Clinical characteristics of ocular angiomatosis in von Hippel-Lindau disease and correlation with germline mutation

Objectives: To examine the epidemiologic and clinical characteristics of th e ocular manifestations of von Hippel-Lindau (VHL) disease and to detect ph enotype-genotype relationships of disease severity. Design: A cross-sectional clinical and molecular genetic study. Patients and Methods: One hundred eighty-three affected VHL gene carriers f rom 81 unrelated pedigrees were interviewed and examined; clinical data wer e also obtained from 12 living and 39 deceased affected relatives. DNA extr acted from venous blood was used to identify mutations in the VHL gene. Results: The prevalence of ocular angiomatosis (hemangioblastomas) in von H ippel-Lindau disease was 67.8% (124/183), and the mean number of angiomas i n gene carriers was 1.85 (range, 0-15). Neither prevalence nor angioma coun t increased with age. Severe vision loss in 1 or both eyes was associated w ith presentation at a young age. The cumulative probability of incurring vi sion loss by age 50 years was 35% in all gene carriers, 55% in those with a ngiomatosis, and significantly worse in those coming to us with symptoms. A ngiomas were nonrandomly distributed in the fundus, occurring rarely at the posterior pole (1% of retinal tumors) and commonly on the optic disc (8% o f eyes) and supratemporal retina. Complications of ocular angiomatosis incl uded disc and retinal neovascularization; secondary angioma formation; reti nal detachment, exudation, and membrane; and retinal and vitreous hemorrhag e. Germ-line VHL mutations were detected in 161 of 183 patients and 69 (85% ) of 81 pedigrees and included deletions (n = 16), missense (mutations caus ing amino acid substitutions; n = 24), nonsense (premature stop codons; n = 15), frameshift (n = 13), and splice-site (n = 1) mutations. There was no association between the type or position of mutation and the severity of oc ular angiomatosis. Conclusions: A systematic clinical description of a large cohort of VHL gen e carriers further defines the ocular phenotype. There is no general influe nce of germline mutation on severity of ocular disease in VHL. Clinical Relevance: The ophthalmic and molecular genetic description of pat ients with VHL disease.