Germline mutations in the von Hippel-Lindau (VHL) gene in patients from Poland: disease presentation in patients with deletions of the entire VHL gene

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Abstract
Von Hippel-Lindau (VHL) disease is a rare autosomal dominant disorder characterised by a predisposition to haemangioblastomas of the central nervous system (cHAB) and retina (rHAB), renal cell carcinomas (RCC), phaeochromocytomas and paragangliomas, endolymphatic sac tumours (ELST), pancreatic neuroendocrine tumours (PNET), papillary cystadenomas of epididymis, and adnexal papillary tumours of probable mesonephric origin (APMO). Renal, pancreatic, epididymal, and broad ligament cysts also occur frequently.1 It is caused by germline mutations in the VHL tumour suppressor gene on chromosome 3p25-26.2,3 VHL disease occurs with an estimated incidence of 1:36 000 live births and shows variable expression and age dependent penetrance that is almost complete by the age of 65.4 Median actuarial life expectancy of VHL subjects is reduced to 49 years, renal cell carcinoma5 or CNS haemangioblastoma6 being the most common cause of death. At present, early diagnosis and treatment of VHL associated tumours result in improved prognosis for VHL subjects.7 The disease can be diagnosed on the basis of clinical criteria in the presence of a single haemangioblastoma, phaeochromocytoma, multiple pancreatic cysts, or renal cell carcinoma in a member of a VHL family. For clinical diagnosis of isolated cases of VHL, at least two haemangioblastomas or a single haemangioblastoma in association with a visceral manifestation are required.8 In early studies, using standard Southern analysis and sequencing of the VHL coding region, disease causing mutations were detected in 38-80% of families fulfilling clinical VHL criteria.1 More recently, the development of quantitative Southern analysis (QSA) to detect partial and complete deletions has improved VHL mutation detection. QSA analysis in conjunction with direct sequencing of the coding region showed germline mutations in 100% of 93 families with definite VHL.9 However, the results implying that all cases fulfilling clinical VHL criteria are related to mutations …