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

Genet Med. 2019 Jul;21(7):1525-1533. doi: 10.1038/s41436-018-0384-y. Epub 2018 Dec 7.


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.

Keywords: LZTR1; NF2; diagnostic criteria; neurofibromatosis type 2; schwannoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Child
  • Databases, Factual*
  • Diagnosis, Differential
  • Female
  • Humans
  • Male
  • Molecular Diagnostic Techniques
  • Neurofibromatosis 2 / diagnosis*
  • Neurofibromatosis 2 / physiopathology
  • Terminology as Topic
  • Young Adult