The molecular biology of NF2/Merlin on tumorigenesis and development.

The neurofibromatosis type 2 (NF2) gene, known for encoding the tumor suppressor protein Merlin, is central to the study of tumorigenesis and associated cellular processes. This review comprehensively examines the multifaceted role of NF2/Merlin, detailing its structural characteristics, functional diversity, and involvement in various signaling pathways such as Wnt/ß-catenin, Hippo, TGF-ß, RTKs, mTOR, Notch, and Hedgehog. These pathways are crucial for cellular growth, proliferation, and differentiation. NF2 mutations are specifically linked to the development of schwannomas, meningiomas, and ependymomas, although the precise mechanisms of tumor formation in these specific cell types remain unclear. Additionally, the review explores Merlin's role in embryogenesis, highlighting the severe developmental defects and embryonic lethality caused by NF2 deficiency. The potential therapeutic strategies targeting these genetic aberrations are also discussed, emphasizing inhibitors of mTOR, HDAC, and VEGF as promising avenues for treatment. This synthesis of current knowledge underscores the necessity for ongoing research to elucidate the detailed mechanisms of NF2/Merlin and develop effective therapeutic strategies, ultimately aiming to improve the prognosis and quality of life for individuals with NF2 mutations.

Tumors of the nervous system and hearing loss: Beyond vestibular schwannomas.

Hearing loss is a common side effect of many tumor treatments. However, hearing loss can also occur as a direct result of certain tumors of the nervous system, the most common of which are the vestibular schwannomas (VS). These tumors arise from Schwann cells of the vestibulocochlear nerve and their main cause is the loss of function of NF2, with 95 % of cases being sporadic and 5 % being part of the rare neurofibromatosis type 2 (NF2)-related Schwannomatosis. Genetic variations in NF2 do not fully explain the clinical heterogeneity of VS, and interactions between Schwann cells and their microenvironment appear to be critical for tumor development. Preclinical in vitro and in vivo models of VS are needed to develop prognostic biomarkers and targeted therapies. In addition to VS, other tumors can affect hearing. Meningiomas and other masses in the cerebellopontine angle can compress the vestibulocochlear nerve due to their anatomic proximity. Gliomas can disrupt several neurological functions, including hearing; in fact, glioblastoma multiforme, the most aggressive subtype, may exhibit early symptoms of auditory alterations. Besides, treatments for high-grade tumors, including chemotherapy or radiotherapy, as well as incomplete resections, can induce long-term auditory dysfunction. Because hearing loss can have an irreversible and dramatic impact on quality of life, it should be considered in the clinical management plan of patients with tumors, and monitored throughout the course of the disease.

Natural history of hearing and tumor growth in vestibular schwannoma in neurofibromatosis type 2-related schwannomatosis.

OBJECTIVES: To determine the natural history of hearing loss and tumor volume in patients with untreated neurofibromatosis type 2 (NF2)-related schwannomatosis. Moreover, we statistically examined the factors affecting hearing prognosis. METHODS: This retrospective cohort study was conducted on 37 ears of 24 patients with NF2-related vestibular schwannomatosis followed up without treatment for more than 1 year. We obtained detailed chronological changes in the PTA and tumor volume in each case over time, and the rate of change per year was obtained. Multivariate analysis was also conducted to investigate factors associated with changes in hearing. RESULTS: The average follow-up period was approximately 9 years, and hearing deteriorated at an average rate of approximately 4 dB/year. The rate of maintaining effective hearing decreased from 30 ears (81%) at the first visit to 19 ears (51%) at the final follow-up. The average rate of change in tumor growth for volume was approximately 686.0 mm3/year. This study revealed that most patients with NF2 experienced deterioration in hearing acuity and tumor growth during the natural course. A correlation was observed between an increase in tumor volume and hearing loss (r = 0.686; p < 0.001). CONCLUSIONS: Although the hearing preservation rate in NF2 cases is poor with the current treatment methods, many cases exist in which hearing acuity deteriorates, even during the natural course. Patients with an increased tumor volume during the follow-up period were more likely to experience hearing deterioration. Trial registration number 20140242 (date of registration: 27 October 2014).

Functional interactions between neurofibromatosis tumor suppressors underlie Schwann cell tumor de-differentiation and treatment resistance.

Schwann cell tumors are the most common cancers of the peripheral nervous system and can arise in patients with neurofibromatosis type-1 (NF-1) or neurofibromatosis type-2 (NF-2). Functional interactions between NF1 and NF2 and broader mechanisms underlying malignant transformation of the Schwann lineage are unclear. Here we integrate bulk and single-cell genomics, biochemistry, and pharmacology across human samples, cell lines, and mouse allografts to identify cellular de-differentiation mechanisms driving malignant transformation and treatment resistance. We find DNA methylation groups of Schwann cell tumors can be distinguished by differentiation programs that correlate with response to the MEK inhibitor selumetinib. Functional genomic screening in NF1-mutant tumor cells reveals NF2 loss and PAK activation underlie selumetinib resistance, and we find that concurrent MEK and PAK inhibition is effective in vivo. These data support a de-differentiation paradigm underlying malignant transformation and treatment resistance of Schwann cell tumors and elucidate a functional link between NF1 and NF2.

Gene-targeted therapy for neurofibromatosis and schwannomatosis: The path to clinical trials.

Numerous successful gene-targeted therapies are arising for the treatment of a variety of rare diseases. At the same time, current treatment options for neurofibromatosis 1 and schwannomatosis are limited and do not directly address loss of gene/protein function. In addition, treatments have mostly focused on symptomatic tumors, but have failed to address multisystem involvement in these conditions. Gene-targeted therapies hold promise to address these limitations. However, despite intense interest over decades, multiple preclinical and clinical issues need to be resolved before they become a reality. The optimal approaches to gene-, mRNA-, or protein restoration and to delivery to the appropriate cell types remain elusive. Preclinical models that recapitulate manifestations of neurofibromatosis 1 and schwannomatosis need to be refined. The development of validated assays for measuring neurofibromin and merlin activity in animal and human tissues will be critical for early-stage trials, as will the selection of appropriate patients, based on their individual genotypes and risk/benefit balance. Once the safety of gene-targeted therapy for symptomatic tumors has been established, the possibility of addressing a wide range of symptoms, including non-tumor manifestations, should be explored. As preclinical efforts are underway, it will be essential to educate both clinicians and those affected by neurofibromatosis 1/schwannomatosis about the risks and benefits of gene-targeted therapy for these conditions.

Recommendations for the collection and annotation of biosamples for analysis of biomarkers in neurofibromatosis and schwannomatosis clinical trials.

INTRODUCTION: Neurofibromatosis 1 and schwannomatosis are characterized by potential lifelong morbidity and life-threatening complications. To date, however, diagnostic and predictive biomarkers are an unmet need in this patient population. The inclusion of biomarker discovery correlatives in neurofibromatosis 1/schwannomatosis clinical trials enables study of low-incidence disease. The implementation of a common data model would further enhance biomarker discovery by enabling effective concatenation of data from multiple studies. METHODS: The Response Evaluation in Neurofibromatosis and Schwannomatosis biomarker working group reviewed published data on emerging trends in neurofibromatosis 1 and schwannomatosis biomarker research and developed recommendations in a series of consensus meetings. RESULTS: Liquid biopsy has emerged as a promising assay for neurofibromatosis 1/schwannomatosis biomarker discovery and validation. In addition, we review recommendations for a range of biomarkers in clinical trials, neurofibromatosis 1/schwannomatosis-specific data annotations, and common data models for data integration. CONCLUSION: These Response Evaluation in Neurofibromatosis and Schwannomatosis consensus guidelines are intended to provide best practices for the inclusion of biomarker studies in neurofibromatosis 1/schwannomatosis clinical trials, data, and sample annotation and to lay a framework for data harmonization and concatenation between trials.

Comparing Speech Recognition Outcomes Between Cochlear Implants and Auditory Brainstem Implants in Patients With NF2-Related Schwannomatosis.

OBJECTIVE: To compare cochlear implant (CI) and auditory brainstem implant (ABI) performance in patients with NF2-related schwannomatosis (NF2). STUDY DESIGN: Historical cohort. SETTING: Tertiary academic center. PATIENTS: A total of 58 devices among 48 patients were studied, including 27 ABIs implanted from 1997 to 2022 and 31 CIs implanted from 2003 to 2022. Three patients had bilateral ABIs, three had bilateral CIs, three had an ABI on one side and a CI on the other, one had a CI that was later replaced with an ipsilateral ABI, and one had an ABI and CI concurrently on the same side. INTERVENTIONS: CI or ABI ipsilateral to vestibular schwannoma. MAIN OUTCOME MEASURES: Open-set speech perception, consonant-nucleus-consonant word scores, and AzBio sentence in quiet scores. RESULTS: Among all patients, 27 (47%) achieved open-set speech perception, with 35 (61%) daily users at a median of 24 months (interquartile range [IQR], 12-87 mo) after implantation. Comparing outcomes, CIs significantly outperformed ABIs; 24 (77%) CIs achieved open-set speech perception compared with 3 (12%) ABIs, with median consonant-nucleus-consonant and AzBio scores of 31% (IQR, 0-52%) and 57% (IQR, 5-83%), respectively, for CIs, compared with 0% (IQR, 0-0%) and 0% (IQR, 0-0%), respectively, for ABIs. Patients with ABIs were younger at diagnosis and at implantation, had larger tumors, and were more likely to have postoperative facial paresis. CONCLUSION: Many patients with NF2-associated vestibular schwannoma achieved auditory benefit with either a CI or an ABI; however, outcomes were significantly better in those patients who were able to receive a CI. When disease and anatomy permit, hearing rehabilitation with a CI should be considered over an ABI in these patients. Tumor management strategies that increase the ability to successfully use CIs should be strongly considered given the high risk of losing bilateral functional acoustic hearing in this population.

Ischemic Cerebellar Stroke in a Young Patient With Neurofibromatosis Type 2: A Case Report.

BACKGROUND: Neurofibromatosis type 2 (NF2) is a multifaceted disease characterized primarily by benign CNS tumors, especially meningiomas and vestibular schwannomas. There have been several cases of brainstem ischemic stroke in young NF2 patients reported in the literature. To date, there is no unified theory about the connection between NF2 and pediatric stroke. METHODS: We present a case of ischemia in the left cerebellar peduncle of a young patient with NF2, as well as a narrative review of the literature of previous cases. RESULTS: Serial magnetic resonance images (MRIs) displayed an initial area of restricted diffusion in the left cerebellar peduncle with peripheral enhancement which did improve over several months, consistent with maturing infarct. CONCLUSIONS: Our case joins several others with similar presentations and findings. The primary theory for the cause of brainstem ischemia in juvenile NF2 is a microvascular cause due to deficiency of neurofibromin 2, a regulator of endothelial development. Multicenter studies with large NF2 cohorts are needed to better characterize this syndrome.

[Neurofibromatosis]. / Neurofibromatose.

BACKGROUND & FOCUS: While the Neurofibromatoses have been observed and classified by their phenotypes for several centuries, their great variability constitutes a considerable challenge in diagnostics and therapy selection. This article focuses on highlighting the three most frequent sub-types NF1, NF2 and NF3. METHODS: All three NF types are outlined by the following measures: the history of their clinical detection, the typical appearance, the underlying genetic constitution and its consequences, the official diagnostic criteria, the mandatory diagnostic steps and finally the treatment opportunities and specific risks. RESULTS: About 50% of NF patients have a positive family history and the other 50% are the first symptomatic generations and suffer from new mutations. A considerable (unknown) number of patients do not exhibit a complete genetic NF constitution, but have a so-called mosaic sub-form with only a limited number of cells being genetically affected and prone to tumorous changes. The neurofibromatoses are neuro-cutaneous diseases with manifestations at the skin and nervous system, except for NF 3, where the skin and eyes are never affected. Skin and eye manifestations, especially pigmentation disturbances, mostly started early in childhood and adolescence. The underlying genetic constitutions, on chromosome 17 in NF1 and on chromosome 22 in NF2 and NF3, cause a defect in tumor suppressor genes and lead to excessive proliferation of Schwann cells. Major features are tumors of the peripheral nerves, including cranial and spinal nerves leading to tumors with considerable nerve, brain and spinal cord compression and resulting in pain, sensory and motor deficits. A further variable disease feature may be neuropathy with neuropathic pain, related to tumor formation or even independent of it.Although benign by histopathology and growing rather slowly, those tumors often cause progressive neurological deficit and loss of function. Loss of function may be prevented by adequate timing of therapy such as nerve decompression by microsurgical tumor resection or reduction, medication with immunotherapy or radiotherapy in selected cases. To date it is unknown why some tumors remained silent and stable while others progress and show periods of accelerated growth.As a consequence, NF patients need to be accompanied by a specialized interdisciplinary NF team at long-term, with a clear-cut standardized protocol for clinical and imaging controls along with counseling and support in decision-making.Further, NF patients may suffer from reactive depression due to the danger of losing essential neural functions, such as vision or audition or movement. And especially NF1 patients show characteristics of ADHS and other cognitive compromise in at least 50% of cases. CONCLUSIONS: As the neurofibromatosis belong to the so-called rare diseases, all patients with a suspicion or diagnosis of NF should get the opportunity to present to an interdisciplinary NF Center, mostly situated at University Hospitals, where competent counseling on the individual disease phenotype may be provided. Here the patients will be informed on the necessary diagnostic steps, their frequency as well as on practical steps in case of acute deterioration. Most NF centers are run by neurosurgeons or neurologists or pediatricians, working in a network with geneticists, neuro-radiologists, ophthalmologists, dermatologists, plastic and general surgeons, psychologists, psychiatrists and social work experts. They participate regularly in neuro-oncological tumor and sarcoma tumor boards, skull base tumor centers, comprehensive hearing centers, and deliver all the treatment opportunities provided by certified brain tumor centers, among those the inclusion in special diagnostic and treatment studies or the contact information to patient support groups.

Advances in Targeted Therapy for Neurofibromatosis Type 2 (NF2)-Associated Vestibular Schwannomas.

PURPOSE OF REVIEW: Neurofibromatosis 2 (NF2) is an autosomal-dominant genetic disorder characterized by bilateral vestibular schwannomas (VS), meningiomas, ependymomas, spinal and peripheral schwannomas, optic gliomas, and juvenile cataracts. Ongoing studies provide new insight into the role of the NF2 gene and merlin in VS tumorigenesis. RECENT FINDINGS: As NF2 tumor biology becomes increasingly understood, therapeutics targeting specific molecular pathways have been developed and evaluated in preclinical and clinical studies. NF2-associated VS are a source of significant morbidity with current treatments including surgery, radiation, and observation. Currently, there are no FDA-approved medical therapies for VS, and the development of selective therapeutics is a high priority. This manuscript reviews NF2 tumor biology and current therapeutics undergoing investigation for treatment of patients with VS.

Updates in the Management of Central and Peripheral Nervous System Tumors among Patients with Neurofibromatosis Type 1 and Neurofibromatosis Type 2.

BACKGROUND: Neurofibromatosis type 1 and neurofibromatosis type 2 are unrelated, distinct genetic disorders characterized by the development of central and peripheral nervous system tumors. SUMMARY: Neurofibromatosis type 1 is the most common inherited tumor predisposition syndrome with a lifelong increased risk of benign and malignant tumor development, such as glioma and nerve sheath tumors. Neurofibromatosis type 2 classically presents with bilateral vestibular schwannoma, yet it is also associated with non-vestibular schwannoma, meningioma, and ependymoma. Historically, the number of effective therapies for neurofibromatosis-related neoplasms has been limited. KEY MESSAGE: In the past decade, there have been significant advances in the development of precision-based therapies for NF-associated tumors with an increased emphasis on functional outcomes in addition to tumor response. Continued scientific discovery and advancement of targeted therapies for NF-associated neoplasms are necessary to continue to improve outcomes for patients with NF.

Regression of a spinal schwannoma after Pomalidomide.

A 77-year old female with a history of neurofibromatosis type 2 (NF2) was diagnosed with a spinal schwannoma that was managed conservatively over a decade. During this time, follow up imaging revealed this lesion had been growing and the patient had become symptomatic from it necessitating surgical decompression. However, the patient had been diagnosed with multiple myeloma and underwent treatment with Pomalidomide chemotherapy which delayed surgery for the spinal schwannoma. Further imaging of the spine revealed significant regression in the size of the spinal schwannoma. This phenomenon has not previously been reported and this report aims to explore the implications of Pomalidomide in patients with NF2 related spinal schwannomas.

Pediatric Cerebral Meningioma: A Single-Center Study with 10 Children Not Associated with Neurofibromatosis Type 2 and Literature Review.

INTRODUCTION: Pediatric meningiomas (PMs) are rare tumors; they differ from their adult counterparts by their atypicality of location, higher rates of malignant change, male preponderance, recurrence, and sometimes, their association with neurofibromatosis. This case series analyzes the clinical behavior, pathological presentation, location, and its association with neurofibromatosis type 2 (NF2). METHODS: This case series consists of pediatric patients between the ages of 4 and 16 years who were hospitalized in the neurosurgical department of our hospital from 2012 to 2021 with different neurological symptoms and a literature review using the PubMed/MEDLINE database. RESULTS: Sixty percent of the patients were males, while 40% were females. The most common neurological manifestations were signs of increased intracranial pressure. NF2 was absent in all patients. The predominant histopathology subtypes are atypical and WHO grade II, representing 30% and 40%, respectively. CONCLUSION: This study supports the relationship between NF2 and pediatric cerebral meningioma but at a lower concomitant rate from 0 to 13%, taking into consideration our original data and the literature review, contrasting some reported cases, which suggest rates as high as 33%, 50%, and 100% in a very small number of patients. Gross total resection without postoperative radiation therapy for nonmalignant and non-NF2-associated PM proved to be a sufficient and a good treatment option.

CUDC907, a dual phosphoinositide-3 kinase/histone deacetylase inhibitor, promotes apoptosis of NF2 Schwannoma cells.

Neurofibromatosis Type 2 (NF2) is a rare tumor disorder caused by pathogenic variants of the merlin tumor suppressor encoded by NF2. Patients develop vestibular schwannomas (VS), peripheral schwannomas, meningiomas, and ependymomas. There are no approved drug therapies for NF2. Previous work identified phosphoinositide-3 kinase (PI3K) as a druggable target. Here we screened PI3K pathway inhibitors for efficacy in reducing viability of human schwannoma cells. The lead compound, CUDC907, a dual histone deacetylase (HDAC)/PI3K inhibitor, was further evaluated for its effects on isolated and nerve-grafted schwannoma model cells, and primary VS cells. CUDC907 (3 nM IG50) reduced human merlin deficient Schwann cell (MD-SC) viability and was 5-100 fold selective for MD over WT-SCs. CUDC907 (10 nM) promoted cell cycle arrest and caspase-3/7 activation within 24 h in human MD-SCs. Western blots confirmed a dose-dependent increase in acetylated lysine and decreases in pAKT and YAP. CUDC907 decreased tumor growth rate by 44% in a 14-day treatment regimen, modulated phospho-target levels, and decreased YAP levels. In five primary VS, CUDC907 decreased viability, induced caspase-3/7 cleavage, and reduced YAP levels. Its efficacy correlated with basal phospho-HDAC2 levels. CUDC907 has cytotoxic activity in NF2 schwannoma models and primary VS cells and is a candidate for clinical trials.

Dermatologic manifestations in paediatric neurofibromatosis type 2: a cross sectional descriptive multicentric study.

BACKGROUND: Neurofibromatosis type 2 (NF2) is characterized by bilateral vestibular schwannoma (VS) more often in adults but a severe paediatric form with multiple neurological tumours is also described. In this population, a early diagnosis is important to prevent the onset of neurological complications but is difficult, particularly without a familial history. Cutaneous manifestations, which may precede VS or neurological tumours by several years, may contribute to an early diagnosis, but specific studies are lacking. The objective of this study was to characterize cutaneous manifestations of NF2 in a paediatric population. RESULTS: This observational, descriptive and multicentric study was conducted from April 2019 to April 2020 in seven academic French hospitals. We included patients ≤ 18 years old who fulfilled the Manchester diagnostic criteria or had a pathogenic mutation identified in the NF2 gene. All patients underwent a dermatological examination guided by a standardized questionnaire. 21 children were included, of whom 20 had at least one skin tumour (mean number 5 ± 4.6 [range 0-15]), which led to a diagnosis in four cases. In the other 17 cases, the diagnosis of NF2 was based on neurosensory complications (n = 10), family screening (n = 4) or ocular signs (n = 3). Before the NF2 diagnosis, 15 children had at least one "undiagnosed" cutaneous tumour that did not lead to a specific management. Patients' dermatological examination also revealed < 6 non specific café au lait macules (n = 15), hypopigmented macules (n = 12) with more than 3 lesions in 4 cases, and purple reticulated macules of the trunk (n = 4). CONCLUSION: Dermatological lesions are frequent and early in children with NF2 but rarely lead to the diagnosis. Cutaneous schwannomas are the most frequent but are often underdiagnosed. Café au lait macules are frequent, but atypical and mostly in small numbers. Multiple hypopigmented macules seem suggestive although inconsistent. The sensitivity of reticulated capillary malformation-like lesions remains to be assessed by further studies.

Natural history and volumetric analysis of meningiomas in neurofibromatosis type 2.

OBJECTIVE: The objective of this paper was to describe the volumetric natural history of meningiomas in patients with neurofibromatosis type 2 (NF2). METHODS: The authors performed a retrospective descriptive study by reviewing NF2 patients with meningiomas at their institution between 2000 and 2019. Demographic data were collected from the electronic medical records. Tumor volume was collected using volumetric segmentation software. Imaging characteristics including peritumoral brain edema (PTBE) and tumor calcification were collected for each patient from their first to most recent MRI at the authors' institution. An increase of 15% or more per year from original tumor size was used as the cutoff to define growth. RESULTS: A total of 137 meningiomas from 48 patients were included in the analysis. The average number of tumors per person was 2.9. Ninety-nine (72.3%) tumors were in female patients. The median length of follow-up from first imaging to last imaging was 32 months (IQR 10.9, 68.3 months). Most tumors were located in the cerebral convexity (24.8%), followed by the falcine region (18.2%) and spine (10.2%). The median tumor growth was 0.12 cm3/yr (IQR 0.03, 0.52 cm3/yr). At the time of first imaging, 21.9% of tumors had calcifications, while 13.9% of meningiomas had PTBE. Of 137 tumors, 52 showed growth. Characteristics associated with tumor growth included PTBE (OR 9.12, 95% CI 1.48-56.4), tumor volume (per cm3) at first imaging (OR 0.91, 95% CI 0.83-0.99), and 10-year increased age at first imaging (OR 0.57, 95% CI 0.43-0.74). PTBE had the shortest median time to growth at 9.2 months. CONCLUSIONS: Although the majority of NF2-associated meningiomas do not grow in the short term, a wide range of growth patterns can be seen. Younger age at first imaging and presence of PTBE are associated with growth. Patients with these characteristics likely benefit from closer follow-up.

Novel patient-derived xenograft and cell line models for therapeutic screening in NF2-associated schwannoma.

Treatment of schwannomas in patients with neurofibromatosis type 2 (NF2) is extremely unsatisfactory, and innovative therapeutic approaches are urgently needed. However, the lack of clinically relevant NF2-associated schwannoma models has severely hampered drug discovery in this rare disease. Here we report the first establishment and characterization of patient-derived xenograft (PDX) and cell line models of NF2-associated schwannoma, which recapitulates the morphological and histopathological features of patient tumors, retain patient NF2 mutations, and maintain gene expression profiles resembling patient tumor profiles with the preservation of multiple key signaling pathways commonly dysregulated in human schwannomas. Using gene expression profiling, we identified elevated PI3K/AKT/mTOR networks in human NF2-associated vestibular schwannomas. Using high-throughput screening of 157 inhibitors targeting the PI3K/AKT/mTOR pathways in vitro, we identified a dozen inhibitors (such as BEZ235, LY2090314, and AZD8055) with significant growth-suppressive effects. Interestingly, we observed that three cell lines displayed differential therapeutic responses to PI3K/AKT/mTOR inhibitors. Furthermore, we demonstrated that two orally bioavailable inhibitors, AZD8055 and PQR309, suppressed NF2-associated schwannoma growth both in vitro and in vivo. In conclusion, our novel patient-derived models of NF2-associated schwannoma closely mimic the phenotypes and genotypes of patient tumors, making them reliable preclinical tools for testing novel personalized therapies. © 2022 The Pathological Society of Great Britain and Ireland.

Multiple Meningiomas as a Criterion for the Diagnosis of Neurofibromatosis Type 2 and Other Tumor Predisposition Syndromes.

BACKGROUND: Bilateral vestibular schwannomas (VS) are pathognomonic of neurofibromatosis type 2 (NF2), but the diagnostic criteria also include unilateral VS (UVS) in combination with multiple meningiomas (MM) and other schwannomas, as well as MM without VS. OBJECTIVE: To investigate the diagnostic value of these criteria and establish the presence of other genetic conditions in patients presenting in this manner. METHODS: The Manchester International NF2 database was accessed to obtain information on patients presenting with a UVS and MM or ≥2 nonintradermal schwannomas (NIDS). We gathered data on patients diagnosed with NF2 due to MM without VS and on patients presenting with MM without meeting NF2 criteria. Analysis was performed for pathogenic variants (PVs) in NF2, SMARCE1, SMARCB1, and LZTR1. RESULTS: A total of 31 of 131 patients presenting with a UVS and MM had a nonrefuted diagnosis of NF2 after molecular studies, in comparison with 85 of 96 patients presenting with UVS and ≥2 NIDS (P ≤ .00001). Fifty percent of patients presenting with a UVS and ≥2 NIDS with NF2 developed bilateral VS, compared with only 26% of those who presented with a UVS and MM (P = .0046). In total, 11 of 152 patients presenting with MM without fulfilling NF2 criteria were found to have a PV in SMARCE1, and 7 of 152 were confirmed to have mosaic NF2. CONCLUSION: Patients presenting with UVS and MM are significantly more likely to have a nonrefuted diagnosis of NF2 than patients presenting with UVS and ≥2 NIDS, but significantly less likely to develop bilateral VS. Seven percent of those presenting with MM without meeting NF2 criteria had PV in SMARCE1, and 5% had mosaic NF2.

Prevalence and natural history of schwannomas in neurofibromatosis type 2 (NF2): the influence of pathogenic variants.

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.

Safety of 3 Tesla Magnetic Resonance Imaging in Patients With Auditory Brainstem Implants.

OBJECTIVE: To evaluate the safety of 3 Tesla (T) magnetic resonance imaging (MRI) in patients with auditory brainstem implants (ABI) with the magnet removed at implantation and report incidence of complications. STUDY DESIGN: Retrospective chart review. SETTING: Tertiary neurotology ambulatory practice. PATIENTS: Patients with diagnosis of Neurofibromatosis, type 2 (NF2) with functional ABIs. INTERVENTIONS: Observational recordings. MAIN OUTCOME MEASURES: Of the 89 patients meeting inclusion criteria, 7 patients underwent 3T MRI, with a total of 39 scans done. Three patients had 1 scan each, one patient had 4 scans, one patient had 5 scans, one patient had 6 scans, and one patient had 21 scans. The mean time between ABI placement and first 3 T scan was 118 ±â€Š73 months. The most common indication for imaging was surveillance of NF2 lesions. The most frequent scans were MRI brain (25.6%), followed by MRI of cervical (15%), thoracic (15%) and lumbar (15%) spine, and MRI IAC (8%). There were no reported complications for any of the scans. No scans were interrupted due to patient discomfort. There were no device malfunctions. CONCLUSIONS: 3 T MRIs are safe in patients with ABIs as long as the magnet is removed. It is recommended that the magnet be removed at the time of implantation in all NF2 patients, who require frequent surveillance.