Background: von Hippel-Lindau syndrome (VHL) is a rare autosomal dominant disease caused by alterations of the vhl tumor-suppressor gene. Patients with VHL are at risk for development of retinal, central nervous system and spine hemangioblastomas, clear-cell renal cell carcinomas, pheochromocytomas, endolymphatic sac tumors and cysts; and pancreatic islet cell tumors. Based on the presence or absence of pheochromocytoma as a phenotypic marker, VHL can be divided into different subtypes. According to Knudsons two-hit hypothesis, tumor formation in VHL requires inactivation of both copies of the tumor suppressor vhl gene. Some specific genotype-phenotype correlations have been recognized, but the majority of families have their own specific genetic alteration.
Objective: To identify the disease-causing vhl gene mutation in a large Hungarian VHL kindred and to study the genotype-phenotype correlations.
Patients and methods: 32 family members spanning 5 generations were evaluated. Initial screening included medical history, physical examination, abdominal ultrasonography, abdominal and cranial CT or MRI, as well as ophthalmologic examination and laboratory tests. Mutation analysis of the vhl gene was performed in DNA samples obtained from peripheral blood. Written informed consent was obtained from all family members who participated in the study.
Results and conclusions: Two genetic alterations of the vhl gene (P25L and S80I), both resulting in an amino acid change were identified. The detailed medical examination confirmed that VHL-specific tumors were associated with the presence of S80I mutation. In three family members this mutation was associated with the presence of pheochromocytoma. To our knowledge, the S80I mutation has not been previously described in VHL patients who had pheochromocytoma. Therefore, this finding represents a novel genotype-phenotype association. The P25L variant was identified in clinically healthy family members, suggesting that this variant represents a sequence polymorphism rather than a real disease-causing mutation.