VHL germline mutations in Argentinian patients with clinical diagnosis or single typical manifestations of type 1 von Hippel-Lindau disease

Abstract

Aims: von Hippel-Lindau (VHL) disease is caused by mutations in the VHL tumor-suppressor gene. As tumors that develop in the context of VHL also occur in a sporadic context, the frequency of this syndrome may be underestimated. Our aim was to identify VHL gene mutations in Argentinian patients who fulfilled the clinical criteria for type 1 VHL disease and in patients with VHL-associated manifestations that did not meet these criteria. Methods: We performed a retrospective cohort study including patients who met current diagnostic criteria for type 1 VHL (Group 1, n=19) and patients with VHL-associated manifestations that did not meet these criteria (Group 2, n=21). Genomic DNA was extracted from peripheral blood leukocytes. Mutation analysis involved DNA sequencing, while large deletions were determined by universal primer quantitative fluorescent multiplex PCR (UPQFM-PCR) and MLPA analysis. Results: The VHL mutations detected in 16/19 (84.2%) patients included in Group 1 were: gross deletions (4/16) and nonsense (6/16), frameshift (4/16), missense (1/16) and splicing (1/16) mutations, 3 of which were novel. No alterations were found in 3/19 patients. In Group 2, one nonsense VHL mutation was detected in a young patient with a solitary CNS hemangioblastoma without familial history. The study of 30 first-degree relatives revealed 4 carriers with VHL mutations. Conclusions: we found 3 novel mutations in the VHL gene in our population. Our results emphasize the importance of a complete genetic study of VHL to confirm type 1 von Hippel-Lindau disease, not only in patients with clinical diagnostic criteria but also in those presenting a single typical manifestation.