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Clinical and molecular predictors of mortality in neurofibromatosis 2: a UK national analysis of 1192 patients
  1. Adam Hexter1,
  2. Adrian Jones2,
  3. Harry Joe2,
  4. Laura Heap1,
  5. Miriam J Smith3,
  6. Andrew J Wallace1,
  7. Dorothy Halliday4,
  8. Allyson Parry5,
  9. Amy Taylor6,
  10. Lucy Raymond6,
  11. Adam Shaw7,
  12. Shazia Afridi8,
  13. Rupert Obholzer9,
  14. Patrick Axon10,
  15. Andrew T King11,
  16. The English Specialist NF2 Research Group,
  17. Jan M Friedman12,13,
  18. D Gareth R Evans1,3
    1. 1Manchester Centre for Genomic Medicine, Central Manchester NHS Foundation Trust, St Mary's Hospital, Manchester, UK
    2. 2Department of Statistics, University of British Columbia, Vancouver, Canada
    3. 3Manchester Centre for Genomic Medicine, Institute of Human Development, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
    4. 4Medical Genetics, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
    5. 5Neurology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
    6. 6Medical Genetics, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
    7. 7Department of Medical Genetics, Guy's and St. Thomas’ Hospital, London, UK
    8. 8Department of Neurology, Guy's and St. Thomas’ Hospital, London, UK
    9. 9Department of Ear, Nose and Throat, Guy's and St. Thomas’ Hospital, London, UK
    10. 10Department of Otolaryngology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
    11. 11Department of Neurosurgery, Salford Royal NHS Foundation Trust, St. Mary's Hospital, Manchester, UK
    12. 12Department of Medical Genetics, University of British Columbia, Vancouver, Canada
    13. 13Child & Family Research Institute, Vancouver, Canada
    1. Correspondence to Professor J M Friedman, Medical Genetics Research Unit, Children's & Women's Hospital, Box 153, 4500 Oak Street, Vancouver, B.C. Canada V6H 3N1; jan.friedman{at}ubc.ca

    Abstract

    Background Neurofibromatosis 2 (NF2) is an autosomal-dominant tumour predisposition syndrome characterised by bilateral vestibular schwannomas, considerable morbidity and reduced life expectancy. Although genotype–phenotype correlations are well established in NF2, little is known about effects of mutation type or location within the gene on mortality. Improvements in NF2 diagnosis and management have occurred, but their effect on patient survival is unknown.

    Methods We evaluated clinical and molecular predictors of mortality in 1192 patients (771 with known causal mutations) identified through the UK National NF2 Registry. Kaplan–Meier survival and Cox regression analyses were used to evaluate predictors of mortality, with jackknife adjustment of parameter SEs to account for the strong intrafamilial phenotypic correlations that occur in NF2.

    Results The study included 241 deaths during 10 995 patient-years of follow-up since diagnosis. Early age at diagnosis and the presence of intracranial meningiomas were associated with increased mortality, and having a mosaic, rather than non-mosaic, NF2 mutation was associated with reduced mortality. Patients with splice-site or missense mutations had lower mortality than patients with truncating mutations (OR 0.459, 95% CI 0.213 to 0.990, and OR 0.196, 95% CI 0.213 to 0.990, respectively). Patients with splice-site mutations in exons 6–15 had lower mortality than patients with splice-site mutations in exons 1–5 (OR 0.333, 95% CI 0.129 to 0.858). The mortality of patients with NF2 diagnosed in more recent decades was lower than that of patients diagnosed earlier.

    Conclusions Continuing advances in molecular diagnosis, imaging and treatment of NF2-associated tumours offer hope for even better survival in the future.

    • Neurofibromatosis 2
    • Mortality
    • Genotype-phenotype correlation
    • Survival

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