Background: The NF2 Genetic Severity Score (GSS) predicts disease severity in NF2-related schwannomatosis (NF2-SWN), but its utility in childhood-onset disease is less well defined. We assessed genotype-phenotype in symptomatic children with NF2-SWN managed through a national specialist service.

Methods: A retrospective study of children with symptomatic NF2-SWN before 16 years of age and available genetic data from a national UK database. Patients were stratified by GSS and compared for genotype, age at first symptom and diagnosis, presenting phenotype, subsequent symptom development and tumour occurrence.

Results: Among 220 children, 37 were classified as GSS 2A, 83 as GSS 2B and 100 as GSS 3. Children with GSS 3 developed symptoms earlier than those with GSS 2B, with median age at first symptom of 8.5 versus 11.0 years (p=0.034), and were diagnosed earlier, at 13.0 versus 15.0 years (p=0.024). Diagnostic delay was similar across groups. Genetic findings differed by GSS, with de novo and truncating variants more common in GSS 3, while mosaicism was observed only in GSS 2A and 2B. Visual loss was more common at presentation in GSS 3 than GSS 2B or 2A (26% vs 16% vs 8%; p=0.039). Vestibular schwannomas were near-universal and developed earlier in GSS 3 than GSS 2A or 2B (median 11.0 vs 13.0 vs 12.0 years; p=0.018).

Conclusion: Childhood-onset NF2-SWN is enriched for severe genotypes. GSS identifies differences in age at onset, visual presentation and timing of vestibular schwannoma development, but separates paediatric patients less distinctly than adults because morbidity is high across patients presenting in childhood.

Background: While many patients with NF2-schwannomatosis will present with tumors during adulthood, some patients develop multiple tumors in early childhood, impacting quality of life and prognosis. The genetic differences between pediatric and adult tumors are not well known. In this study, we used optical genome mapping, which utilizes ultra-long DNA molecules to construct and evaluate long genomic fragments, to investigate the structural variant (SV) profile of NF2-associated meningiomas and schwannomas in children, adolescents and young adults.

Methods: Ultra high molecular weight DNA was extracted from a cohort of NF2 associated meningiomas and schwannomas and matched normal samples when available. OGM was performed on a Saphyr instrument and SVs (large insertions/deletions, inversions, translocations) were identified. We then subclassified SVs into functional pathways and determined which genes impact specific cell developmental functions.

Results: Tumor-associated, low population frequency SVs were identified in all samples. The most common chromosome aberration was loss of chromosome 22. Additional chromosome gains and losses were most common in young children and tumors with an aggressive clinical behavior. Additional SVs (inversions, deletions, duplications, translocations) were also identified in all samples, many of which had not been previously reported in NF2-associated tumors before, and some overlapping with genes known to have tumorigenic potential.

Conclusion: NF2-associated tumors in young children or with an aggressive clinical behavior had a more complex SV phenotype (particularly chromosome abnormalities) than slow growing tumors in adult patients. Future studies will expand testing to a larger cohort of samples to better understand patterns of SVs in different tumors and age groups.

Background:
Ring Chromosome 22 (R22) can result in cells haploinsufficient for the schwannomatosis predisposition genes NF2 and SMARCB1. Individuals with R22 are therefore at increased risk of developing NF2-related schwannomatosis (NF2-SWN). The phenotype of NF2-SWN in R22 has not been well characterised and there is no agreed UK-wide screening protocol.

Methods:
We collated anonymised clinical data on individuals with R22 from 5 English NF2-SWN centres.

Results:
Data was collected on 25 individuals, although was not available in every domain. The mean age at presentation with clinical features was 13 years (range 0-48years). Most individuals presented with developmental delay/intellectual disability (17/24). Other presenting features included intracranial tumours on imaging (2/24), family history (3/24) and dysmorphic features (3/24). 15/21 developed NF2-related tumours, including vestibular schwannomas (VS) (12/21) and other tumours such as meningiomas, trigeminal/spinal schwannomas and ependymomas (15/21). Average age of VS development was 29 years (range 8-48years). Neurological symptoms were common (14/19), and over half had impaired hearing (11/18). Ocular features were less common (3/15). Some received therapies, including Avastin (3/19), surgical management (6/18) or Gamma Knife (2/18). 35% of individuals had no imaging features of NF2-SWN by average age of 21 years.

Conclusion:
This is the largest reported cohort of patients with R22. In this Ring22 ascertained cohort, we demonstrate that although age of onset and NF2-SWN severity is variable, NF2-SWN features are common, occurring in 84%. Although this study is limited by small numbers and its retrospective nature, findings suggest that routine screening, in-line with that offered to NF2-SWN patients, should be considered.

Background: NF2-related schwannomatosis is an autosomal dominant genetic disorder characterized by multiple benign tumors of the nervous system, mainly schwannomas. Current treatment options remain limited. Herein, we report for the use of combined drug strategy to treat NF2-deficient Schwann cells.

Methods: We generated isogenic human Schwann cell lines differing in NF2 status and characterized proliferation and signaling profiles using growth assays, RT-qPCR, and immunoblotting. A genome-wide CRISPR-Cas9 screen was performed to compare genes essentiality between NF2-deficient and wild-type (WT) cells. Candidate and signaling vulnerabilities were further evaluated using pharmacological inhibition and drug synergy assays. The mechanism between the candidate gene and the Merlin–Hippo signaling axis was further explored at transcriptional, translational, and post-translational levels.

Results: NF2-deficient Schwann cells showed increased proliferation, reduced Hippo activity, and enhanced RAS-MAPK signaling compared with WT cells under sparse condition. Genome-wide screening identified a core set of consistently depleted genes, with one mitotic regulator emerging as a top hit. This candidate was regulated by Merlin and Hippo activity. Pharmacological inhibition of this target increased the sensitivity of NF2-deficient cells. Although combined YAP–TEAD and MEK inhibition showed broad synergy, it also caused widespread cytotoxicity. In contrast, combined inhibition of the candidate target and MEK showed greater selectivity for NF2-deficient cells, reducing their growth while having a more limited effect on WT cells.

Conclusion: We identify a novel mitotic-related synthetic-lethal target in NF2-deficient Schwann cells. Combining inhibition of this candidate target with MEK inhibition may provide a selective therapeutic strategy for NF2-related schwannomatosis.

Background
LZTR1 acts as a substrate adaptor for the E3 ubiquitin ligase CUL3, with RAS GTPases as its primary substrates. Loss-of-function mutations in LZTR1 have been implicated in LZTR1-related schwannomatosis and Noonan syndrome, both of which share a neuropathic phenotype characterised by debilitating neuropathic pain. Despite this association the role of LZTR1 in the peripheral nervous system remains poorly understood. 
Methods
To address this, I employed a Schwann cell (SC)-specific LZTR1 knockout (KO) mouse model and characterised its neuropathic phenotype using sensory assessments, electron microscopy and molecular analyses.
Results
Von Frey and Hot filament assays revealed heightened mechanical sensitivity at a young age, which shifts to heat sensitivity with age. Electron microscopy of sciatic nerves revealed striking axonal hypermyelination, while the mice exhibited marked sciatic nerve enlargement, mirroring the nerve hypertrophy of Noonan syndrome patients. Proteomic analysis uncovered a novel role for LZTR1 in lipid metabolism that were corroborated by a lipidomics analysis of sciatic nerves. The results showed that loss of LZTR1 leads to a significant lipid catabolic effect and marked dysregulation of myelin sheath lipids. Pharmacological ERK inhibition with ulixertinib partially rescued the neuropathic phenotype, reducing nerve hypertrophy but failing to ameliorate mechanical allodynia.
Conclusion
Taken together, these findings support a model in which LZTR1 deficiency disrupts lipid homeostasis in SCs contributing to myelination defects. At the same time, hyperactivation of the MAPK/ERK pathway likely drives structural changes such as the nerve hypertrophy. The partial rescue by ERK inhibition identifies this axis as a promising therapeutic target for LZTR1-related peripheral neuropathies.

Background: Vestibular schwannomas are benign tumors arising from the vestibular branch of the eighth cranial nerve. Besides sporadic occurrence, they are associated with neurofibromatosis type 2 (NF2)-related schwannomatosis. While surgery represents the standard treatment for vestibular schwannomas, patients with recurrent disease, hereditary tumor syndromes, or significant comorbidities are not always suitable for surgery. Therefore, alternative systemic therapies are required, prompting development of a patient-derived three-dimensional (3D) organoid model for testing.

Methods: Tumor specimens from 20 vestibular schwannoma patients operated between 2023 and 2025 were collected prospectively. Mean patient age at surgery was 42 ± 16 years (range 19–71 years). Tissue was sectioned into approximately 0.55 mm slices and cultured as organoids in vitro. Organoids were characterized regarding morphology, tumor microenvironment preservation, apoptosis, proliferation, and long-term stability. Brigatinib treatment effects (40 µM; n=8) were evaluated using CellTiter-Glo, Alamar Blue, cleaved caspase-3, and Ki67 assays. Standard monolayer cultures served as 2D controls.

Results: The organoid model maintained characteristic vestibular schwannoma morphology and microenvironment stability for more than 12 weeks. Compared with standard monolayer cultures, organoids showed approximately tenfold higher cellularity. Baseline apoptosis and proliferation rates remained consistently low (<2%) during long-term cultivation. Pharmacological testing was feasible for at least three weeks. Treatment responses to Brigatinib demonstrated marked inter- and intraindividual variability. Drug effects were less pronounced in organoids than in monolayer cultures, suggesting closer resemblance to in vivo tumor biology.

Conclusion: This 3D vestibular schwannoma organoid model enables long-term cultivation while preserving the native tumor microenvironment and represents a clinically relevant platform for individualized drug testing.