Molecular Genetics of Schwannomatosis

Abstract

Abstract 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.