Germline mutations in the NF2 gene are responsible for 80 percent of typical cases of neurofibromatosis type 2. Mutations are mainly in the form of truncations or deletions but missense mutations have been reported only in a few cases. Major phenotypic variation is found among gene carriers. Clinical data of 154 patients with an NF2 germline alteration characterised in our laboratory were reviewed to assess whether NF2-associated phenotypic variability is linked to genotype.

A retrospective questionnaire was sent to patients’ physicians. Statistical analyses of genotypic and phenotypic data were performed by comparisons of group averages and by correlations.

In French patients, the type of mutation (de novo or inherited) was not correlated with sex or mode of disease onset. Disease associated with missense mutations occurred later, and was less severe. Patients with nonsense or frameshift mutations had more intracranial meningiomas and spinal tumours in addition to VIII nerve schwanomas, an observation that suggests a genetic basis for the number and type of NF2-related tumours.

Results from the literature complement this study to show that there are few correlations between genotype and phenotype in NF2-associated disease. However, missense mutations are associated with a more benign evolution and lower mortality. Nonsense and frameshift mutations are associated with greater numbers of meningiomas and spinal tumours. Therefore, NF2 gene screening is indicated in both typical and moderate forms of disease. Mutations are responsible of 80 percent of cases with typical disease; in moderate forms, identification of a missense mutation indicates a more benign form. In both cases assessments and follow-up should be identical. Finally, in a small number of cases, the NF2 gene is associated with clinical forms that differ significantly from those defined by the NIH. This finding suggests that an enlargement of the definition of NF2-associated clinical features is required.

21 references.