Predictors of Mortality in Neurofibromatosis 2
Predictors of Mortality in Neurofibromatosis 2
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 (NF2) is an autosomal-dominant tumour predisposition syndrome with an estimated birth incidence of 1 in 33 000. NF2 is characterised by the presence of bilateral vestibular schwannomas, which can manifest with deafness, tinnitus and problems with balance. Many patients with NF2 also have other histologically benign central nervous system tumours, such as meningiomas and spinal ependymomas.
The NF2 gene is located on chromosome 22 and consists of 17 exons. It codes for a protein called merlin (or schwannomin), which is a member of the band 4.1 family of cytoskeleton-associated proteins. Merlin's functions include modulation of numerous signalling pathways involved in cell proliferation and regulation of the formation of plasma membrane domains.
NF2 is a chronic condition associated with considerable morbidity, reduced quality of life and a reduced life expectancy. Twenty-three years ago, Evans and associates reported that the mean age of death in people with NF2 in the UK was 36.25 years. The severity of the clinical problems that patients with NF2 experience and the importance of expert surgical management have led to a shift towards care provision in specialty centres.
The most important factors associated with mortality in patients with NF2 are mosaicism for the NF2 mutation (associated with lower risk of death), age at diagnosis (inversely associated with risk of death) and the presence of intracranial meningiomas (associated with higher risk of death).
Missense mutations produce merlin protein that is defective in its negative growth regulatory and tumour suppressive functions, whereas nonsense mutations usually produce unstable forms of merlin. Both nonsense mutations and deletions of the NF2 gene result in haploinsufficiency of merlin protein. Splice-site and frameshift mutations have a variable effect on the protein, depending on where in the gene they occur and the functional consequences on the abnormal protein product.
Genotype–phenotype correlations have been clearly demonstrated in patients with NF2, with mortality risk varying with NF2 mutation class. Missense mutations are associated with a considerably lower risk of mortality and a milder NF2 phenotype. Nonsense mutations and frameshift mutations that result in truncation of the NF2 gene product are associated with a more severe phenotype. Large deletions are generally the second most severe type of constitutional mutations but can yield varying phenotypes, with some large deletions producing unexpectedly mild disease. Splice-site mutations are associated with variable disease severity, with mutations in exons 1–5 associated with more severe disease than mutations in exons 11–15.
Although these genotype–phenotype correlations are well established, it is currently unknown whether the effect of truncating mutations differs by location within the NF2 gene. It is also unknown whether the advent of centres with special expertise in the diagnosis and management of NF2 has improved survival among patients with NF2. In the present investigation, we evaluate the clinical and molecular predictors of mortality in the largest series of patients with NF2 ever studied.
Abstract and Introduction
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.
Introduction
Neurofibromatosis 2 (NF2) is an autosomal-dominant tumour predisposition syndrome with an estimated birth incidence of 1 in 33 000. NF2 is characterised by the presence of bilateral vestibular schwannomas, which can manifest with deafness, tinnitus and problems with balance. Many patients with NF2 also have other histologically benign central nervous system tumours, such as meningiomas and spinal ependymomas.
The NF2 gene is located on chromosome 22 and consists of 17 exons. It codes for a protein called merlin (or schwannomin), which is a member of the band 4.1 family of cytoskeleton-associated proteins. Merlin's functions include modulation of numerous signalling pathways involved in cell proliferation and regulation of the formation of plasma membrane domains.
NF2 is a chronic condition associated with considerable morbidity, reduced quality of life and a reduced life expectancy. Twenty-three years ago, Evans and associates reported that the mean age of death in people with NF2 in the UK was 36.25 years. The severity of the clinical problems that patients with NF2 experience and the importance of expert surgical management have led to a shift towards care provision in specialty centres.
The most important factors associated with mortality in patients with NF2 are mosaicism for the NF2 mutation (associated with lower risk of death), age at diagnosis (inversely associated with risk of death) and the presence of intracranial meningiomas (associated with higher risk of death).
Missense mutations produce merlin protein that is defective in its negative growth regulatory and tumour suppressive functions, whereas nonsense mutations usually produce unstable forms of merlin. Both nonsense mutations and deletions of the NF2 gene result in haploinsufficiency of merlin protein. Splice-site and frameshift mutations have a variable effect on the protein, depending on where in the gene they occur and the functional consequences on the abnormal protein product.
Genotype–phenotype correlations have been clearly demonstrated in patients with NF2, with mortality risk varying with NF2 mutation class. Missense mutations are associated with a considerably lower risk of mortality and a milder NF2 phenotype. Nonsense mutations and frameshift mutations that result in truncation of the NF2 gene product are associated with a more severe phenotype. Large deletions are generally the second most severe type of constitutional mutations but can yield varying phenotypes, with some large deletions producing unexpectedly mild disease. Splice-site mutations are associated with variable disease severity, with mutations in exons 1–5 associated with more severe disease than mutations in exons 11–15.
Although these genotype–phenotype correlations are well established, it is currently unknown whether the effect of truncating mutations differs by location within the NF2 gene. It is also unknown whether the advent of centres with special expertise in the diagnosis and management of NF2 has improved survival among patients with NF2. In the present investigation, we evaluate the clinical and molecular predictors of mortality in the largest series of patients with NF2 ever studied.
