Genetic Severity Score predicts clinical phenotype in NF2

Abstract

​BackgroundThe clinical severity of disease in neurofibromatosis type 2 (NF2) is variable. Patients affected with a constitutional truncating NF2 mutation have severe disease, while missense mutations or mosaic mutations present with a milder attenuated phenotype. Genotype-derived natural history data are important to inform discussions on prognosis and management.MethodsWe have assessed NF2 clinical phenotype in 142 patients in relation to the UK NF2 Genetic Severity Score to validate its use as a clinical and research tool.ResultsThe Genetic Severity Score showed significant correlations across 10 measures, including mean age at diagnosis, proportion of patients with bilateral vestibular schwannomas, presence of intracranial meningioma, spinal meningioma and spinal schwannoma, NF2 eye features, hearing grade, age at first radiotherapy, age at first surgery and age starting bevacizumab. In addition there was moderate but significant correlation with age at loss of useful hearing, and weak but significant correlations for mean age at death, quality of life, last optimum Speech Discrimination Score and total number of major interventions. Patients with severe disease presented at a younger age had a higher disease burden and greater requirement of intervention than patients with mild and moderate disease.ConclusionsThis study validates the UK NF2 Genetic Severity Score to stratify patients with NF2 for both clinical use and natural history studies.

Diagnosis of sporadic neurofibromatosis type 2 in the paediatric population

“…In contrast, a recent NF2 cohort including adults found 34% of sporadic cases (40/118) had a moderate/severe mutation, and in >50% of cases no mutation was identified in blood, suggesting NF2 mosaicism 5. The current study highlights the tendency of severe disease to present at a young age, and from this study 1 in 110 611 live births will present as de novo childhood-onset NF2.…”

Progression of hearing loss in neurofibromatosis type 2 according to genetic severity

“…We undertook a retrospective anonymized cohort study by reviewing routinely recorded patient information held in the departmental database to extract demographics, genetic severity, and hearing data for all patients managed within the South West of England National NF2 Service. All eligible patients had a confirmed diagnosis of NF2 and were classified using a genetic severity score . All patients were included regardless of whether they were treatment naive, had undergone surgery, radiotherapy, bevacizumab, or a combination of treatment modalities.…”

“…Recently, a genetic severity score was found to reliably predict phenotype for NF2 patients in several dimensions of morbidity such as hearing, ocular findings, tumor load, and burden of interventions . It would therefore be highly instructive to stratify the risk of hearing loss according to genetic severity.…”

“…It would therefore be highly instructive to stratify the risk of hearing loss according to genetic severity. This study sets out to describe the first large‐scale observational study of the progression of hearing loss as experienced for more than a decade by NF2 patients managed in a multidisciplinary center and to examine potential differences arising as a consequence of the patients’ genetic severity . The primary aim was to describe the rate of hearing loss and age at loss of serviceable hearing for patients with NF2 regardless of treatment intervention, stratifying according to genetic severity.…”

Trends in phenotype in the English paediatric neurofibromatosis type 2 cohort stratified by genetic severity

“…9,32,37 Other studies divided patients into milder and severe phenotypes according to number of lesions or age of onset. [39][40][41] The UK-NF2 genetic severity score was devised and validated 42 to integrate molecular data into clinical use and to facilitate collation of genotype stratified natural history data. [39][40][41] The UK-NF2 genetic severity score was devised and validated 42 to integrate molecular data into clinical use and to facilitate collation of genotype stratified natural history data.…”