Clinical And Mutation Analysis Of Four Chinese Families With Von Hippel-Lindau Disease

Objective: Von Hippel-Lindau (VHL) disease is a hereditary tumor syndromepredisposed to the development of tumors in a variety of body organs. The majoretiopathogenesis of VHL is a mutation of the VHL tumor-suppressor gene on the shortarm of chromosome3(3p25-26). We report on the clinical and molecular features offour Chinese kindreds with VHL disease.Materials and methods: The VHL gene was screened for mutation by using a directDNA sequencing analysis and a multiplex ligation-dependent probe amplification(MLPA) for44volunteers from these four families. Any unaffected person, withgermline VHL gene mutation, was required to undergo further examination, surveillanceand treatment.Results: Clinical data was collected from71members in these four Chinese familiesincluding15affected family patients, five asymptomatic patients, one carrier, and44 members volunteered for genetic analysis. Two families were classified as type I(without pheochromocytoma) and the other two families belonged to type II (withpheochromocytoma). The gender distribution was33.3%female (n=7) and66.7%male(n=14) in the21members. The main lesions and the average diagnostic year of the20patients were central nervous system hemangioblastoma (60%,34.92years), renallesion (60%,39.08years), pancreatic lesion (60%,37.67years), adrenalpheochromocytoma (25%,37.8years) and retinal hemangioblastomas (10%,25.5years).Among15affected family patients,13of them experienced17operations meanwhilethe other two died without promptly surgery. The nine deaths, six dying from centralnervous system hemangioblastoma and the other three from renal cell carcinomas, had amean age of36.44years at death. VHL gene mutation or deletions were identified in allindex patients with VHL disease as well as in several other members of four VHLfamilies. Nucleotide substitutions or small deletion was detected in three families,including two missense mutations (c.674C>T [p.Pro154Leu], c.452G>T [Ser80Ile]) andone in-frame deletion (c.439delTCT p.Phe76del). In addition, MLPA revealed exon onedeletion in family A. All the members with genetic VHL mutation were screened forVHL disease-related tumors and followed with annual examinations. The fiveasymptomatic patients were initially diagnosed by genetic analysis and verifiedradiologically or surgically.Conclusions: The spectrum of clinical manifestation of VHL in the mainland Chinesepopulation is similar to the observation in Western kindreds. Genetic testing which playsa crucial role in early diagnosis asymptomatic patients, is obviously superior to clinicalinformation when diagnosing VHL disease. The members of VHL disease family maybenefit from pedigree study, genetic testing, periodic follow-up, early diagnosis andprompt treatment.