ABSTRACT
Von Hippel-Lindau (VHL) disease is an autosomal dominantly inherited cancer predisposition syndrome due to germline mutations in the VHL tumor suppressor gene which is associated with virtually complete penetrance. The VHL syndrome has a highly variable phenotypic expressivity including retinal and CNS haemangioblastomas, pheochromocytomas, renal clear cell carcinomas, and multifocal cysts. In order to establish VHL gene testing, we analyzed three families affected by VHL disease, using SSCP mutation screening and DNA sequencing. Among 18 family members with and without clinical manifestations, eight cases with germline VHL mutations were detected. In family A, a c.490G>T/ p.Gly93Cys substitution was found. In family B, with pheochromocytoma only phenotype, we detected a previously not described c.463G>A/p.Val84Met replacement. Within this family, a prenatal diagnosis was also performed. Affected members of the third family with a VHL type 1 disease carried a c.475T>C/p.Trp88Arg exchange. All these mutations were located in exon 1 of the VHL tumor suppressor gene. Alterations in this hydrophobic region of the core beta domain of the VHL protein are known to have a variety of phenotypic consequences. We observed also intrafamiliar variation in time of onset and severity of the disease.
