NF2-Related Schwannomatosis (NF2): Molecular Insights and Therapeutic Avenues.

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.

[Features of course of pain syndrome in patients with schwannomatosis]. / Osobennosti techeniya bolevogo sindroma u patsientov s shvannomatozami.

OBJECTIVE: To identify the characteristics of pain syndrome in patients with schwannomas depending on genetic predisposition. MATERIAL AND METHODS: The study included 46 patients with peripheral, spinal and intracranial schwannomas, corresponding to the schwannomatosis phenotype according to the 2022 clinical criteria. All patients underwent sequencing of the LZRT1, Nf2 and SMARCB1 and a copy number study in the NF2. RESULTS: The most severe widespread pain was observed in patients with pathogenic LZRT1 variants, while patients with mosaic variants may not even have local tumor-related pain. Patients with SMARCB1variants may have no pain or have localized pain that responds well to surgical treatment. CONCLUSION: Further studies of the molecular features of schwannomatosis and driver mutations in the pathogenesis of pain are necessary to improve the effectiveness of pain therapy in this group of patients. Schwannomatosis is a disease from the group of neurofibromatosis, manifested by the development of multiple schwannomas. Neuropathic pain is one of the main symptoms characteristic of peripheral schwannomas, however, the severity and prevalence of the pain syndrome does not always correlate with the location of the tumors. According to modern concepts, the key factors influencing the characteristics of the pain syndrome are the target gene and the type of pathogenic variant. The most severe widespread pain is observed in patients with pathogenic variants in the LZRT1 gene, while patients with mosaic variants may not even have local pain associated with tumors. Patients with variants in SMARCB1 may have no pain or localized pain that responds well to surgical treatment.

Improved sensitivity for detection of pathogenic variants in familial NF2-related schwannomatosis.

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

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.

[New classification and approaches to the treatment of schwannomatosis]. / Novaya klassifikatsiya i podkhody k terapii shvannomatozov.

Schwannomatoses is a new classification unit for all the hereditary diseases caused by chromosome 22 damage followed by multiple benign neoplasms of the peripheral and central nervous system. Schwannomatosis occurs as a result of damage to different genes: NF2, SMARCB1, LZRT1, loss of heterozygosity of the long arm of chromosome 22. Nevertheless, clinical manifestations are similar. Molecular diagnostics not only confirms the diagnosis, but also predicts the course of disease. Thus, the most severe clinical manifestations are observed in patients with violation of semantic sequences and reading frame shift in exons 2-13 of the NF2 gene. A more favorable course with less number of tumors is observed in patients with somatic mosaicism. Stereotactic irradiation and surgery are the main treatment options for schwannomatosis. However, there is evidence of effective targeted therapy with bevacizumab (inhibitor of vascular endothelial growth factor). Bevacizumab is used in patients with bilateral vestibular schwannomas and high risk of hearing loss, as well as for intramedullary tumor growth control.

Schwannomatosis: a Realm Reborn: year one.

PURPOSE OF REVIEW: In 2022, an international consensus recommendation revised the nomenclature for neurofibromatosis type 2 ( NF2 ) and Schwannomatosis (SWN), now grouped under the umbrella term Schwannomatosis, and defined new diagnostic criteria. RECENT FINDINGS: This review describes the molecular criteria for diagnosis of schwannomatosis and the subsequent diagnosis strategy, while setting out the most recent advances in our understanding of the natural history, pathology, molecular biology and treatment of schwannomatosis-associated tumors, including schwannomas, meningiomas and ependymomas. SUMMARY: Somatic mutation screening should become a new standard for the diagnosis of NF2 -, LTZTR1 -, SMARCB1 - and 22q-schwannomatosis to discriminate those conditions. Constitutional events in NF2 -Schwannomatosis have a major influence on disease severity and justifiably motivate ongoing efforts on gene replacement therapy research. On the other hand, underlying mechanisms of disease severity and associated pain remain largely unknown in non- NF2 -SWN and independent of germline mutation. Research efforts therefore focus on pain relief in ongoing trials and the discovery of new molecular mechanisms underlying schwannoma tumorigenesis/pain/neuropathies.

Neurofibromatosis- and schwannomatosis-associated tumors: Approaches to genetic testing and counseling considerations.

Neurofibromatosis (NF) and schwannomatosis (SWN) are genetic conditions characterized by the risk of developing nervous system tumors. Recently revised diagnostic criteria include the addition of genetic testing to confirm a pathogenic variant, as well as to detect the presence of mosaicism. Therefore, the use and interpretation of both germline and tumor-based testing have increasing importance in the diagnostic approach, treatment decisions, and risk stratification of these conditions. This focused review discusses approaches to genetic testing of NF- and SWN-related tumor types, which are somewhat rare and perhaps lesser known to non-specialized clinicians. These include gastrointestinal stromal tumors, breast cancer, plexiform neurofibromas with or without transformation to malignant peripheral nerve sheath tumors, gliomas, and schwannomas, and emphasizes the need for inclusion of genetic providers in patient care and appropriate pre- and post-test education, genetic counseling, and focused evaluation by a medical geneticist or other healthcare provider familiar with clinical manifestations of these disorders.

Radiogenomics in NF2-Associated Schwannomatosis (Neurofibromatosis Type II): Exploratory Data Analysis.

Our pilot study aimed at exploratory radiogenomic data analysis in patients with NF2-associated schwannomatosis (formerly neurofibromatosis type II) to assume the potential of image biomarkers in this pathology. Fifty-three unrelated patients (37 (69.8%) women, avg. age 30.2 ± 11.2 y.o.) were enrolled in the study. First-order, gray-level co-occurrence matrix (GLCM), gray-level run length matrix (GLRLM), and geometry-based statistics were calculated (3718 features per region of interest). We demonstrated imaging patterns and statistically significant differences in radiomic features potentially related to the genotype and clinical phenotype of the disease. However, the clinical utility of these patterns should be further evaluated. The study was supported by the Russian Science Foundation grant 21-15-00262.

[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.

Atypical neurofibromas reveal distinct epigenetic features with proximity to benign peripheral nerve sheath tumor entities.

BACKGROUND: Plexiform neurofibromas can transform into atypical neurofibromas (ANF) and then further progress to aggressive malignant peripheral nerve sheath tumors (MPNST). ANF have been described to harbor distinct histological features and frequent loss of CDKN2A/B. However, histological evaluation may be rater-dependent, and detailed knowledge about the molecular mechanisms of malignant transformation is scarce. In general, malignant transformation can be accompanied by significant epigenetic changes, and global DNA methylation profiling is able to differentiate relevant tumor subgroups. Therefore, epigenetic profiling might provide a valuable tool to distinguish and characterize ANF with differing extent of histopathological atypia from neurofibromas and MPNST. METHODS: We investigated 40 tumors histologically diagnosed as ANF and compared their global methylation profile to other peripheral nerve sheath tumors. RESULTS: Unsupervised class discovery and t-SNE analysis indicated that 36/40 ANF cluster with benign peripheral nerve sheath tumors with clear separation from MPNST. 21 ANF formed a molecularly distinct cluster in proximity to schwannomas. Tumors in this cluster had a frequent heterozygous or homozygous loss of CDKN2A/B and significantly more lymphocyte infiltration than MPNST, schwannomas, and NF. Few ANF clustered closely with neurofibromas, schwannomas, or MPNST, raising the question, whether diagnosis based on histological features alone might pose a risk to both over- and underestimate the aggressiveness of these lesions. CONCLUSIONS: Our data suggest that ANF with varying histological morphology show distinct epigenetic similarities and cluster in proximity to benign peripheral nerve sheath tumor entities. Future investigations should pay special respect to correlating this methylation pattern to clinical outcomes.

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

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

Neurofibromatosis-Noonan syndrome and growth deficiency in an Iranian girl due to a pathogenic variant in NF1 gene.

BACKGROUND: Mutations in NF1 gene could cause allelic disorders with clinical spectrum of Neurofibromatosis type 1 to Noonan syndrome. Here, a 7-year-old Iranian girl is described with Neurofibromatosis-Noonan syndrome due to a pathogenic variant in NF1 gene. METHODS: Clinical evaluations were performed along with genetic testing using whole exome sequencing (WES). The variant analysis including pathogenicity prediction was also done using bioinformatics tools. RESULTS: The chief compliant of the patient was short stature and lack of proper weight gain. Other symptoms were developmental delay, learning disability, inadequate speech skill, broad forehead, hypertelorism, and epicanthal folds, low set ears and webbed neck. A small deletion, c.4375-4377delGAA, was found in NF1 gene using WES. This variant was classified as pathogenic according to ACMG. CONCLUSIONS: NF1 variants may show variable phenotypes among the patients; identifying such variants is helpful in therapeutic management of the disease. WES is considered as an appropriate test to diagnose Neurofibromatosis-Noonan syndrome.

Genome-wide association analysis identifies a susceptibility locus for sporadic vestibular schwannoma at 9p21.

Vestibular schwannomas are benign nerve sheath tumours that arise on the vestibulocochlear nerves. Vestibular schwannomas are known to occur in the context of tumour predisposition syndromes NF2-related and LZTR1-related schwannomatosis. However, the majority of vestibular schwannomas present sporadically without identification of germline pathogenic variants. To identify novel genetic associations with risk of vestibular schwannoma development, we conducted a genome-wide association study in a cohort of 911 sporadic vestibular schwannoma cases collated from the neurofibromatosis type 2 genetic testing service in the north-west of England, UK and 5500 control samples from the UK Biobank resource. One risk locus reached genome-wide significance in our association analysis (9p21.3, rs1556516, P = 1.47 × 10-13, odds ratio = 0.67, allele frequency = 0.52). 9p21.3 is a genome-wide association study association hotspot, and a number of genes are localized to this region, notably CDKN2B-AS1 and CDKN2A/B, also referred to as the INK4 locus. Dysregulation of gene products within the INK4 locus have been associated with multiple pathologies and the genes in this region have been observed to directly impact the expression of one another. Recurrent associations of the INK4 locus with components of well-described oncogenic pathways provides compelling evidence that the 9p21.3 region is truly associated with risk of vestibular schwannoma tumorigenesis.

A Rare Case of Familial Schwannomatosis Showing Intrafamilial Variability with Identification of a Shared Novel Germline SMARCB1 Mutation.

Schwannomatosis is characterized by the presence of multiple schwannomas without landmarks of NF2. It is considered the rarest form of neurofibromatosis (NF). Here, we report the first case of familial schwannomatosis with regard to the segmental/generalized phenotype, in which the proband and the daughter present a distinct phenotype in this classification. The proband presents a generalized, painless, extradural type of schwannomatosis, while the daughter shows a segmental, painful, intradural type of schwannomatosis. Whole-exome sequencing of the affected individuals revealed a shared novel SMARCB1 gene mutation (c.92A > G, p.Glu31Gly) despite the clinical variability. We thus suggest two points in the diagnosis of familial schwannomatosis: The identified novel germline SMARCB1 variant can be reflective of a phenotypical progression from a segmental to a generalized type of schwannomatosis, or an intrafamilial variability in inherited schwannomatosis, which was not reported in previous literature. The specific combination of somatic NF2 mutations may be a major factor in regulating the severity and scope of the resulting phenotype in schwannomatosis.

Understanding barriers to diagnosis in a rare, genetic disease: Delays and errors in diagnosing schwannomatosis.

Diagnosis of rare, genetic diseases is challenging, but conceptual frameworks of the diagnostic process can guide quality improvement initiatives. Using the National Academy of Medicine diagnostic framework, we assessed the extent of, and reasons for diagnostic delays and diagnostic errors in schwannomatosis, a neurogenetic syndrome characterized by nerve sheath tumors and chronic pain. We reviewed the medical records of 97 people with confirmed or probable schwannomatosis seen in two US tertiary care clinics. Time-to-event analysis revealed a median time from first symptom to diagnosis of 16.7 years (95% CI, 7.5-26.0 years) and median time from first medical consultation to diagnosis of 9.8 years (95% CI, 3.5-16.2 years). Factors associated with longer times to diagnosis included initial signs/symptoms that were intermittent, non-specific, or occurred at younger ages (p < 0.05). Thirty-six percent of patients were misdiagnosed; misdiagnoses were of underlying genetic condition (18.6%), pain etiology (16.5%), and nerve sheath tumor presence/pathology (11.3%) (non-mutually exclusive categories). One-fifth (19.6%) of patients had a clear missed opportunity for genetics workup that could have led to an earlier schwannomatosis diagnosis. These results suggest that interventions in clinician education, genetic testing availability, expert review of pathology findings, and automatic triggers for genetics referrals may improve diagnosis of schwannomatosis.

Updated diagnostic criteria and nomenclature for neurofibromatosis type 2 and schwannomatosis: An international consensus recommendation.

PURPOSE: Neurofibromatosis type 2 (NF2) and schwannomatosis (SWN) are genetically distinct tumor predisposition syndromes with overlapping phenotypes. We sought to update the diagnostic criteria for NF2 and SWN by incorporating recent advances in genetics, ophthalmology, neuropathology, and neuroimaging. METHODS: We used a multistep process, beginning with a Delphi method involving global disease experts and subsequently involving non-neurofibromatosis clinical experts, patients, and foundations/patient advocacy groups. RESULTS: We reached consensus on the minimal clinical and genetic criteria for diagnosing NF2 and SWN. These criteria incorporate mosaic forms of these conditions. In addition, we recommend updated nomenclature for these disorders to emphasize their phenotypic overlap and to minimize misdiagnosis with neurofibromatosis type 1. CONCLUSION: The updated criteria for NF2 and SWN incorporate clinical features and genetic testing, with a focus on using molecular data to differentiate the 2 conditions. It is likely that continued refinement of these new criteria will be necessary as investigators study the diagnostic properties of the revised criteria and identify new genes associated with SWN. In the revised nomenclature, the term "neurofibromatosis 2" has been retired to improve diagnostic specificity.