Ring chromosome 22 and neurofibromatosis type II: proof of two hit model for the loss of the NF2 gene in the development of meningioma

Carriers of a ring chromosome 22 are mentally retarded and show variable facial dysmorphism. They may also present with features of neurofibromatosis type II (NF2) such as vestibular schwannomas and multiple meningiomas. In these cases, tumourigenesis has been suspected to be caused by the loss of both alleles of the NF2 gene, a tumour suppressor localized in 22q12.2.

Here, we describe a patient with constitutional ring chromosome 22 and rapid onset spastic paraparesis due to a spinal meningioma. Array CGH and MLPA analyses in blood revealed a terminal deletion in 22q13.32, not comprising the NF2 gene. In tumour tissue, loss of the whole ring chromosome 22 including one NF2 gene due to mitotic instability constituted the first hit, while a point mutation in the remaining NF2 gene (c.784C>T, p.R262X) was demonstrated as second hit.

This is the first molecular proof of the two hit model with loss of both NF2 alleles in the pathogenesis of meningioma in a patient with ring chromosome 22.

ring chromosome 22 - neurofibromatosis type II - NF2 gene - meningioma - two hit model in tumourigenesis