High frequency of mosaic NF2-related schwannomatosis diagnosed after somatic analysis of multi-nodular schwannomas in schwannomatosis patients

Hum Genet. 2026 Mar 13;145(1):30. doi: 10.1007/s00439-026-02825-6.

Abstract

Following the recent introduction of molecular diagnosis criteria for schwannomatosis, we decided to study the results of somatic molecular testing in patients with a tumor burden suggestive of non-NF2-related Schwannomatosis, with a particular focus on patients harboring multi-nodular schwannomas. We selected 22 patients harboring multiple peripheral nerve schwannomas, with or without associated lumbar schwannomas after a brain and spine MRI workup ruling out cranial nerve schwannomas, meningiomas and ependymomas. For each patient, at least 2 separate anatomically distinct tumor nodules were available for analysis. We distinguished mono-nodular from multi-nodular tumors and performed targeted sequencing of the NF2, SMARCB1 and LZTR1 genes for all tumors and germline DNA when available. We analyzed 69 tumor nodules in 22 patients, 19 of whom had a non-familial disease. Most patients (54%) had a diffuse schwannomatosis. Following germline and somatic genetic analysis, 11 patients were diagnosed with LZTR1-related schwannomatosis (50%), 3 patients with possible LZTR1- or SMARCB1-related Schwannomatosis (14%), 7 patients with mosaic NF2-related Schwannomatosis (32%), and 1 patient with 22q-related schwannomatosis (4%). Patients with multi-nodular schwannomas (n = 9), all with a non-familial disease, harbored a mosaic NF2-related Schwannomatosis in a majority of cases (5/9; 55%; p = 0.02), while patients with mononodular schwannomas harbored more frequently a LZTR1-related Schwannomatosis (9/13; 69%; p = 0.03). This study illustrates the underestimated high frequency of mosaic NF2-related schwannomatosis in patients harboring multi-nodular peripheral nerve schwannomas. As multi-nodular schwannomas are associated with higher surgical morbidity, the pivotal role of the NF2 gene in their tumorigenesis opens perspectives for Schwannomatosis research.

Keywords: LZTR1; NF2; Peripheral nerve sheath tumor; Schwannoma; Schwannomatosis.

MeSH terms

  • Adult
  • Aged
  • Female
  • Humans
  • Male
  • Middle Aged
  • Mosaicism*
  • Neurilemmoma* / diagnosis
  • Neurilemmoma* / genetics
  • Neurilemmoma* / pathology
  • Neurofibromatoses* / diagnosis
  • Neurofibromatoses* / genetics
  • Neurofibromatoses* / pathology
  • Neurofibromatosis 2* / diagnosis
  • Neurofibromatosis 2* / genetics
  • Neurofibromin 2* / genetics
  • SMARCB1 Protein / genetics
  • Skin Neoplasms* / diagnosis
  • Skin Neoplasms* / genetics
  • Skin Neoplasms* / pathology
  • Transcription Factors / genetics
  • Young Adult

Substances

  • SMARCB1 Protein
  • Neurofibromin 2
  • LZTR1 protein, human
  • NF2 protein, human
  • Transcription Factors
  • SMARCB1 protein, human

Supplementary concepts

  • Schwannomatosis