increased with genetic severity. Median age of survival to visual acuity worse than 1.0 logarithm of minimum angle of resolution in one eye significantly decreased with genetic severity and was 38 years in the genetically severe group, 49 years in moderate classics, 64 years in mild classics, and 84 years in the tissue mosaics. In the genetically severe, the visually damaging pathologies were largely untreatable. The ONOS correlated with genetic severity longitudinally and cross-sectionally. CONCLUSIONS: Mutations associated with severe systemic disease result in greater visual morbidity at an earlier age. Those with tissue mosaicism are unlikely to have visually debilitating pathology secondary to NF2. Potentially treatable sources of damage to vision, however, affect all groups and must be identified early and treated effectively to retain useful vision throughout life.

Progression of hearing loss in neurofibromatosis type 2 according to genetic severity.

OBJECTIVES/HYPOTHESIS: This study set out to describe the progression of hearing loss in patients with neurofibromatosis type 2 (NF2), treated in a quaternary multidisciplinary clinic. It also aimed to compare hearing loss across patients grouped according to a known genetic severity score to explore its utility for prognostication. STUDY DESIGN: Retrospective cohort study. METHODS: We conducted a study of 147 patients with confirmed NF2 diagnosis for a mean observational period of 10 years. Pure-tone average (PTA), optimum discriminations scores (ODS), and genotype data were collected. Patients were classified according to hearing class (American Academy of Otolaryngology), their candidacy for auditory implantation (UK National NF2 consensus) and grouped by genetic severity as: 1 = tissue mosaic, 2A = mild classic, 2B = moderate classic, and 3 = severe. Survival analysis investigated the effect of genetic severity on the age of loss of serviceable hearing. RESULTS: Genetic severity was a significant predictor of hearing outcomes such as ODS, hearing classification, and maximum annual PTA deterioration. Although the overall median age of loss of serviceable hearing was 78 years, there was significant variation according to the genetic severity; the median for severe patients was 32 years compared to a median of 80 for tissue mosaic patients. CONCLUSIONS: This is the first description of long-term hearing outcomes in a clinical setting across a large heterogeneous cohort of patients with NF2. The results highlight the potential importance and benefit of considering the genetic severity score of patients when undertaking treatment decisions, as well as planning future natural history studies. LEVEL OF EVIDENCE: 2c Laryngoscope, 129:974-980, 2019.

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

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