Schwannomatosis 2

A number sign (#) is used with this entry because susceptibility to the development of schwannomatosis-2 (SWNTS2) is conferred by germline heterozygous mutation in the LZTR1 gene (600574) on chromosome 22q11.

Description

Schwannomatosis is an adult-onset tumor predisposition syndrome characterized by the development of multiple schwannomas in various areas of the body (summary by Piotrowski et al., 2014).

For a general phenotypic description and a discussion of genetic heterogeneity of schwannomatosis, see SWNTS1 (162091).

Clinical Features

Piotrowski et al. (2014) identified 16 probands with schwannomatosis who did not have germline mutations in the SMARCB1 gene (601607), including 5 with a family history of the disorder. The onset of tumors ranged from approximately 20 to 60 years of age, and occurred in various regions, including extremities, spinal cord, chest wall, and subcutaneous regions.

Inheritance

The transmission pattern of schwannomatosis-2 in the families reported by Piotrowski et al. (2014) was consistent with autosomal dominant inheritance and incomplete penetrance.

Molecular Genetics

In 16 of 20 probands with schwannomatosis-2, Piotrowski et al. (2014) identified 15 different germline heterozygous mutations in the LZTR1 gene (see, e.g., 600574.0001-600574.0006). There were 6 truncating mutations, 1 in-frame splice site mutation, 1 deletion affecting a splice site, and 7 missense mutations at highly conserved residues. All schwannomas studied also carried the heterozygous LZTR1 mutation, and all showed loss of heterozygosity (LOH) at chromosome 22q11, including the LZTR1, NF2 (607379), and SMARCB1 genes. In addition, all tumors carried a heterozygous somatic mutation in the NF2 gene. These findings were consistent with biallelic loss of function of both LZTR1 and NF2 in all tumors. Functional studies of the variants were not performed. Piotrowski et al. (2014) characterized the pathogenesis of tumor development as resulting from 3 mutational events: a germline LZTR1 mutation (E1), a deletion of 22q that includes the LZTR1 and NF2 genes (E2), and a somatic NF2 mutation (E3). The findings suggested that loss of LZTR1 function can predispose to the development of autosomal dominant multiple schwannomas, thus implicating LZTR1 as a tumor suppressor gene.