Identifying the deficiencies of current diagnostic criteria for neurofibromatosis 2 using databases of 2777 individuals with molecular testing

Purpose: We have evaluated deficiencies in existing diagnostic criteria for neurofibromatosis 2 (NF2). Methods: Two large databases of individuals fulfilling NF2 criteria (n = 1361) and those tested for NF2 variants with criteria short of diagnosis (n = 1416) were interrogated. We assessed the proportions meeting each diagnostic criterion with constitutional or mosaic NF2 variants and the positive predictive value (PPV) with regard to definite diagnosis. Results: There was no evidence for usefulness of old criteria glioma or neurofibroma. Ependymoma had 100% PPV and high levels of confirmed NF2 diagnosis (67.7%). Those with bilateral vestibular schwannoma (VS) alone aged >= 60 years had the lowest confirmation rate (6.6%) and reduced PPV (80%). Siblings as a first-degree relative, without an affected parent, had 0% PPV. All three individuals with unilateral VS and an affected sibling were proven not to have NF2. The biggest overlap was with LZTR1- associated schwannomatosis. In this category, seven individuals with unilateral VS plus >= 2 nondermal schwannomas reduced PPV to 67%. Conclusions: The present study confirms important deficiencies in NF2 diagnostic criteria. The term glioma should be dropped and replaced by ependymoma. Similarly neurofibroma should be removed. Dropping sibling from first-degree relatives should be considered and testing of LZTR1 should be recommended for unilateral VS.