Clinical And Genetic Study Of Von Hippel-Lindau Families With Pheochromocytoma

Objective von Hippel–Lindau (VHL) disease is an autosomal-dominant familial syndrome caused by mutations in the VHL tumor suppressor gene, and the mutations can lead to the development of tumors and cysts, including retinal and cerebrospinal haemangioblastomas, pancreatic tumors or cysts, renal cell carcinomas or cysts, and pheochromocytomas. Reports about VHL disease with pheochromocytoma in Chinese are scanty. This study examined the clinical and genetic features of 9 families with VHL disease accompanying with pheochromocytoma. Methods Nine patients with VHL disease accompanying with pheochromocytoma were diagnosed and treated in PUMC hospital since 2004. The clinical data of the patients were collected and the family members were clinically evaluated and followed up. Genomic DNA extracted from the peripheral blood of patients and their family members were amplified by polymerase chain reaction (PCR) and the PCR products were directly sequenced. Results Total 18 patients are identified in the 9 families with the diagnosis of pheochromocyotmas (n=16), brain haemangioblastomas (n=4), retinal haemangioblastomas (n=1), pancreatic tumors or cysts (n=4), hepatic haemangiomas or cysts (n=3), renal cyst (n=1). 6 kinds of missense germline mutations of the VHL gene were detected in the 9 families. Arg161Gln (695G-A) mutation was found in three families with the phenotype of pheochromocytomas, pancreatic tumors, retinal and brain haemangioblastomas. Two families with Arg167Trp (712C-T) mutation have phenotype of pheochromocytomas and pancreatic tumors. One family with Arg167Gln (713G-A) mutation presented with pheochromocytomas, brain haemangioblastomas, pancreatic and hepatic cysts. One family with Val170Gly (722T-G) mutation presented with pheochromocytomas, brain haemangioblastomas and renal cyst. Two new mutation of Tyr98Cys (506A-G) and Leu163Phe (700C-T) presented only with pheochromocytomas. Conclusions VHL disease should be suspected in patients with pheochromocytomas, and VHL gene screening helps achieve early diagnosis of the disease. There are tight relation between genotype and phenotype in VHL disease. Follow-up study should be routinely conducted for all patients and carriers.