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

Abstract

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 specificity with regard to refuted diagnosis. Results: There was no evidence for usefulness of old criteria 'glioma' or 'neurofibroma'. 'Ependymoma' had 100% specificity 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 specificity (80%). Siblings as a firstdegree-relative, without an affected parent, had 0% specificity. All three individuals with a 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 a unilateral VS plus ≥2 non-dermal schwannomas reduced specificity to 67%. Conclusion: The present study has confirmed 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-degreerelatives should be considered and testing of LZTR1 should be recommended for unilateral VS.

Genetic Counseling for Neurofibromatosis 1, Neurofibromatosis 2, and Schwannomatosis—Practice Resource of the National Society of Genetic Counselors

“…6 Literature exists in support of NF2 genetic testing for individuals with one or more feature of NF2 who do not meet clinical diagnostic criteria, such as individuals with NF2‐associated ocular findings and solitary ependymoma. (Evans, et al., 2019; Gaudioso et al., 2019). 7 Whenever possible, genetic testing should be done on a known affected individual.…”

“…Lymphocyte variant detection rates vary based on founder versus non‐founder status because of the high rate of somatic mosaicism in NF2. Although many reports have published somatic mosaicism in up to 30% of simplex cases (Moyhuddin et al., 2003), the recent use of next‐generation sequencing suggests mosaicism to be as high as 60% in first‐generation affected individuals (Evans, Hartley et al, 2019; Evans et al, 2019). Therefore, careful consideration of laboratory methodology and cautious interpretation of seemingly uninformative results are necessary.…”

“…Evans et al review age‐based strategies for the evaluation of individuals with UVS, and recommend NF2 genetic testing for individuals aged 20 years and younger (Aghi et al., 2006; Evans et al., 2007, 2008). UVS has also been observed in individuals with LZTR1 variants, and additional testing for this gene could be considered (Evans, et al., 2019; Figure 2).…”

“…There is no increased incidence of developmental delay, cognitive or learning problems, or attention difficulties in NF2 or SWN, and, if present, other etiologies should be considered and ring chromosome 22 should be ruled out (Evans et al, 2019).…”

The Effect of Bevacizumab on Vestibular Schwannoma Related to Neurofibromatosis Type 2

“…Neurofibromatosis type 2 (NF2) is a rare, predominantly hereditary, genetic mutation of the NF2 suppressor gene on chromosome 22. It occurs as an autosomal dominant inherited mutation, or as a sporadic somatic mutation, with up to 50% of patients presenting with a de novo mutation (Evans, 2009;Evans et al, 2019). Individuals with NF2 are at high risk of developing tumours of the cen-The mean age of onset of symptomatic VS is 20-30 years (Parry et al, 1994).…”