Germline mutations in theVHLgene associated with 3 different renal lesions in a Chinese von Hippel-Lindau disease family

Abstract

Von Hippel-Lindau (VHL) disease is a rare autosomal dominant inherited cancer syndrome that is characterized by hemangioblastomas in the central nervous system and retina, renal cell carcinoma and cysts, pancreatic tumors and cysts, and pheochromocytoma. The underlying gene in this disease is the VHL tumor suppressor gene. We characterized a family with 2 affected siblings. The brother and sister displayed VHL type 2B and type 2A features, respectively. Renal lesions in the brother exhibited 3 different phenotypes, including simple renal cysts, multilocular cystic renal cell carcinoma and clear cell renal cell carcinoma. The phenotypes of the 3 concurrent renal lesions were first reported in this study. Mutation detection of the VHL gene revealed 2 recurrent mutations, namely c.256C>T (p.P86S) and c.340 C 5G > C. The former was predicted to be deleterious and to destabilize the hydrophobic core and lead to VHL dysfunction; however, the latter was predicted to be a benign variant. Our findings provided new data for the genotype-phenotype of VHL diseases and elucidated the pathogenic mechanism with in silico analysis.

Von Hippel-Lindau “Black Forest” mutation inherited in a large Chinese family

“…Furthermore, clinical features and genotype-phenotype associations of patients with VHL Y98H mutation were summarized and analysed. VHL disease is an autosomal dominant inherited neoplastic syndrome caused by inactivation of the VHL tumor suppressor gene mapped to chromosome 3p25.3 (2,23). The clinical diagnosis of VHL disease is traditionally described as follows: (I) at least two haemangioblastomas in the CNS or retina; (II) one haemangioblastoma in the CNS or retina plus at least one VHL-related visceral tumor (excluding epididymal and renal cysts); (III) any one of above items with a family history of VHL (24).…”

“…Von Hippel-Lindau (VHL) disease, an autosomal dominant inherited neoplastic syndrome, presents with various clinical phenotypes and age-dependent penetrance. Many kinds of tumors are related to VHL, such as central nervous system (CNS) haemangioblastomas, retinal angiomas (RAs), clearcell renal cell carcinomas (ccRCCs), pheochromocytomas (PCCs), pancreatic neuroendocrine tumors, pancreatic cysts, and endolymphatic sac tumors (1)(2)(3). Meanwhile, paragangliomas (PGLs), and epididymal and broad ligament cystadenomas may also be possible manifestations of VHL disease (4)(5)(6).…”