We have evaluated deficiencies in existing diagnostic criteria for neurofibromatosis 2 (NF2).


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.


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%.


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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1.

    Neurofibromatosis. Conference statement. National Institutes of Health Consensus Development Conference. Arch Neurol. 1988;45:575–578.

  2. 2.

    Evans DG, Huson SM, Donnai D, et al. A clinical study of type 2 neurofibromatosis. Q J Med. 1992;84:603–618.

  3. 3.

    Baser ME, Friedman JM, Joe H, et al. Empirical development of improved diagnostic criteria for neurofibromatosis 2. Genet Med. 2011;13:576–581.

  4. 4.

    Baser ME, Friedman JM, Wallace AJ, Ramsden RT, Joe H, Evans DG. Evaluation of clinical diagnostic criteria for neurofibromatosis 2. Neurology. 2002;59:1759–1765.

  5. 5.

    King AT, Rutherford SA, Hammerbeck-Ward C, et al. High-grade glioma is not a feature of neurofibromatosis type 2 in the unirradiated patient. Neurosurgery. 2018;83:193–196.

  6. 6.

    Hagel C, Stemmer-Rachamimov AO, Bornemann A, et al. Clinical presentation, immunohistochemistry and electron microscopy indicate neurofibromatosis type 2-associated gliomas to be spinal ependymomas. Neuropathology. 2012;32:611–616.

  7. 7.

    Piotrowski A, Xie J, Liu YF, et al. Germline loss-of-function mutations in LZTR1 predispose to an inherited disorder of multiple schwannomas. Nat Genet. 2014;46:182–187.

  8. 8.

    Smith MJ, Isidor B, Beetz C, et al. Mutations in LZTR1 add to the complex heterogeneity of schwannomatosis. Neurology. 2015;84:141–147.

  9. 9.

    Smith MJ, Bowers NL, Bulman M, et al. Revisiting neurofibromatosis type 2 diagnostic criteria to exclude LZTR1-related schwannomatosis. Neurology. 2017;88:87–92.

  10. 10.

    Evans DG, Freeman S, Gokhale C, et al. Bilateral vestibular schwannomas in older patients: NF2 or chance? J Med Genet. 2015;52:422–424.

  11. 11.

    Smith MJ, Wallace AJ, Bennett C, et al. Germline SMARCE1 mutations predispose to both spinal and cranial clear cell meningiomas. J Pathol. 2014;234:436–440.

  12. 12.

    Smith MJ, O’Sullivan J, Bhaskar SS, et al. Loss-of-function mutations in SMARCE1 cause an inherited disorder of multiple spinal meningiomas. Nat Genet. 2013;45:295–298.

  13. 13.

    Kalamarides M, Essayed W, Lejeune JP, et al. Spinal ependymomas in NF2: a surgical disease? J Neurooncol. 2018;136:605–611.

  14. 14.

    Evans DG, Wallace A. An update on age related mosaic and offspring risk in neurofibromatosis 2 (NF2). J Med Genet. 2009;46:792.

  15. 15.

    Evans DG, Bowers NL, Tobi S, et al. Schwannomatosis: a genetic and epidemiological study. J Neurol Neurosurg Psychiatry. 2018;89:1215–1219.

  16. 16.

    Antinheimo J, Sankila R, Carpen O, Pukkala E, Sainio M, Jaaskelainen J. Population-based analysis of sporadic and type 2 neurofibromatosis-associated meningiomas and schwannomas. Neurology. 2000;54:71–76.

  17. 17.

    van den Munckhof P, Christiaans I, Kenter SB, Baas F, Hulsebos TJ. Germline SMARCB1 mutation predisposes to multiple meningiomas and schwannomas with preferential location of cranial meningiomas at the falx cerebri. Neurogenetics. 2011;13:1–7.

  18. 18.

    Aavikko M, Li SP, Saarinen S, et al. Loss of SUFU function in familial multiple meningioma. Am J Hum Genet. 2012;91:520–526.

  19. 19.

    Sestini R, Vivarelli R, Balestri P, Ammannati F, Montali E, Papi L. Neurofibromatosis type 2 attributable to gonosomal mosaicism in a clinically normal mother, and identification of seven novel mutations in the NF2 gene. Human Genet. 2000;107:366–371.

  20. 20.

    Parry DM, Eldridge R, Kaiser-Kupfer MI, Bouzas EA, Pikus A, Patronas N. Neurofibromatosis 2 (NF2): clinical characteristics of 63 affected individuals and clinical evidence for heterogeneity. Am J Med Genet. 1994;52:450–461.

  21. 21.

    Evans DG, Raymond FL, Barwell JG, Halliday D. Genetic testing and screening of individuals at risk of NF2. Clin Genet. 2012;82:416–424.

  22. 22.

    Ruggieri M, Pratico AD, Serra A, et al. Childhood neurofibromatosis type 2 (NF2) and related disorders: from bench to bedside and biologically targeted therapies. Acta Otorhinolaryngol Ital. 2016;36:345–367.

  23. 23.

    Anand G, Vasallo G, Spanou M, et al. Diagnosis of sporadic neurofibromatosis type 2 in the paediatric population. Arch Dis Child. 2018;103:463–469.

  24. 24.

    Painter SL, Sipkova Z, Emmanouil B, Halliday D, Parry A, Elston JS. Neurofibromatosis type 2-related eye disease correlated with genetic severity type. J Neuroophthalmol. 2018. [Epub ahead of print].

  25. 25.

    Montgomery BK, Alimchandani M, Mehta GU, et al. Tumors displaying hybrid schwannoma and neurofibroma features in patients with neurofibromatosis type 2. Clin Neuropathol. 2016;35:78–83.

  26. 26.

    Hexter A, Jones A, Joe H, et al. Clinical and molecular predictors of mortality in neurofibromatosis 2: a UK national analysis of 1192 patients. J Med Genet. 2015;52:699–705.

  27. 27.

    Ron E, Modan B, Boice JD Jr, et al. Tumors of the brain and nervous system after radiotherapy in childhood. N Engl J Med. 1988;319:1033–1039.

  28. 28.

    Sznajder L, Abrahams C, Parry DM, Gierlowski TC, Shore-Freedman E, Schneider AB. Multiple schwannomas and meningiomas associated with irradiation in childhood. Arch Intern Med. 1996;156:1873–1878.

  29. 29.

    Bokstein F, Dubov T, Toledano-Alhadef H, et al. Cranial irradiation in childhood mimicking neurofibromatosis type II. Am J Med Genet. 2017;173:1635–1639.

  30. 30.

    Evans DG, Birch JM, Ramsden RT, Sharif S, Baser ME. Malignant transformation and new primary tumours after therapeutic radiation for benign disease: substantial risks in certain tumour prone syndromes. J Med Genet. 2006;43:289–294.

Download references


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


  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


  1. Search for D. Gareth Evans FRCP in:

  2. Search for Andrew T. King FRCS in:

  3. Search for Naomi L. Bowers BSc in:

  4. Search for Simon Tobi PhD in:

  5. Search for Andrew J. Wallace PhD in:

  6. Search for Mary Perry RN in:

  7. Search for Raji Anup RN in:

  8. Search for Simon K. L. Lloyd FRCS in:

  9. Search for Scott A. Rutherford FRCS in:

  10. Search for Charlotte Hammerbeck-Ward FRCS in:

  11. Search for Omar N. Pathmanaban FRCS in:

  12. Search for Emma Stapleton FRCS in:

  13. Search for Simon R. Freeman FRCS in:

  14. Search for Mark Kellett FRCP in:

  15. Search for Dorothy Halliday FRCP in:

  16. Search for Allyson Parry FRCP in:

  17. Search for Juliette J. Gair MSc in:

  18. Search for Patrick Axon FRCS in:

  19. Search for Roger Laitt FRCP in:

  20. Search for Owen Thomas DPhil in:

  21. Search for Shazia Afridi FRCP in:

  22. Search for Rosalie E. Ferner FRCP in:

  23. Search for Elaine F. Harkness PhD in:

  24. Search for Miriam J. Smith PhD in:


  1. The English Specialist NF2 Research Group


    The authors declare no conflicts of interest.

    Corresponding author

    Correspondence to D. Gareth Evans FRCP.

    About this article

    Publication history