NF2-related schwannomatosis (NF2) is a genetic syndrome characterized by the growth of benign tumors in the nervous system, particularly bilateral vestibular schwannomas, meningiomas, and ependymomas. This review consolidates the current knowledge on NF2 syndrome, emphasizing the molecular pathology associated with the mutations in the gene of the same name, the NF2 gene, and the subsequent dysfunction of its product, the Merlin protein. Merlin, a tumor suppressor, integrates multiple signaling pathways that regulate cell contact, proliferation, and motility, thereby influencing tumor growth. The loss of Merlin disrupts these pathways, leading to tumorigenesis. We discuss the roles of another two proteins potentially associated with NF2 deficiency as well as Merlin: Yes-associated protein 1 (YAP), which may promote tumor growth, and Raf kinase inhibitory protein (RKIP), which appears to suppress tumor development. Additionally, this review discusses the efficacy of various treatments, such as molecular therapies that target specific pathways or inhibit neomorphic protein-protein interaction caused by NF2 deficiency. This overview not only expands on the fundamental understanding of NF2 pathophysiology but also explores the potential of novel therapeutic targets that affect the clinical approach to NF2 syndrome.

BACKGROUND: NF2-related schwannomatosis (NF2-SWN, formerly called neurofibromatosis type 2) is a tumor predisposition syndrome that is manifested by multiple vestibular schwannomas, nonvestibular schwannomas, meningiomas, and ependymomas. The condition is relentlessly progressive with no approved therapies. On the basis of preclinical activity of brigatinib (an inhibitor of multiple tyrosine kinases) in NF2-driven nonvestibular schwannoma and meningioma, data were needed on the use of brigatinib in patients with multiple types of progressive NF2-SWN tumors.
METHODS: In this phase 2 platform trial with a basket design, patients who were 12 years of age or older with NF2-SWN and progressive tumors were treated with oral brigatinib at a dose of 180 mg daily. A central review committee evaluated one target tumor and up to five nontarget tumors in each patient. The primary outcome was radiographic response in target tumors. Key secondary outcomes were safety, response rate in all tumors, hearing response, and patient-reported outcomes.
RESULTS: A total of 40 patients (median age, 26 years) with progressive target tumors (10 vestibular schwannomas, 8 nonvestibular schwannomas, 20 meningiomas, and 2 ependymomas) received treatment with brigatinib. After a median follow-up of 10.4 months, the percentage of tumors with a radiographic response was 10% (95% confidence interval [CI], 3 to 24) for target tumors and 23% (95% CI, 16 to 30) for all tumors; meningiomas and nonvestibular schwannomas had the greatest benefit. Annualized growth rates decreased for all tumor types during treatment. Hearing improvement occurred in 35% (95% CI, 20 to 53) of eligible ears. Exploratory analyses suggested a decrease in self-reported pain severity during treatment (-0.013 units per month; 95% CI, -0.002 to -0.029) on a scale from 0 (no pain) to 3 (severe pain). No grade 4 or 5 treatment-related adverse events were reported.
CONCLUSIONS: Brigatinib treatment resulted in radiographic responses in multiple tumor types and clinical benefit in a heavily pretreated cohort of patients with NF2-SWN. (Funded by the Children\'s Tumor Foundation and others; INTUITT-NF2 ClinicalTrials.gov number, NCT04374305.).

Neurofibromatosis Type II (NFII) is a genetic condition caused by loss of the NF2 gene, resulting in activation of the YAP/TAZ pathway and recurrent Schwann cell tumors, as well as meningiomas and ependymomas. Unfortunately, few pharmacological options are available for NFII. Here, we undertake a genome-wide CRISPR/Cas9 screen to search for synthetic-lethal genes that, when inhibited, cause death of NF2 mutant Schwann cells but not NF2 wildtype cells. We identify ACSL3 and G6PD as two synthetic-lethal partners for NF2, both involved in lipid biogenesis and cellular redox. We find that NF2 mutant Schwann cells are more oxidized than control cells, in part due to reduced expression of genes involved in NADPH generation such as ME1. Since G6PD and ME1 redundantly generate cytosolic NADPH, lack of either one is compatible with cell viability, but not down-regulation of both. Since genetic deficiency for G6PD is tolerated in the human population, G6PD could be a good pharmacological target for NFII.

BACKGROUND: Programmed death-ligand 1 (PD-L1) expression is an immune evasion mechanism that has been demonstrated in many tumors and is commonly associated with a poor prognosis. Over the years, anti-PD-L1 agents have gained attention as novel anticancer therapeutics that induce durable tumor regression in numerous malignancies. They may be a new treatment choice for neurofibromatosis type 2 (NF2) patients.
OBJECTIVE: The aims of this study were to detect the expression of PD-L1 in NF2-associated meningiomas, explore the effect of PD-L1 downregulation on tumor cell characteristics and T-cell functions, and investigate the possible pathways that regulate PD-L1 expression to further dissect the possible mechanism of immune suppression in NF2 tumors and to provide new treatment options for NF2 patients.
RESULTS: PD-L1 is heterogeneously expressed in NF2-associated meningiomas. After PD-L1 knockdown in NF2-associated meningioma cells, tumor cell proliferation was significantly inhibited, and the apoptosis rate was elevated. When T cells were cocultured with siPD-L1-transfected NF2-associated meningioma cells, the expression of CD69 on both CD4+ and CD8+ T cells was partly reversed, and the capacity of CD8+ T cells to kill siPD-L1-transfected tumor cells was partly restored. Results also showed that the PI3K-AKT-mTOR pathway regulates PD-L1 expression, and the mTOR inhibitor rapamycin rapidly and persistently suppresses PD-L1 expression. In vivo experimental results suggested that anti-PD-L1 antibody may have a synergetic effect with the mTOR inhibitor in reducing tumor cell proliferation and that reduced PD-L1 expression could contribute to antitumor efficacy.
CONCLUSIONS: Targeting PD-L1 could be helpful for restoring the function of tumor-infiltrating lymphocytes and inducing apoptosis to inhibit tumor proliferation in NF2-associated meningiomas. Dissecting the mechanisms of the PD-L1-driven tumorigenesis of NF2-associated meningioma will help to improve our understanding of the mechanisms underlying tumor progression and could facilitate further refinement of current therapies to improve the treatment of NF2 patients.

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.

听觉脑干植入（auditory brainstem implant，ABI）是耳蜗和蜗神经病变而无法接受人工耳蜗植入的重度和极重度感音神经性聋患者重建听觉的唯一有效疗法。近年来，ABI逐渐成为一种安全有效的技术。本文就ABI的发展史、应用现状、影响疗效的因素、局限性以及发展前景等方面进行概述。.

OBJECTIVE: Distinguishing between sporadic and germline/mosaic NF2-related schwannomatosis is important to ensure that patients have appropriate long-term care. With this report, we describe a unique case of a patient with 4 ipsilateral schwannomas and identify a combination of sequencing modalities that can accurately diagnose mosaic NF2-related schwannomatosis.
METHODS: We present a 32-year-old woman with a familial history of vestibular schwannoma in her father and right-sided schwannomas involving the apical and basal turns of cochlea, lateral semicircular canal, and internal auditory canal (IAC). Genetic analysis of blood and frozen tissue from 2 tumors (intralabyrinthine and IAC tumors) was performed using next-generation sequencing (NGS), multiplex ligation-dependent probe amplification (MLPA), and optical genome mapping (OGM).
RESULTS: Germline testing for NF2, LZTR1, and SMARCB1 was negative. Tumor genetic testing revealed a shared NF2 pathogenic variant between the 2 tumors (\"first hit\") but distinct \"second hit\" NF2 variants, including mosaic loss of chromosome 22 in the IAC tumor seen only with OGM, consistent with mosaic NF2-related schwannomatosis.
CONCLUSIONS: Multimodality sequencing, including NGS, MLPA, and OGM, was required to ensure appropriate diagnosis of mosaic NF2-related schwannomatosis in this patient. A similar approach can be used for other patients with multiple ipsilateral tumors and suspected tumor predisposition.

NF2-related schwannomatosis (NF2-SWN) is a rare genetic disorder and is associated with progressive morbidities. This study aimed to investigate the relationship between NF2-SWN disease severity, health-related Quality of Life (QoL), and mental health aspects of patients. Standardised questionnaires assessing mental health problems (symptoms of depression, anxiety, and somatic burden), psychological factors (resilience, loneliness, and personality functioning), and health-related QoL were administered to 97 patients with NF2-SWN. The results of these questionnaires were compared with physician-rated disease severity. Questionnaires were completed by 77 patients. Physician-rated disease severity scores were available for 55 patients. NF2-SWN patients showed a high prevalence of clinically relevant symptoms of depression (30%), anxiety (16%), and somatic burden (32%). Almost all variables showed moderate to high correlations with NF2-SWN-related QoL. NF2-SWN-related QoL was associated with physician-reported disease severity (r = 0.614). In the stepwise hierarchical linear regression analysis, a significant model with four predictors (disease severity type, depression symptoms, personality functioning, and gender) explained 64% of the variance in NF2-SWN-related QoL. Our results showed a strong association between NF2-SWN-related QoL and depression symptoms. Moreover, personality functioning is an important influencing factor, representing a modifiable construct that can be targeted by prevention programs or psychotherapy.

Neurofibromatosis type 2 (NF2) is a rare autosomal dominant disease (frequency 1 in 25-90 000) characterized by the formation of tumors of the central nervous system due to a mutation in the NF2 gene on chromosome 22q12. Bilateral vestibular schwannomas are recognized as absolute diagnostic criteria of NF2 and occur in 95% of patients, are accompanied by hearing impairment, manifest at the age of 18-24 years. Skin manifestations can precede vestibular schwannomas for several years and predict the course of the disease: neurofibromas, cafe-au-lait macules, hypopigmented spots, recently described mesh capillary malformations. Despite the benign nature of schwannomas, they can lead to hearing loss, vestibular dysfunction, facial nerve paralysis, gait disorders, pain and convulsions, there is a risk of early death from compression of the brain stem. The probability of progressive hearing loss is partly determined by the type of mutation. We described a clinical case of NF2 in a 21-year-old patient with bilateral vestibular schwannomas without hearing loss, whose skin examination by ENT specialist revealed this disease. The importance of the presented observation is that the doctor should assume neurofibromatosis type 2 in a young patient with bilateral vestibular schwannomas. It is necessary to undertake a further examination of this patient, including: skin examination for the identification of characteristic neurofibromas and cafe-au-lait macules, consultation with an ophthalmologist, neurologist, MRI of the brain and spinal cord with contrast, genetic analysis - for timely initiation of therapy that prevents hearing loss and vestibular disorders.
Нейрофиброматоз 2-го типа (НФ2) — редкое аутосомно-доминантное заболевание (частота 1 случай на 25—90 000 населения), характеризующееся образованием опухолей центральной нервной системы вследствие мутации в гене NF2 на хромосоме 22q12. Двусторонние вестибулярные шванномы признаны абсолютным диагностическим критерием НФ2, они возникают у 95% больных НФ2, сопровождаются нарушением слуха, манифестируют в возрасте 18—24 лет. Кожные проявления могут предшествовать вестибулярным шванномам на несколько лет и прогнозировать течение заболевания: нейрофибромы, пятна цвета кофе с молоком, гипопигментированные пятна, описанные недавно сетчатые капиллярные мальформации. Несмотря на доброкачественный характер опухолей, они могут привести к потере слуха, вестибулярной дисфункции, параличу лицевого нерва, нарушению походки, болям и судорогам, существует риск ранней смерти от сдавления ствола головного мозга. Вероятность прогрессирования потери слуха частично определяется типом мутации. Описан клинический случай НФ2 у девушки 21 года с двусторонними вестибулярными шванномами без нарушений слуха, осмотр кожи которой оториноларингологом позволил выявить заболевание. Важность представленного наблюдения в том, что врач, встретившийся с наличием двусторонних неврином слуховых нервов у молодого пациента без нарушения слуха, должен предположить нейрофиброматоз 2-го типа и назначить дальнейшее тщательное обследование данного пациента, включающее: осмотр кожи на предмет выявления характерных нейрофибром и пятен, консультацию офтальмолога, невролога, магнитно-резонансную томографию головного и спинного мозга с контрастом, генетический анализ — для своевременного выбора и начала терапии, предотвращающей снижение слуха и вестибулярные нарушения.

OBJECTIVE: To evaluate long-term hearing outcomes following cochlear implantation in patients with neurofibromatosis type 2 and ipsilateral vestibular schwannoma.
METHODS: Retrospective study.
METHODS: Tertiary general hospital.
METHODS: Twenty-two patients undergoing cochlear implantation between 2004 and 2018 with at least 1 year of follow-up were included. Patients were categorized as \"users\" or \"nonusers\" of their cochlear implant (CI). For users, speech perception (disyllabic words) without lip-reading was assessed in quiet conditions 1-year postimplantation, and annually thereafter. CI users were classified into 2 groups on the basis of speech intelligibility (≥40% or <40%). Demographic data, treatment options, and tumor size were also recorded.
RESULTS: One year after implantation, 16 (73%) patients used their CI daily. Twelve of these patients had a speech intelligibility ≥40% (mean: 74 ± 21.9%). Three had a Koos stage IV tumor. At the last visit (mean duration of follow-up: 6 ± 5 years), 12 of these 16 patients were still using their implant daily, and 6 had a speech intelligibility ≥40%. No predictive factors for good performance at 1 year or performance stability were identified.
CONCLUSIONS: Neurofibromatosis type 2 is a complex disease profoundly affecting patient quality of life, and cochlear implantation should always be considered on a case-by-case basis. In some individuals, cochlear implantation can provide good speech intelligibility for extended periods, even posttreatment or in cases of large tumors.