Retinal hemangioblastoma in von Hippel-Lindau disease: a clinical and molecular study

PURPOSE: To assess the natural history of retinal manifestations in von Hippel-Lindau (VHL) disease and to study the genotype-phenotype correlation. METHODS: Data concerning 103 patients with VHL retinal manifestations and 108 patients without VHL retinal manifestations were extracted from the French VHL database. A retrospective study was performed by questionnaire. Patients were classified into three visual morbidity groups. Molecular analysis of the VHL gene was performed in 196 patients. RESULTS: The mean age of ocular manifestations detection was 24.8 years. In half of the cases, the ocular manifestations revealed the disease. Half of the cases had bilateral involvement. Visual morbidity was significantly associated with the retinal hemangioblastoma count but not with other ocular or general characteristics. One third of the patients were classified in the worst visual morbidity group at the end of follow-up. Mutations were detected in 81% of patients with retinal hemangioblastomas and in 71% of patients without retinal involvement. Using a Poisson model and a marginal approach, the number of hemangioblastomas, age-adjusted, was 2.1 times higher in patients who had a substitution than in patients with a truncation (95% CI, 1.05-4.44; P < 0.05). CONCLUSIONS: Visual loss remains one of the major complications of VHL disease, confirming the importance of early ophthalmologic screening. Visual morbidity was not related to the type of extraocular manifestation but appeared to be related to the type of germline mutation. However, only further genetic and clinical studies in a larger series of patients will clearly determine the genotype-phenotype relationship.