D Gareth Evans1, Andrew T King2, Naomi L Bowers3, Simon Tobi3, Andrew J Wallace3, Mary Perry3, Raji Anup3, Simon K L Lloyd4, Scott A Rutherford2, Charlotte Hammerbeck-Ward2, Omar N Pathmanaban2, Emma Stapleton4,5, Simon R Freeman4,5, Mark Kellett6, Dorothy Halliday7, Allyson Parry7, Juliette J Gair8, Patrick Axon8, Roger Laitt9, Owen Thomas9, Shazia Afridi10, Rosalie E Ferner10, Elaine F Harkness11, Miriam J Smith3. 1. Department of Genomic Medicine, St Mary's Hospital, Manchester Academic Health Sciences Centre (MAHSC), Division of Evolution and Genomic Science, University of Manchester, Manchester, UK. gareth.evans@mft.nhs.uk. 2. Department of Neurosurgery, Manchester Centre for Clinical Neurosciences, Salford Royal Foundation Trust, Manchester Academic Health Sciences Centre (MAHSC), Manchester, UK. 3. Department of Genomic Medicine, St Mary's Hospital, Manchester Academic Health Sciences Centre (MAHSC), Division of Evolution and Genomic Science, University of Manchester, Manchester, UK. 4. Department of Otolaryngology, Manchester Royal Infirmary, Manchester Academic Health Sciences Centre (MAHSC), University of Manchester, Manchester, UK. 5. Salford Royal Foundation Trust, Manchester Academic Health Sciences Centre (MAHSC), Manchester, UK. 6. Department of Neurology, Manchester Centre for Clinical Neurosciences, Salford Royal Foundation Trust, Manchester Academic Health Sciences Centre (MAHSC), Manchester, UK. 7. Oxford Centre for Genomic Medicine, Nuffield Orthopaedic Centre, Oxford University Hospitals NHS Trust, Oxford, UK. 8. Department of Otolaryngology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK. 9. Department of Neuroradiology, Manchester Centre for Clinical Neurosciences, Salford Royal Foundation Trust, Manchester Academic Health Sciences Centre (MAHSC), Manchester, UK. 10. Department of Neurology, Guy's and St Thomas' NHS Foundation Trust, London, UK. 11. Division of Informatics, Imaging and Data Sciences, School of Health Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
Abstract
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.
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.
Entities:
Keywords:
LZTR1; NF2; diagnostic criteria; neurofibromatosis type 2; schwannoma
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