Molecular Genetics of Schwannomatosis


Schwannomatosis is characterised by the development of multiple schwannomas, and in some cases meningiomas, but without the involvement of bilateral vestibular schwannomas, the latter being the hallmark of neurofibromatosis type 2 (NF2). Severe pain is the most important clinical symptom in patients. Germ line mutations in SMARCB1 or LZTR1 on chromosome 22 predispose to the development of schwannomas in schwannomatosis. These genes explain 86% of the familial but only 40% of the sporadic cases. Independent somatic mutations in NF2, which is also on chromosome 22, are found in the schwannomas of patients, but not in their germ line. Most mutations in SMARCB1 are hypomorphic mutations, giving rise to a SMARCB1 protein with modified activity. Many mutations in LZTR1 are loss‐of‐function mutations, resulting in the absence of LZTR1 protein. Unilateral vestibular schwannomas may occur in LZTR1‐associated schwannomatosis. Overlap exists of the clinical symptoms of schwannomatosis and mosaic NF2. Comprehensive testing of the genes involved in blood and tumours of the patient may help in the clinical diagnosis of schwannomatosis. Identification of additional genes and pathways involved should be performed to identify possible targets for therapy and relief of pain.

Key Concepts

  • Schwannomatosis patients develop multiple schwannomatosis, but not bilateral vestibular schwannomas, the latter being characteristic for neurofibromatosis type 2 (NF2).
  • Pain is the most important clinical symptom in schwannomatosis. It often persists after removal of the schwannoma.
  • The tumour suppressor genes SMARCB1 and LZTR1 are predisposing genes in schwannomatosis. These genes explain many, but not all, sporadic and familial cases.
  • Most germ line SMARCB1 mutations in schwannomatosis are hypomorphic mutations, resulting in the synthesis of a protein with modified activity.
  • Many germ line LZTR1 mutations are loss‐of‐function mutations, resulting in the absence of protein.
  • Independent somatically acquired NF2 mutations are found in the multiple schwannomas of schwannomatosis patients.
  • Unilateral vestibular schwannoma may occur in LZTR1‐associated schwannomatosis. Bilateral vestibular schwannomas have not been reported in schwannomatosis patients.
  • The similarities in clinical phenotype between schwannomatosis and mosaic NF2 may cause diagnostic confusion.

Keywords: schwannomatosis; rhabdoid tumour; vestibular schwannoma; SMARCB1; LZTR1; NF2; tumour suppressor gene; mutation

Figure 1. Immunohistochemical SMARCB1 staining of a schwannoma derived from a schwannomatosis patient with a constitutional SMARCB1 mutation (c.34C > T; p.Gln12*, a) and of a malignant rhabdoid tumour derived from a rhabdoid tumour predisposition syndrome patient with a constitutional SMARCB1 mutation (c.500+1G > A; p.Trp167*, b). Note mosaic nuclear staining of tumour cells in the schwannoma and absence of nuclear staining in the tumour cells of the malignant rhabdoid tumour. In contrast, the nuclei of endothelial cells of the blood vessels in both tumours show positive staining with the SMARCB1 antibody. Original magnification ×200. (a) Reproduced from Hulsebos et al. © Elsevier. (b) Reproduced with permission from Ammerlaan et al. © Nature Publishing Group.
Figure 2. Four‐hit, three‐step mechanism for SMARCB1 and NF2 inactivation in multiple schwannomas of a SMARCB1 mutation‐positive schwannomatosis patient. Tumorigenesis begins with a germ line mutation in SMARCB1 (hit 1) and is followed by loss of a portion of chromosome 22 that contains the second SMARCB1 allele and one NF2 allele (hits 2 and 3) and by mutation of the remaining wild‐type NF2 allele (hit 4). Reproduced with permission from Plotkin et al. © John Wiley and Sons.
Figure 3. Nucleotide sequence of the coding region in exon 1 of SMARCB1 and amino acid sequence of the encoded N‐terminal part of the SMARCB1 protein. Nucleotide numbering starts at the A of the first ATG codon and amino acid numbering starts at the first methionine. The nucleotides that are affected by the c.30delC, c.34C > T, c.38delA and c.46A > T mutations are indicated in red colour, as are the premature termination codon TGA at position 44, generated by the c.30delC and c.38delA mutations, and the possible reinitiation codon ATG at position 79. The c.79A > G mutation, introduced to convert the latter codon into GTG, encoding valine, is also indicated (see text for details). Reproduced with permission from Hulsebos et al. © Springer.


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Further Reading

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Hulsebos, Theo JM(Nov 2017) Molecular Genetics of Schwannomatosis. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0021427.pub2]