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Clinical and molecular predictors of mortality in neurofibromatosis 2: A UK national analysis of 1192 patients

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Adam Hexter ; Adrian Jones ; Harry Joe ; Laura Heap ; Miriam J. Smith ; Andrew J. Wallace ; Dorothy Halliday ; Allyson Parry ; Amy Taylor ; Lucy Raymond ; Adam Shaw ; Shazia Afridi ; Rupert Obholzer ; Patrick Axon ; Andrew T. King ; Jan M. Friedman ; D. Gareth R Evans ; Neil Burnet ; Neil Donnelly ; Juliette Durie-Gair ; Martin English ; Nicola Folland ; Karen Foweraker ; Fiona Harris ; Frances Harris ; David Heney ; Sarah Jeffries ; Raj Jena ; Richard Knight ; Tamara Lamb ; Robert Macfarlane ; Richard Mannion ; James Nicholson ; Richard Price ; Ella Rands ; Paul Sanghera ; Daniel Scoffings ; James Tysome ; Rosalie E. Ferner ; Christina L. Hammond ; Karine Lascelles ; Terry Nunn ; Shakeel Saeed ; Angela Swampillai ; Suki Thomson ; Daniel Walsh ; Victoria Williams ; Sue Wood ; Raji Anup ; Chris Duff ; D. Gareth Evans ; Simon R. Freeman ; Emma Howie ; Susan M. Huson ; Nicola Jarvis ; Ian Kamaly-Asi ; Andrew King ; Mark Kellett ; John Paul Kilday ; Simon K. Lloyd ; Connor Malluci ; Deborah Mawman ; Catherine McBain ; Sam Mills ; Martin O'Driscoll ; Sonia Patel ; Mary Perry ; Scott A. Rutherford ; Vilka Scott-Kitching ; Stavros M. Stivaros ; Owen Thomas ; Grace Vassallo ; Charlotte L. Ward ; Claire Blesing ; Lucy Cogswell ; Louise Dalton ; Caroline Dodridge ; John Elston ; Henk Giele ; C. Oliver Hanemann ; Richard Kerr ; Avianna Laws ; Elle Mace ; Anne May ; Chris Milford ; Peter Pretorius ; James Ramsden ; Caroline Redman ; Nicola Warner ; Shaun Wilson

Original languageEnglish
JournalJournal of Medical Genetics
DOIs
StateAccepted/In press - 14 Aug 2015

King's Authors

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.

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