Subjects

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.

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Acknowledgements

The authors wish to acknowledge National Health Service (NHS) England for their support of the National NF2 program. D.G.E., E.F.H., and M.J.S. are supported by the Manchester National Institute for Health Research (NIHR) Biomedical Research Centre (IS-BRC-1215-20007)

English Specialist NF2 Research Group members:

Cambridge/Central: Patrick Axon, Juliette Gair, James Tysome, Neil Donnelly, Lucy Raymond, Anke Hensiek, Rajesh Jena, Robert Macfarlane, Richard Mannion, James Nicholson, Brinda Muthusamy, Amy Taylor, Richard Price, Gabriella Rands, Nicola Gamazo, Zebunnisa Daniel Scoffings, Sarah Jefferies, Richard Knight, Tamara Lamb, Vanat, Yu Chuen Tam, Karen Foweraker, Fiona Harris, David Heney, Paul Sanghera, Richard Irving, Peter Monksfield, Saba Sharif, Nicola Ragge, Carolyn Smyth, Julian Barwell, Martin English. London: Shazia Afridi, Rosalie Ferner, Rupert Obholzer, Victoria Williams, Chris Hammond, Karine Lascelles, Chris Skilbeck, Shakeel Saeed, Adam Shaw, Angela Swampillai, Suki Thomson, Nick Thomas, Eleni Maratos, Sinan Barazi, Rebecca Mullin, Susie Henley, Sally Trump, Vanessa Everett, Terry Nunn, Charles Nduka. Manchester/North: D Gareth Evans, Raji Anup, Chris Duff, Simon R Freeman, Emma Stapleton, Nicola Jarvis, Ian Kamaly-Asl, Andrew King, Mark Kellett, John-Paul Kilday, Simon Lloyd, Connor Malluci, Deborah Mawman, Catherine McBain, Roger Laitt, Martin O’Driscoll, Martin McCabe, Mary Perry, Scott Rutherford, Kirsty Henshaw, Stavros Stivaros, Owen Thomas, Grace Vassallo, Charlotte Hammerbeck-Ward, Omar Pathmanaban, Jincy Kurian. Oxford/South-West: Claire Blesing, Kate Browne, Rosie Crabtree, Lucy Cogswell, Louise Dalton, Caroline Dodridge, Beatrice Emmanouil, Henk Giele, Dorothy Halliday, C Oliver Hanemann, Wendy Howard, Sanjeeva Jeyaretna, Richard Kerr, Elle Mace, Sam MacKeith, Anne May, Allyson Parry, Peter Pretorius, James Ramsden, Carolyn Redman, Srilakshmi Sharma Ros Taylor, Helen Tomkins, Shaun Wilson, Rachael Woolrich.

Author information

Affiliations

  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

    • D. Gareth Evans FRCP
    • , Naomi L. Bowers BSc
    • , Simon Tobi PhD
    • , Andrew J. Wallace PhD
    • , Mary Perry RN
    • , Raji Anup RN
    •  & Miriam J. Smith PhD
  2. Department of Neurosurgery, Manchester Centre for Clinical Neurosciences, Salford Royal Foundation Trust, Manchester Academic Health Sciences Centre (MAHSC), Manchester, UK

    • Andrew T. King FRCS
    • , Scott A. Rutherford FRCS
    • , Charlotte Hammerbeck-Ward FRCS
    •  & Omar N. Pathmanaban FRCS
  3. Department of Otolaryngology, Manchester Royal Infirmary, Manchester Academic Health Sciences Centre (MAHSC), University of Manchester, Manchester, UK

    • Simon K. L. Lloyd FRCS
    • , Emma Stapleton FRCS
    •  & Simon R. Freeman FRCS
  4. Salford Royal Foundation Trust, Manchester Academic Health Sciences Centre (MAHSC), Manchester, UK

    • Emma Stapleton FRCS
    •  & Simon R. Freeman FRCS
  5. Department of Neurology, Manchester Centre for Clinical Neurosciences, Salford Royal Foundation Trust, Manchester Academic Health Sciences Centre (MAHSC), Manchester, UK

    • Mark Kellett FRCP
  6. Oxford Centre for Genomic Medicine, Nuffield Orthopaedic Centre, Oxford University Hospitals NHS Trust, Oxford, UK

    • Dorothy Halliday FRCP
    •  & Allyson Parry FRCP
  7. Department of Otolaryngology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK

    • Juliette J. Gair MSc
    •  & Patrick Axon FRCS
  8. Department of Neuroradiology, Manchester Centre for Clinical Neurosciences, Salford Royal Foundation Trust, Manchester Academic Health Sciences Centre (MAHSC), Manchester, UK

    • Roger Laitt FRCP
    •  & Owen Thomas DPhil
  9. Department of Neurology, Guy’s and St Thomas’ NHS Foundation Trust, London, UK

    • Shazia Afridi FRCP
    •  & Rosalie E. Ferner FRCP
  10. Division of Informatics, Imaging and Data Sciences, School of Health Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK

    • Elaine F. Harkness PhD

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Consortia

  1. The English Specialist NF2 Research Group

    Disclosure

    The authors declare no conflicts of interest.

    Corresponding author

    Correspondence to D. Gareth Evans FRCP.

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    DOI

    https://doi.org/10.1038/s41436-018-0384-y