Loss of the NF2 gene and merlin occur by the tumorlet stage of schwannoma development in neurofibromatosis 2

Loss of the neurofibromatosis 2 (NF2) gene-encoded protein merlin is a univ ersal finding in sporadic and NF2-associated schwannomas. Certain NF2 patie nts may develop numerous minute Schwann cell tumorlets of the spinal nerve roots in addition to larger, frank schwannomas and thereby provide an oppor tunity to investigate the timing of NF2 gene/merlin loss in Schwann cell tu morigenesis. We studied an NF2 patient with a germline NF2 gene frameshift mutation who had many Schwann cell tumorlets and schwannomas. Loss of heter ozygosity studies of DNA from microdissected specimens showed allelic loss of the NF2 region of chromosome 22q in tumorlets as well as schwannomas. Im munohistochemistry further demonstrated loss of merlin expression in tumorl ets as well as schwannomas, with intact expression in adjacent nerve. Thus, loss of both NF2 alleles and merlin occur early in Schwann cell tumorigene sis, before the tumorlet stage. The study of tumorlets and schwannomas in s uch patients may also provide an opportunity to elucidate mechanisms respon sible for the subsequent growth of Schwann cell lesions into symptomatic tu mors.