Manchester diagnostic criteria for neurofibromatosis type 2 (NF2)

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Bibliography

Evans, D. G., A. T. King, N. L. Bowers, et al. 2019. "Identifying the deficiencies of current diagnostic criteria for neurofibromatosis 2 using databases of 2777 individuals with molecular testing." Genet Med 21(7): 1525-1533.

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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.

Smith, M.J., N.L. Bowers, M. Bulman, et al. 2017. "Revisiting neurofibromatosis type 2 diagnostic criteria to exclude LZTR1-related schwannomatosis." Neurology 88(1):87-92.

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OBJECTIVE: To determine the specificity of the current clinical diagnostic criteria for neurofibromatosis type 2 (NF2) relative to the requirement for unilateral vestibular schwannoma (VS) and at least 2 other NF2-related tumors. METHODS: We interrogated our Manchester NF2 database, which contained 205 individuals meeting NF2 criteria who initially presented with a unilateral VS. Of these, 83 (40.7%) went on to develop a contralateral VS. We concentrated our genetic analysis on a group of 70 who initially fulfilled NF2 criteria with a unilateral vestibular schwannoma and at least 2 additional nonintradermal schwannomas. RESULTS: Overall, 5/70 (7%) individuals with unilateral VS and at least 2 other schwannomas had a pathogenic or likely pathogenic LZTR1 mutation. Twenty of the 70 subsequently developed bilateral disease. Of the remaining 50, 5 (10%) had a germline LZTR1 mutation, equivalent to the number (n = 5) with a germline NF2 mutation. CONCLUSIONS: The most common etiology for unilateral VS and 2 additional NF2-associated tumors in this cohort was mosaic NF2. Germline LZTR1 and germline NF2 mutations were equally common in our cohort. This indicates that LZTR1 must be considered when making a diagnosis of NF2 in the presence of unilateral VS in individuals without a germline NF2 mutation.

Version 5

Date

Summary of changes

14/08/2021

Document reviewed in line with ID 1909 and ID 1910 at May 2021 cancer genetics reference committee meeting. Approved for publication with the following changes made: Subheading removed: 'Revised Manchester criteria for neurofibromatosis type 2 (NF2)' 'Neurofibroma' removed 'Glioma' changed to 'ependymoma (glioma)' '(cataract)' added Formatting changes applied New reference added Version increased to V.5. To be reviewed in line with ID 1909 and ID 1910.

Version 4

Date	Summary of changes
31/05/2017	Transferred to new eviQ website. Version change to V.2. Previous website ID: 357
20/09/2018	Presented at May 2018 RCM. Document updated based on revisions to criteria discussed at international meeting. Approved to publish with the following updates: Version changed to V.3 '<70 years' added to bilateral vestibular schwannoma and unilateral vestibular schwannoma. 'cerebral calcification (if unilateral vestibular schwannoma + two nonintradermal schwannomas need negative LZTR1 test)' added to second and third bullet points. 'Multiple meningiomas AND unilateral vestibular schwannoma OR any two of schwannoma, glioma neurofibroma, cataract' updated to 'Multiple meningiomas (two or more) AND two of: unilateral vestibular schwannoma, posterior subcapsular lenticular opacities, glioma, neurofibroma, schwannoma, cerebral calcification' 'Constitutional or mosaic pathogenic NF2 gene mutation in blood OR identical mutations in 2 distinct tumours' added. References updated along with footnote regarding expected publication of international diagnostic criteria in 2019.  Review due date amended to November 2019, to review publication of new Manchester criteria.
06/09/2019	"Mutation" changed to "pathogenic variant" throughout document for consistency among eviQ cancer genetics protocols per agreement among the cancer genetics reference committees' chairs. Definition of "pathogenic variant" added as a pop-up. Version number increased to V.4.