NF2-related schwannomatosis (NF2-SWN) is a rare genetic disorder characterized by bilateral vestibular schwannomas. NF2-SWN represents a difficult management problem with most patients facing substantial morbidity and reduced life expectancy. Gene therapy involves replacing a faulty gene or adding a new gene in an attempt to cure disease or improve the patient's condition. Several studies of gene therapy for NF2-SWN have utilized adeno-associated viral vector serotype-1 (AAV1) to deliver apoptosis-inducing enzyme, the pore-forming protein gasdermin-D, apoptosis-associated speck-like protein containing a caspase recruitment domain, and functional merlin causing schwannoma regression in a xenograft mouse model. These studies support the potential therapeutic efficacy of gene therapy against NF2-SWN. Currently, gene therapy approaches primarily include bystander-killing effect by inducing immune responses, gene replacement or augmentation therapy, and gene knockdown and replacement combination approach through genome-editing technology. Although these gene therapeutic strategies have shown potential in preclinical animal model studies, they still face many specific challenges apart from the traditional challenges in gene therapy, such as immunogenicity, delivery vector, manufacturing, and long-term effects of treatments. In this article, we discuss the current understanding and future directions of gene therapy and genome-editing for schwannoma in NF2-SWN.

In this review, we aim to provide a survey of hereditable tumor predisposition syndromes with a Mendelian inheritance pattern and ocular involvement. We focus our discussion on von Hippel-Lindau disease, neurofibromatosis type 1, NF2-related schwannomatosis, tuberous sclerosis complex, retinoblastoma, and the BAP1 tumor predisposition syndrome. For each of the six diseases, we discuss the clinical presentation and the molecular pathophysiology. We emphasize the genetics, current research models, and therapeutic developments. After reading each disease section, readers should possess an understanding of the clinical presentation, genetic causes and inheritance patterns, and current state of research in disease modeling and treatment.

Neurofibromatosis type 2 (NF2) is an autosomal dominant disease characterized by bilateral vestibular schwannomas and other central nervous tumors such as meningiomas and spinal ependymomas. Symptoms vary according to the age at diagnosis and the location of these tumors. The diagnostic criteria of NF2 have been regularly revised and recently updated in 2022 with a new nomenclature "NF2-related schwannomatosis" to differentiate NF2 from other schwannoma predisposing disorders, such as SMARCB1 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily b, member 1)-, LZTR1 (leucine zipper-like transcription regulator 1)-, and 22q-related schwannomatosis. Addition to the clinical features, genetic testing for pathogenic variants in these genes became an important essence to support diagnosis of NF2 and other schwannomatosis, including mosaic conditions.

Pathogenic variants and allele-loss of the NF2 gene with Merlin loss as consequence is the driving genetic event for vestibular schwannoma development. Our knowledge about the pathogenic NF2 variants in sporadic vestibular schwannoma is insufficient. Therefore, we analyzed a cohort of sporadic vestibular schwannomas by panel-sequencing.

Forty-one sporadic vestibular schwannomas from 26 male and 15 female patients were included. DNA from tumor tissues was sequenced with a custom panel for the NF2 and LZTR1 genes. Allele-loss of the NF2 locus was also examined using multiplex-ligation-dependent probe-amplification. These genetic data were correlated with clinical parameters including hearing, tumor extension and growth.

Among the 41 tumor samples, 34 had one pathogenic variant or an allele-loss of NF2 gene and one tumor showed a pathogenic variant in the LZTR1 gene. Allele frequencies of the total of 46 pathogenic variants varied from 0.05 to 0.82, and none of these variants was found in blood. For 6 tumors, no pathogenic variants were found while 4 of them had allele-loss of the NF2 gene. When the tumors were divided into 3 groups according to the counts of inactivating events (pathogenic variants and allele loss), the clinical parameters including hearing, tumor structure in MRI, tumor growth, tumor size and postoperative facial function did not differ significantly.

There was no correlation between phenotype and genetic alterations of the NF2 or LZTR1 gene in sporadic schwannomas. Genetic inactivating events are the precondition for the development of vestibular schwannomas but do not influence their growth and other features.

Vestibular schwannomas are benign tumors on the vestibular nerve caused by bi-allelic inactivation of the NF2 tumor suppressor gene. This study identifies sporadic vestibular schwannomas with two pathogenic NF2-variants in each of them and compares the allele-frequencies of the two variants.

Sporadic vestibular schwannomas were subjected to genetic analysis regarding pathogenic variants in the NF2 gene using targeted sequencing. Cases with two different pathogenic NF2 variants were identified and the allele-frequencies of the two variants in each tumor were compared.

Nine tumors were identified which had two different pathogenic NF2 variants in each of them. For all the 9 tumors, the allele-frequencies of the two pathogenic NF2 variants in each were nearly identical.

This finding may indicate that the two inactivating NF2 variants occurred shortly after one another, leaving no room for the Schwann cells with one inactivating NF2 variant to expand. Alternatively, the variants occurred in a late development stage whereas Schwann cells do not expand anymore or expand only extremely slowly. In addition, our finding suggests that Schwann cells with one inactivating variant do not gain a growth advantage.

NF2-related schwannomatosis (NF2) is a rare genetic disease that significantly impacts patients' quality of life due to the occurrence of multiple tumors within the nervous system. The high clinical heterogeneity in tumor number, location, and size makes predicting each patient's clinical outcome impossible. Genetic investigation can be crucial in diagnosis, prognosis, and management. This study aims to explore the genetic basis of eight Iranian patients with NF2.

To investigate potential genetic causes, we conducted comprehensive medical evaluations, whole-exome sequencing (WES), and multiplex ligation-dependent probe amplification (MLPA) on the probands of each family. The identified variants in the family members were confirmed using Sanger sequencing and MLPA. The variants were classified according to the American College of Medical Genetics and Genomics guidelines. Seven distinct variants linked to the NF2 gene were identified as causes of NF2-related schwannomatosis in these patients, among which the c.862_863del frameshift was a novel variant not previously reported. Seventy-five percent of these mutations were de novo. The mean diagnostic age was lower among patients with truncating mutations compared to other patients.

This study identified a novel mutation in the NF2 gene and showed a high rate of de novo mutations in Iranian NF2 patients. Moreover, patients with truncating mutations experienced earlier symptoms than others. Comparing the manifestations of each patient with similar mutations to previous reports expands our understanding of the phenotype of NF2. These results can provide more comprehensive insights into prognosis and early interventions.

NF2-related Schwannomatosis (NF2 SWN) is a rare disease characterised by the growth of multiple nervous system neoplasms, including bilateral vestibular schwannoma (VS). VS tumours are characterised by extensive leucocyte infiltration. However, the immunological landscape in VS and the spatial determinants within the tumour microenvironment that shape the trajectory of disease are presently unknown. In this study, to elucidate the complex immunological networks across VS, we performed imaging mass cytometry (IMC) on clinically annotated VS samples from NF2 SWN patients. We reveal the heterogeneity in neoplastic cell, myeloid cell and T cell populations that co-exist within VS, and that distinct myeloid cell and Schwann cell populations reside within varied spatial contextures across characteristic Antoni A and B histomorphic niches. Interestingly, T-cell populations co-localise with tumour-associated macrophages (TAMs) in Antoni A regions, seemingly limiting their ability to interact with tumorigenic Schwann cells. This spatial landscape is altered in Antoni B regions, where T-cell populations appear to interact with PD-L1+ Schwann cells. We also demonstrate that prior bevacizumab treatment (VEGF-A antagonist) preferentially reduces alternatively activated-like TAMs, whilst enhancing CD44 expression, in bevacizumab-treated tumours. Together, we describe niche-dependent modes of T-cell regulation in NF2 SWN VS, indicating the potential for microenvironment-altering therapies for VS.

Neurofibromatosis type 2 (NF2) is a neurocutaneous syndrome characterized by the development of multiple benign tumors, including vestibular schwannomas and meningiomas, in the nervous system. Seizures are rarely associated with NF2, and the lethality of this condition typically stems from tumor growth and related complications, leaving the incidence of sudden death largely unreported. This report discribes a 16-year-old girl with a history of NF2 and occasional seizures who died unexpectedly in a bathtub. Postmortem examination revealed multiple tumors in the cranial nerves (schwannoma), under the dura mater (meningioma), and in the upper cervical cord (neurofibroma). Typical signs of drowning, such as foam in the airways, were not present. Upon histological examination, meningioangiomatosis (MA) was observed in the cerebellum and the cerebral cortex, specifically in the frontal lobe, temporal lobe, and insula. The MA extended into the white matter, exhibiting severe perivascular fibrosis and cystic dilatation of perivascular spaces in the frontal lobe and cerebellum. Additionally, glial microhamartomas were detected both around and separate from the MA. These autopsy findings suggest that sudden unexpected death in epilepsy (SUDEP) was the cause of death rather than drowning. Moreover, while NF2-associated MA is typically asymptomatic, unlike sporadic MA, which commonly presents with seizures, the spread of MA into the white matter is unusual in an NF2 patient. Therefore, MA with the white matter involvement could have been a factor causing the seizures and the occurrence of SUDEP in this NF2 patient.

Linear and volumetric analysis are the typical methods to measure tumor size. 3D volumetric analysis has risen in popularity; however, this is very time and labor intensive limiting its implementation in clinical practice. This study aims to show that an AI-led approach can shorten the length of time required to conduct 3D volumetric analysis of VS tumors and improve image processing accuracy. From Yale New Haven Hospital and public patient recruitment, 143 MRIs were included in the ground truth dataset. To create the tumor models for the ground truth dataset, an image processing software (Simpleware ScanIP, Synopsys) was used. The helper (DPP V1.0) was trained using proprietary AI- and ML-based algorithms and information. A proof-of-concept AI model achieved a mean DICE score of 0.76 (standard deviation 0.21). After the final testing stage, the model improved to a final mean DICE score of 0.88 (range 0.74-0.93, standard deviation 0.04). Our study has demonstrated an efficient, accurate AI for 3D volumetric analysis of vestibular schwannomas. The use of this AI will enable faster 3D volumetric analysis compared to manual segmentation. Additionally, the overlay function would allow visualization of growth patterns. The tool will be a method of assessing tumor growth and allow clinicians to make more informed decisions.

NF2-related schwannomatosis (NF2) is a tumor predisposition syndrome that typically presents with bilateral vestibular schwannomas, together with other intracranial and spinal schwannomas, meningiomas, and/or ependymomas. Bevacizumab, a VEGF inhibitor, has the potential to decrease schwannoma volume and improve hearing in adults, but the literature on the effects in children is sparse. This narrative review aims to evaluate the use of bevacizumab in pediatric NF2 patients, focusing on hearing, tumor progression, and toxicity.

A literature review was conducted following PRISMA guidelines. Articles were searched in PubMed, Embase, Web of Science, Cochrane Library, Emcare, and Academic Search Premier on 18 July 2024. Inclusion criteria were patients ≤ 18 years, diagnosed with NF2 and treated with bevacizumab. Two authors independently assessed the quality of the evidence and extracted relevant data from the included articles.

Seventeen articles including 62 pediatric NF2 patients met the inclusion criteria. Studies varied widely in treatment regimens and outcome parameters. Tumor regression was reported in 6/56 patients (11%) and 38/56 (68%) remained stable. Hearing improved in 15/45 patients (33%) and did not further deteriorate in 27/45 (60%). An improvement in other symptoms was seen in 6/29 patients (28%). Toxicity was reported in five studies, documenting 13 adverse events in 28 patients ranging from grade 1 to grade 3. Treatment was discontinued in both patients who experienced grade 3 toxicity.

Bevacizumab seems to be a viable treatment option for pediatric NF2 patients. Tumor regression or stabilization is achieved in the majority of patients (77%). Moreover, a considerable number of pediatric patients experience hearing stabilization or improvement (93%). Bevacizumab appears to be relatively well tolerated, offering a non-invasive therapeutic option for children with NF2 suffering from progressive vestibular schwannomas and hearing loss.

Neurofibromatosis type 2 (NF2) is a rare autosomal dominant syndrome with a predisposition to the development of central nervous system tumors, ophthalmic manifestations, and dermatological lesions. The latter are present in 70-95% of patients and can precede the evolution of other tumors. However, they are not included in the diagnostic criteria and are frequently undervalued during follow-up.

An observational cross-sectional study characterizing cutaneous lesions in a cohort of NF2 patients was carried out. Dermatological examinations were performed, and lesions were classified into neural cutaneous tumors (superficial, SNCT, and deep, DNCT), hyperpigmented patches (HyperP), and hypopigmented patches (HypoP). The Dermatology Life Quality Index (DLQI) and EQ-5D questionnaires were applied to evaluate the impact on quality of life.

Nineteen patients with a mean age of 36 years were included. Sixteen (84%) patients had cutaneous lesions, mostly developed 10 or more years before the diagnosis. SNCT, DNCT, and HyperP showed similar frequencies (58%). HypoP were observed in only one patient. HyperP developed, on average, earlier than NCT (9.6 vs. 16.5 SNCT, 17.0 DNCT; years). The excised lesions had different histological patterns, including neurofibromas, schwannomas, and a hybrid tumor. Most patients reported a low impact of cutaneous manifestations on the quality of life (DLQI 0 or 1).

Cutaneous lesions are frequent in NF2 and may precede the diagnosis by several years. Their identification is important to establish the diagnosis earlier and potentially reduce morbidity and mortality.

Cancer predisposition syndromes are genetic disorders that significantly raise the risk of developing malignancies. Although the malignant manifestations of cancer predisposition syndromes are well-studied, recognizing their non-malignant features is crucial for early diagnosis, especially in children and adolescents.

A comprehensive literature search was conducted using the PubMed database, focusing on non-malignant manifestations of cancer predisposition syndromes in children and adolescents. Key sources included the Clinical Cancer Research pediatric oncology series and ORPHANET. Studies that described clinical signs and symptoms affecting specific organ systems were included.

Non-malignant dermatological features often serve as early indicators of cancer predisposition syndromes, including café-au-lait spots in Neurofibromatosis Type 1 and facial angiofibromas in Tuberous Sclerosis Complex. Neurological and developmental anomalies such as cerebellar ataxia in ataxia-telangiectasia and intellectual disabilities in neurofibromatosis type 1 and tuberous sclerosis complex are significant indicators. Growth and metabolic anomalies are also notable, including overgrowth in Beckwith-Wiedemann syndrome and growth hormone deficiency in neurofibromatosis Type 1. In addition, facial anomalies, ocular manifestations, hearing issues, and thyroid anomalies are prevalent across various cancer predisposition syndromes. For instance, hearing loss may be significant in neurofibromatosis Type 2, while thyroid nodules are common in PTEN hamartoma tumor syndrome and DICER1 syndrome. Cardiovascular, abdominal, musculoskeletal, pulmonary, genitourinary manifestations, and prenatal deviations further complicate the clinical picture.

Recognizing non-malignant features of cancer predisposition syndromes is essential for early diagnosis and management. This organ-specific overview furthers awareness among healthcare providers, facilitating timely genetic counseling, surveillance programs, and preventive measures, ultimately improving patient outcomes.

Degeneration of cochlear spiral ganglion neurons (SGNs) leads to irreversible sensorineural hearing loss (SNHL), as SGNs lack regenerative capacity. Although cochlear glial cells (GCs) have some neuronal differentiation potential, their specific identities remain unclear. This study identifies a distinct subpopulation, Frizzled10 positive (FZD10+) cells, as an important type of GC responsible for neuronal differentiation in mouse cochlea. FZD10 + cells can differentiate into various SGN subtypes in vivo, adhering to natural proportions. Wnt signaling enhances the ability of FZD10 + cells to function as neural progenitors and increases the neuronal excitability of the FZD10-derived neurons. Single-cell RNA sequencing analysis characterizes FZD10-derived differentiating cell populations, while crosstalk network analysis identifies multiple signaling pathways and target genes influenced by Wnt signaling that contribute to the function of FZD10 + cells as neural progenitors. Pseudotime analysis maps the differentiation trajectory from proliferated GCs to differentiating neurons. Further experiments indicate that glypican 6 (GPC6) may regulate this neuronal lineage, while GPC6 deficiency diminishes the effects of Wnt signaling on FZD10-derived neuronal differentiation and synapse formation. These findings suggest the critical role of Wnt signaling in the neuronal differentiation derived from cochlear FZD10 + cells and provide insights into the mechanisms potentially involved in this process.

Despite their similar nomenclature, Neurofibromatosis type 1 (NF1) and "Neurofibromatosis type 2" are discrete and clinically distinguishable entities. The name of "neurofibromatosis type 2" has been changed to NF2-related schwannomatosis, to reflect the fact that neurofibromas do not occur in this syndrome and therefore the name "Neurofibromatosis" is factually incorrect. Furthermore, multiple schwannomas, a hallmark feature of NF2, can also occur in patients with mutations in genes including SMARCB1 and LZTR1, all exhibiting overlapping clinical features. Current understanding suggests that schwannomatosis (SWN) encompasses a range of clinical presentations consisting of clearly defined, separate subtypes which share a common phenotype of schwannomas. Recognizing these newly emerging subtypes, the International Consensus Group on Neurofibromatosis Diagnostic Criteria (I-NF-DC) proposed a revised nomenclature for NF2 and related disorders in 2022. This review article focuses on this critical update in diagnostic terminology, highlighting the key gene-related SWN subtypes relevant to neuroradiologists. By emphasizing molecular testing alongside clinical features, the revised system facilitates a more precise diagnosis, potentially paving the way for personalized treatment strategies. Additionally, the flexible structure accommodates future discoveries of genes associated with SWN.

Traumatic brain injury (TBI) is a critical condition associated with cognitive impairments, including dementia. This study is aimed to construct a long noncoding RNA (lncRNA)-microRNA (miRNA)-messenger RNA (mRNA) network based on bioinformatics analysis and explore molecular mechanisms underlying post-TBI dementia.

GSE104687 and GSE205661 datasets were downloaded from Gene Expression Omnibus database. Molecular Signatures Database (MSigDB) was used to search oxidative stress-, metabolism- and immune-related genes as the target gene datasets. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes were carried out for functional annotation and enrichment analysis. A TBI mouse model was built to validate the expression of NF2, PLXNA2, NCBP2 and U2SURP in brain tissues.

A total of 7 differentially expressed lncRNAs (DElncRNAs) and 191 DEmRNAs were obtained. Subsequent to differential expression (DE) analysis, a lncRNA-miRNA-mRNA network was established. Notably, 13 key DEmRNAs were identified, potentially playing pivotal roles in the pathogenesis of TBI-induced dementia. By comparing the target gene datasets with 13 DEmRNAs, we identified 4 target genes that overlap with the 13 DEGmRNAs, namely NF2, PLXNA2, NCBP2 and U2SURP. Functional enrichment analysis highlighted the involvement of neuronal projections in the dementia-enriched cluster, while the protective cluster showed associations with protein synthesis and ubiquitination pathways. Importantly, we explored potential drug interventions based on interactions with the above 4 target genes. Additionally, drug interaction prediction showed that NF2 could interact with SELUMETINIB, EVEROLIMUS and TEMSIROLIMUS.

Our study provides insights into the complex regulatory networks underlying post-TBI dementia and suggests a potential role for three classes of drugs in managing dementia symptoms in TBI-induced dementia.

Meningiomas are the most common primary intracranial tumors in adults and are increasing in incidence due to the aging population and increased access to neuroimaging. While most exhibit nonmalignant behavior, a subset of meningiomas are biologically aggressive and are associated with treatment resistance, resulting in significant neurologic morbidity and even mortality. In recent years, meaningful advances in our understanding of the biology of these tumors have led to the incorporation of molecular biomarkers into their grading and prognostication. However, unlike other central nervous system (CNS) tumors, a unified molecular taxonomy for meningiomas has not yet been established and remains an overarching goal of the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy-Not Official World Health Organization (cIMPACT-NOW) working group. Additionally, clinical equipoise still remains on how specific meningioma cases and patient populations should be optimally managed. To address these existing gaps, members of the International Consortium on Meningiomas including field-leading experts, have prepared this comprehensive consensus narrative review directed toward clinicians, researchers, and patients. Included in this manuscript are detailed overviews of proposed molecular classifications, novel biomarkers, contemporary treatment strategies, trials on systemic therapies, health-related quality-of-life studies, and management strategies for unique meningioma patient populations. In each section, we discuss the current state of knowledge as well as ongoing clinical and research challenges to road map future directions for further investigation.

Eosinophilic solid and cystic renal cell carcinoma is now defined in the 5th edition of the 2022 World Health Organization classification of urogenital tumors.

To perform morphologic, immunohistochemical, and preliminary genetic studies about this new entity in China for the purpose of understanding it better.

The study includes 18 patients from a regional tertiary oncology center in northern China (Tianjin, China). We investigated the clinical and immunohistochemical features of these cases.

The mean age of patients was 49.6 years, and the male to female ratio was 11:7. Macroscopically, 1 case had the classic cystic and solid appearance, whereas the others appeared purely solid. Microscopically, all 18 tumors shared a similar solid and focal macrocystic or microcystic growth pattern, and the cells were characterized by voluminous and eosinophilic cytoplasm, along with coarse amphophilic stippling. Immunohistochemically, most of the tumors had a predominant cytokeratin (CK) 20-positive feature, ranging from focal cytoplasmic staining to diffuse membranous accentuation. Initially, we separated these cases into different immunohistochemical phenotypes. Group 1 (7 of 18; 38.5%) was characterized by positive phospho-4EBP1 and phospho-S6, which can imply hyperactive mechanistic target of rapamycin complex 1 (mTORC1) signaling. Group 2 (4 of 18; 23%) was negative for NF2, probably implying a germline mutation of NF2. Group 3 (7 of 18; 38.5%) consisted of the remaining cases. One case had metastatic spread and exhibited an aggressive clinical course, and we detected cyclin-dependent kinase inhibitor 2A (CDKN2A) mutation in this case; other patients were alive and without disease progression.

Our research proposes that eosinophilic solid and cystic renal cell carcinoma exhibits prototypical pathologic features with CK20 positivity and has aggressive potential.

Meningiomas are associated with inactivation of NF2/Merlin, but approximately one-third of meningiomas with favorable clinical outcomes retain Merlin expression. Biochemical mechanisms underlying Merlin-intact meningioma growth are incompletely understood, and non-invasive biomarkers that may be used to guide treatment de-escalation or imaging surveillance are lacking. Here, we use single-cell RNA sequencing, proximity-labeling proteomic mass spectrometry, mechanistic and functional approaches, and magnetic resonance imaging (MRI) across meningioma xenografts and patients to define biochemical mechanisms and an imaging biomarker that underlie Merlin-intact meningiomas. We find Merlin serine 13 (S13) dephosphorylation drives meningioma Wnt signaling and tumor growth by attenuating inhibitory interactions with β-catenin and activating the Wnt pathway. MRI analyses show Merlin-intact meningiomas with S13 phosphorylation and favorable clinical outcomes are associated with high apparent diffusion coefficient (ADC). These results define mechanisms underlying a potential imaging biomarker that could be used to guide treatment de-escalation or imaging surveillance for patients with Merlin-intact meningiomas.

The blood vessel lumen is an extremely rare location for a benign peripheral nerve sheath tumor like schwannoma. Less than 10 cases have been previously reported. In this report, we present a case of a 68-year-old woman who had a soft tissue nodule at the posterior calf of her left leg during a physical examination. Pathological examination was performed after complete surgical excision. The patient underwent follow-up for 12 months after surgery without evidence of recurrence or any other complication. This is the first case of intravascular schwannoma reported as a cause of vein obstruction. Microscopically, the tumor was composed of Schwann spindle cells that were immunoreactive for S100 protein and SOX10. This tumor was surrounded by a well-defined vascular smooth muscle wall. Prospective series are required to improve the knowledge on the underlying mechanisms of intravascular schwannoma development.

NF2-related schwannomatosis (NF2; previously termed neurofibromatosis type 2) is a tumor-prone disorder characterized by development of multiple schwannomas and meningiomas. The diagnostic criteria of NF2 have been regularly revised. Clinical criteria for NF2 were first formulated at the National Institutes of Health Consensus Conference in 1987 and revised in 1990. Revised criteria were also proposed by the Manchester group in 1992 and by the National Neurofibromatosis Foundation (NNFF) in 1997. The 2011 Baser criteria improved the sensitivity of diagnostic criteria, particularly for patients without bilateral vestibular schwannomas. Revisions to the Manchester criteria were published in 2019, with replacement of "glioma" by "ependymoma," removal of "neurofibroma," addition of an age limit of 70 years for development of vestibular schwannomas, and introduction of molecular criteria, which led to the most widely used criteria. In 2022, the criteria were reviewed and updated by the international committee of NF experts. In addition to changes in diagnostic criteria, the committee recommended the use of "schwannomatosis" as an umbrella term for conditions that predispose to schwannomas. Each type of schwannomatosis was classified by the gene containing the disease-causing pathogenic variant. Molecular data from NF2 patients led to further clarification of the diagnostic criteria for NF2 mosaic phenotypes. Given all these changes, the diagnostic criteria of NF2 may be confusing. Herein, to help healthcare professionals who diagnose NF2 conditions in the clinical setting, we review the historical development of diagnostic criteria.

Schwann cells are vital to development and maintenance of the peripheral nervous system and their dysfunction has been implicated in a range of neurological and neoplastic disorders, including NF2 -related schwannomatosis. We developed a novel human induced pluripotent stem cell (hiPSC) model to study Schwann cell differentiation in health and disease. We performed transcriptomic, immunofluorescence, and morphological analysis of hiPSC derived Schwann cell precursors (SPCs) and terminally differentiated Schwann cells (SCs) representing distinct stages of development. To validate our findings, we performed integrated, cross-species analyses across multiple external datasets at bulk and single cell resolution. Our hiPSC model of Schwann cell development shared overlapping gene expression signatures with human amniotic mesenchymal stem cell (hAMSCs) derived SCs and in vivo mouse models, but also revealed unique features that may reflect species-specific aspects of Schwann cell biology. Moreover, we identified gene co-expression modules that are dynamically regulated during hiPSC to SC differentiation associated with ear and neural development, cell fate determination, the NF2 gene, and extracellular matrix (ECM) organization. By cross-referencing results between multiple datasets, we identified new genes potentially associated with NF2 expression. Our hiPSC model further provides a tractable platform for studying Schwann cell development in the context of human disease.

Meningioma and vestibular schwannoma (VS) are the first and second most common benign central nervous system tumors. The coexistence of VS and meningioma presents a rare clinical scenario, particularly in pediatric patients. This report presents a case of bilateral VS with a cooccurring meningioma in a Nepali child and provides an overview of the literature on this condition.

A 15-year-old male presented with bilateral sensorineural hearing loss, seizures, and neurological deficits and was ultimately diagnosed with concomitant bilateral acoustic neuroma and meningioma. The patient underwent radiosurgery for bilateral VS and nonoperative management of the meningioma. Long-term follow-up revealed symptomatic improvement, emphasizing the importance of a multidisciplinary approach in managing such complex cases. The management of these tumors requires tailored treatment strategies guided by tumor characteristics and associated risks.

Meningioma and VS are common tumors of the central nervous system. Their coexistence is possible in neurofibromatosis type 2 but is exceedingly rare in pediatric age group. The tumors, often coexisting, pose diagnostic challenges. Diagnosis relies on clinical and genetic features, with multidisciplinary management involving various specialists. Treatment aims to preserve function and quality of life, utilizing approaches such as bevacizumab and surgical intervention. The role of radiation therapy remains uncertain. Genetic testing and regular monitoring are vital for early detection and intervention.

The cooccurrence of acoustic neuromas and meningiomas is poorly understood, with limited reported cases and unclear pathophysiological mechanisms. Further research into the genetic and molecular mechanisms underlying the coexistence of these tumors is needed to optimize patient outcomes in this rare clinical entity.

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.

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.

Meningiomas, although mostly benign, can be recurrent and fatal. World Health Organization (WHO) grading of the tumor does not always identify high-risk meningioma, and better characterizations of their aggressive biology are needed. To approach this problem, we combined 13 bulk RNA sequencing (RNA-seq) datasets to create a dimension-reduced reference landscape of 1,298 meningiomas. The clinical and genomic metadata effectively correlated with landscape regions, which led to the identification of meningioma subtypes with specific biological signatures. The time to recurrence also correlated with the map location. Further, we developed an algorithm that maps new patients onto this landscape, where the nearest neighbors predict outcome. This study highlights the utility of combining bulk transcriptomic datasets to visualize the complexity of tumor populations. Further, we provide an interactive tool for understanding the disease and predicting patient outcomes. This resource is accessible via the online tool Oncoscape, where the scientific community can explore the meningioma landscape.

Neurofibromatosis type 2 (NF2)-related schwannomatosis is a rare autosomal dominant monogenic disorder caused by mutations in the NF2 gene. The hallmarks of NF2-related schwannomatosis are bilateral vestibular schwannomas (VS). The current treatment options for NF2-related schwannomatosis, such as observation with serial imaging, surgery, radiotherapy, and pharmacotherapies, have shown limited effectiveness and serious complications. Therefore, there is a critical demand for novel effective treatments. Gene therapy, which has made significant advancements in treating genetic diseases, holds promise for the treatment of this disease. This review covers the genetic pathogenesis of NF2-related schwannomatosis, the latest progress in gene therapy strategies, current challenges, and future directions of gene therapy for NF2-related schwannomatosis.

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.

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.

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.

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.

NF2-related Schwannomatosis (NF2-SWN) is a disease that needs new solutions. The hallmark of NF2-SWN, a dominantly inherited neoplasia syndrome, is bilateral vestibular schwannomas (VSs), which progressively enlarge, leading to sensorineural hearing loss, tinnitus, facial weakness, and pain that translates to social impairment and clinical depression. Standard treatments for growing VSs include surgery and radiation therapy (RT); however, both carry the risk of further nerve damage that can result in deafness and facial palsy. The resultant suffering and debility, in combination with the paucity of therapeutic options, make the effective treatment of NF2-SWN a major unmet medical need. A better understanding of these mechanisms is essential to developing novel therapeutic targets to control tumor growth and improve patients' quality of life. Previously, we developed the first orthotopic cerebellopontine angle mouse model of VSs, which faithfully mimics tumor-induced hearing loss. In this model, we observed that mice exhibit symptoms of ataxia and vestibular dysfunction. Therefore, we further developed a panel of five tests suitable for the mouse VS model and investigated how tumor growth and treatment affect gait, coordination, and motor function. Using this panel of ataxia tests, we demonstrated that both ataxia and motor function deteriorated concomitantly with tumor progression. We further demonstrated that (i) treatment with anti-VEGF resulted in tumor size reduction, mitigated ataxia, and improved rotarod performance; (ii) treatment with crizotinib stabilized tumor growth and led to improvements in both ataxia and rotarod performance; and (iii) treatment with losartan did not impact tumor growth nor ameliorate ataxia or motor function. Our studies demonstrated that these methods, paired with hearing tests, enable a comprehensive evaluation of tumor-induced neurological deficits and facilitate the assessment of the effectiveness of novel therapeutics to improve NF2 treatments.

The association between mutations in susceptibility genes and the occurrence of ovarian cancer has been extensively studied. Previous research has primarily concentrated on genes involved in the homologous recombination repair pathway, particularly BRCA1 and BRCA2. However, a wider range of genes related to the DNA damage response pathways has not been fully explored.

To investigate the mutation characteristics of cancer susceptibility genes in the Chinese ovarian cancer population and the associations between gene mutations and clinical data, this study initially gathered a total of 1171 Chinese ovarian cancer samples and compiled a dataset of germline mutations in 171 genes.

In this study, it was determined that MC1R and PRKDC were high-frequency ovarian cancer susceptibility genes in the Chinese population, exhibiting notable distinctions from those in European and American populations; moreover high-frequency mutation genes, such as MC1R: c.359T>C and PRKDC: c.10681T>A, typically had high-frequency mutation sites. Furthermore, we identified c.8187G>T as a characteristic mutation of BRCA2 in the Chinese population, and the CHEK2 mutation was significantly associated with the early onset of ovarian cancer, while the CDH1 and FAM175A mutations were more prevalent in Northeast China. Additionally, Fanconi anemia pathway-related genes were significantly associated with ovarian carcinogenesis.

In summary, this research provided fundamental data support for the optimization of ovarian cancer gene screening policies and the determination of treatment, and contributed to the precise intervention and management of patients.

To determine the impact of additional genetic screening techniques on the rate of detection of pathogenic variants leading to familial NF2-related schwannomatosis.

We conducted genetic screening of a cohort of 168 second-generation individuals meeting the clinical criteria for NF2-related schwannomatosis. In addition to the current clinical screening techniques, targeted next-generation sequencing (NGS) and multiplex ligation-dependent probe amplification analysis, we applied additional genetic screening techniques, including karyotype and RNA analysis. For characterisation of a complex structural variant, we also performed long-read sequencing analysis.

Additional genetic analysis resulted in increased sensitivity of detection of pathogenic variants from 87% to 95% in our second-generation NF2-related schwannomatosis cohort. A number of pathogenic variants identified through extended analysis had been previously observed after NGS analysis but had been overlooked or classified as variants of uncertain significance.

Our study indicates there is added value in performing additional genetic analysis for detection of pathogenic variants that are difficult to identify with current clinical genetic screening methods. In particular, RNA analysis is valuable for accurate classification of non-canonical splicing variants. Karyotype analysis and whole genome sequencing analysis are of particular value for identification of large and/or complex structural variants, with additional advantages in the use of long-read sequencing techniques.

(1) Background: NF2-related schwannomatosis, characterized by the development of bilateral vestibular schwannomas, often necessitates varied treatment approaches. Bevacizumab, though widely utilized, demonstrates variable effectiveness on hearing and tumor growth. At the same time, (serious) adverse events have been frequently reported. (2) Methods: A single center retrospective study was conducted, on NF2-related schwannomatosis patients treated with bevacizumab from 2013 to 2023, with the aim to assess treatment-related and clinical outcomes. Outcomes of interest comprised hearing, radiologic response, symptoms, and adverse events. (3) Results: Seventeen patients received 7.5 mg/kg bevacizumab for 7.1 months. Following treatment, 40% of the patients experienced hearing improvement, 53%, stable hearing, and 7%, hearing loss. Vestibular schwannoma regression occurred in 31%, and 69% remained stable. Further symptomatic improvement was reported by 41%, stable symptoms by 47%, and worsened symptoms by 12%. Treatment discontinuation due to adverse events was observed in 29% of cases. Hypertension (82%) and fatigue (29%) were most frequently reported, with no occurrences of grade 4/5 toxicities. (4) Conclusion: Supporting previous studies, bevacizumab demonstrated positive effects on hearing, tumor control, and symptoms in NF2-related schwannomatosis, albeit with common adverse events. Therefore, careful consideration of an appropriate management strategy is warranted.

Spinal meningiomas are the most common intradural, extramedullary tumor in adults, yet the least common entity when accounting for all meningiomas spanning the neuraxis. While traditionally considered a benign recapitulation of their intracranial counterpart, a paucity of knowledge exists regarding the differences between meningiomas arising from these two anatomic compartments in terms of histopathologic subtypes, molecular tumor biology, surgical principles, long-term functional outcomes, and recurrence rates. To date, advancements at the bench have largely been made for intracranial meningiomas, including the discovery of novel gene targets, DNA methylation profiles, integrated diagnoses, and alternative systemic therapies, with few exceptions reserved for spinal pathology. Likewise, evolving clinical research offers significant updates to our understanding of guiding surgical principles, intraoperative technology, and perioperative patient management for intracranial meningiomas. Nonetheless, spinal meningiomas are predominantly relegated to studies considering non-specific intradural extramedullary spinal tumors of all histopathologic types. The aim of this review is to comprehensively report updates in both basic science and clinical research regarding intraspinal meningiomas and to provide illustrative case examples thereof, thereby lending a better understanding of this heterogenous class of central nervous system tumors.

NF2-related schwannomatosis (NF2) is characterized by bilateral vestibular schwannomas (VS) often causing hearing and neurologic deficits, with currently no FDA-approved drug treatment. Pre-clinical studies highlighted the potential of mTORC1 inhibition in delaying schwannoma progression. We conducted a prospective open-label, phase II study of everolimus for progressive VS in NF2 patients and investigated imaging as a potential biomarker predicting effects on growth trajectory.

The trial enrolled 12 NF2 patients with progressive VS. Participants received oral everolimus daily for 52 weeks. Brain imaging was obtained quarterly. As primary endpoint, radiographic response (RR) was defined as ≥ 20% decrease in target VS volume. Secondary endpoints included other tumors RR, hearing outcomes, drug safety and quality of life (QOL).

Eight participants completed the trial and four discontinued the drug early due to significant volumetric VS progression. After 52 weeks of treatment, the median annual VS growth rate decreased from 77.2% at baseline to 29.4%. There was no VS RR and 3 of 8 (37.5%) participants had stable disease. Decreased or unchanged VS volume after 3 months of treatment was predictive of stabilization at 12 months. Seven of eight participants had stable hearing during treatment except one with a decline in word recognition score. Ten of twelve participants reported only minimal changes to their QOL scores.

Volumetric imaging at 3 months can serve as an early biomarker to predict long-term sensitivity to everolimus treatment. Everolimus may represent a safe treatment option to decrease the growth of NF2-related VS in patients who have stable hearing and neurological condition. TRN: NCT01345136 (April 29, 2011).