Brain Advance Access originally published online on January 29, 2007
Brain 2007 130(3):836-842; doi:10.1093/brain/awl362
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VHL mutation analysis in patients with isolated central nervous system haemangioblastoma
1Cancer Research UK Renal Molecular Oncology Group, Department of Medical and Molecular Genetics, University of Birmingham, Institute of Biomedical Research and 2West Midlands Regional Genetics Service, Birmingham Women's Hospital, Edgbaston, Birmingham, UK
Corresponding author: Prof. E. R. Maher, Department of Medical and Molecular Genetics, University of Birmingham, Institute of Biomedical Research, Edgbaston, Birmingham, B15 2TT, UK. E-mail: e.r.maher{at}bham.ac.uk
Haemangioblastomas of the CNS are a cardinal feature of von Hippel–Lindau (VHL) disease, a dominantly inherited multisystem familial cancer syndrome caused by germline mutation of the VHL tumour suppressor gene. We investigated the frequency of VHL mutations in 188 patients presenting with a single haemangioblastoma, no family history of VHL disease and no evidence of retinal or abdominal manifestations of the disease at the time of diagnosis. We found that 
4% of patients had a detectable VHL mutation and all of these cases presented age 40 years or less. Although the identification of a germline VHL mutation has important consequences for the patient (e.g. risk of further CNS and extra-CNS tumours) and their relatives, four patients had germline VHL missense mutations [C162Y, D179N and R200W (two patients)] that may represent haemangioblastoma-only and/or low penetrance mutations. Approximately 5% of patients without a detectable VHL mutation subsequently developed a further ‘VHL type tumour’ (in most cases a further CNS haemangioblastoma). These findings suggest that a subset of patients with apparently sporadic CNS haemangioblastoma will have a germline VHL mutation but may not be at risk for developing classical VHL disease and a further group may be mosaic for a germline VHL mutation that cannot be detected in blood cells.
Key Words: genetics; haemangioblastoma; mutation; VHL
Abbreviations: CCRCC, clear cell renal cell carcinoma; CHB, cerebellar haemangioblastoma; CNS, central nervous system; CT, computerised tomography; ELST, endolymphatic sac tumour; FDR, first degree relative; h, hour; HB, haemangioblastoma; HIF, hypoxia-inducible factor; m, months; MLPA, multiplex ligation-dependent probe amplification; MRI, magnetic resonance imaging; Phaeo, phaeochromocytoma; RA, retinal angioma; RCC, renal cell carcinoma; USS, ultrasound scan; VEGF, vascular endothelial growth factor; VHL, von Hippel-Lindau; y, years
Received August 18, 2006. Revised November 22, 2006. Accepted November 29, 2006.
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