| Category | Item | Key details | Recent source / year | URL | Evidence |
|---|---|---|---|---|---|
| Disease identifier | Schwannomatosis | Umbrella term adopted in 2022; gene-based subtypes include **NF2-related schwannomatosis**, **SMARCB1-related schwannomatosis**, **LZTR1-related schwannomatosis**, **22q-related schwannomatosis**, **SWN-NOS**, **SWN-NEC** | Nagasaka & Phi, 2025 | https://doi.org/10.3340/jkns.2025.0001 | (pqac-00000001) |
| Disease identifier | MONDO | **MONDO:0008075** schwannomatosis; related entries include **MONDO:0007039** NF2-related schwannomatosis, **MONDO:0024517** SMARCB1-related schwannomatosis, **MONDO:0014299** LZTR1-related schwannomatosis | Open Targets / MONDO context, accessed via current evidence | https://platform.opentargets.org | (pqac-00000000) |
| Modern definition | NF2-related schwannomatosis | Formerly “neurofibromatosis type 2”; renamed because neurofibromas are not a defining feature; classically characterized by bilateral vestibular schwannomas with additional meningiomas/ependymomas/schwannomas | Tamura et al., 2024; Rai et al., 2025 | https://doi.org/10.2176/jns-nmc.2024-0067 ; https://doi.org/10.1177/19714009251313510 | (pqac-00000008, pqac-00000004) |
| Subtype | NF2-related schwannomatosis | Gene: **NF2**; autosomal dominant; high penetrance/near-certain disease with constitutional pathogenic variant; mosaic disease common, especially de novo cases | Nagasaka & Phi, 2025; Perrino et al., 2025 | https://doi.org/10.3340/jkns.2025.0001 ; https://doi.org/10.1158/1078-0432.ccr-24-3278 | (pqac-00000001, pqac-00000007) |
| Subtype | SMARCB1-related schwannomatosis | Gene: **SMARCB1**; autosomal dominant familial tumor predisposition; typically peripheral/spinal schwannomas, no bilateral vestibular schwannomas; meningioma and MPNST risk reported | Perrino et al., 2025 | https://doi.org/10.1158/1078-0432.ccr-24-3278 | (pqac-00000007) |
| Subtype | LZTR1-related schwannomatosis | Gene: **LZTR1**; autosomal dominant with incomplete penetrance; peripheral schwannomas predominate; unilateral vestibular schwannoma can occur | Perrino et al., 2025; Uliana et al., 2024 | https://doi.org/10.1158/1078-0432.ccr-24-3278 ; https://doi.org/10.3390/genes15070916 | (pqac-00000007) |
| Major genes | Core causal genes | Principal disease genes across schwannomatosis are **NF2, SMARCB1, LZTR1** | Open Targets association summary; multiple reviews | https://platform.opentargets.org | (pqac-00000000) |
| Pathogenesis | Non-NF2 three-/four-hit model | For SMARCB1/LZTR1-related disease: germline variant retained in tumor, chromosome 22 loss/LOH removes wild-type allele, followed by somatic **NF2** alteration in tumor | Nagasaka & Phi, 2025; Tamura et al., 2024 | https://doi.org/10.3340/jkns.2025.0001 ; https://doi.org/10.2176/jns-nmc.2024-0067 | (pqac-00000001, pqac-00000002) |
| Hallmark clinical features | Pain | Chronic pain is a major hallmark, often poorly correlated with tumor size/location/burden; symptom-based multidisciplinary pain management is emphasized | Nagasaka & Phi, 2025; Hino et al., 2025 | https://doi.org/10.3340/jkns.2025.0001 ; https://doi.org/10.2147/tcrm.s362794 | (pqac-00000001, pqac-00000020) |
| Hallmark clinical features | NF2-related phenotype | Bilateral vestibular schwannomas, other cranial/spinal schwannomas, intradermal schwannomas, meningiomas, less commonly ependymomas; may also present with unilateral VS plus other tumors | Perrino et al., 2025; Evans et al., 2025 | https://doi.org/10.1158/1078-0432.ccr-24-3278 ; https://doi.org/10.1007/s10689-025-00504-5 | (pqac-00000007, pqac-00000005) |
| Hallmark clinical features | SMARCB1/LZTR1 phenotype | Usually multiple **non-vestibular** schwannomas affecting peripheral and spinal nerves; painful tumors common; bilateral VS generally absent in SMARCB1-related disease | Tamura et al., 2024; Perrino et al., 2025 | https://doi.org/10.2176/jns-nmc.2024-0067 ; https://doi.org/10.1158/1078-0432.ccr-24-3278 | (pqac-00000002, pqac-00000007) |
| Diagnostic criteria | NF2-related schwannomatosis | Diagnosis can be made by bilateral VS, or identical **NF2** pathogenic variant in ≥2 anatomically distinct NF2-related tumors, or major/minor criteria combinations; molecular criteria formally incorporated in recent revisions | Tamura et al., 2024; Rai et al., 2025 | https://doi.org/10.2176/jns-nmc.2024-0067 ; https://doi.org/10.1177/19714009251313510 | (pqac-00000002, pqac-00000004) |
| Diagnostic testing | Mosaicism and tumor testing | Mosaicism may be inferred by blood/saliva variant allele fraction **<50%** or shared pathogenic variant across ≥2 anatomically unrelated tumors; tumor analysis materially improves diagnostic yield | Tamura et al., 2024; Smith et al., 2024 | https://doi.org/10.2176/jns-nmc.2024-0067 ; https://doi.org/10.1136/jmg-2024-110217 | (pqac-00000002, pqac-00000006) |
| Diagnostic yield | Blood vs tumor-inclusive testing | In a 154-person cohort with non-vestibular schwannoma(s), overall molecular diagnosis was **25% using blood alone** and **36% when tumor analysis was included**; **18/19 NF2** findings were mosaic, with **17** detected only when 2 tumors were tested | Smith et al., 2024 | https://doi.org/10.1136/jmg-2024-110217 | (pqac-00000006) |
| Epidemiology | Lifetime schwannoma risk | Lifetime risk of schwannoma estimated **>1/500**; about **75%** are vestibular schwannomas | Smith et al., 2024 | https://doi.org/10.1136/jmg-2024-110217 | (pqac-00000006) |
| Epidemiology | NF2-related prevalence | Diagnostic prevalence in Manchester reported **1 in 50,500**; birth prevalence **1 in 27,956**; updated England prevalence in 2024 at least **1 in 58,000** | Evans et al., 2025 | https://doi.org/10.1007/s10689-025-00504-5 | (pqac-00000005) |
| Epidemiology | Non-NF2 and gene-specific prevalence | UK prevalence estimates: non-NF2 schwannomatosis **1 in 103,700**; germline **LZTR1** variant-related disease **1 in 527,000**; germline **SMARCB1** variant-related disease **1.1 million** | Smith et al., 2024 | https://doi.org/10.1136/jmg-2024-110217 | (pqac-00000006) |
| Quality of life | NF2-SWN mental health burden | In 77 surveyed NF2-SWN patients, clinically relevant symptoms: depression **30%**, anxiety **16%**, somatic burden **32%**; QoL correlated with physician-rated severity (**r=0.614**) | Freier et al., 2024 | https://doi.org/10.1038/s41598-024-57401-7 | (pqac-00000010) |
| Quality of life | Specific NF2-SWN QoL impacts | In the same cohort, **75% (58/77)** reported disease negatively affected outlook on life and **66% (51/77)** reported hearing problems affecting activities | Freier et al., 2024 | https://doi.org/10.1038/s41598-024-57401-7 | (pqac-00000012) |
| Current management | Standard care | Surgical resection for symptomatic/accessible lesions; radiotherapy and bevacizumab used mainly in NF2-related disease; supportive multidisciplinary pain care central | Nagasaka & Phi, 2025 | https://doi.org/10.3340/jkns.2025.0001 | (pqac-00000001) |
| Active trial | **NCT05684692** STARFISH | Schwannomatosis pain platform trial; interventions: **siltuximab** and **erenumab-aooe** vs placebo; primary endpoint: change in worst pain intensity (NRS-11) from baseline to Day 85; status **Recruiting** | ClinicalTrials.gov record, 2023 | https://clinicaltrials.gov/study/NCT05684692 | (pqac-00000015, pqac-00000019) |
| Active trial | **NCT04163419** Tanezumab | Phase 2 randomized placebo-controlled trial for **moderate to severe pain due to schwannomatosis**; intervention **tanezumab**; primary endpoint: change in worst pain (NRS-11) at Week 8; enrollment **9**; status listed **Unknown / last known active-not-recruiting** | ClinicalTrials.gov record, 2020 | https://clinicaltrials.gov/study/NCT04163419 | (pqac-00000017, pqac-00000018) |
| Active trial | **NCT04374305** INTUITT-NF2 | Phase 2 platform trial for **NF2-related schwannomatosis** tumors; interventions: **brigatinib**, **neratinib**, **retifanlimab + bevacizumab**; primary on-study evaluation includes **radiographic response rate**; status **Recruiting** | ClinicalTrials.gov record, 2020 | https://clinicaltrials.gov/study/NCT04374305 | (pqac-00000021) |
| Trial landscape note | Pain vs tumor-directed trials | Current active interventional landscape separates **pain-focused trials** (STARFISH, tanezumab) from **tumor-directed NF2 trials** (INTUITT-NF2); pain trials are mainly in non-NF2 schwannomatosis, whereas INTUITT targets NF2-related tumor burden | ClinicalTrials.gov records and review synthesis | https://clinicaltrials.gov | (pqac-00000019, pqac-00000017, pqac-00000021, pqac-00000020) |


*Table: This table condenses current schwannomatosis nomenclature, genetics, clinical features, epidemiology, diagnostics, and actively recruiting or recent interventional trials. It is designed as a quick-reference artifact for disease knowledge base curation and evidence tracking.*