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Andrew R. Webster, FRCOphth; Eamonn R. Maher, MD, FRCP; Anthony T. Moore, FRCOphth

Arch Ophthalmol. 1999;117:371-378.

Objectives  To examine the epidemiologic and clinical characteristics of the ocular manifestations of von Hippel-Lindau (VHL) disease and to detect phenotype-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 from 81 unrelated pedigrees were interviewed and examined; clinical data were also obtained from 12 living and 39 deceased affected relatives. DNA extracted from venous blood was used to identify mutations in the VHL gene.

Results  The prevalence of ocular angiomatosis (hemangioblastomas) in von Hippel-Lindau disease was 67.8% (124/183), and the mean number of angiomas in gene carriers was 1.85 (range, 0-15). Neither prevalence nor angioma count increased with age. Severe vision loss in 1 or both eyes was associated with presentation at a young age. The cumulative probability of incurring vision loss by age 50 years was 35% in all gene carriers, 55% in those with angiomatosis, and significantly worse in those coming to us with symptoms. Angiomas were nonrandomly distributed in the fundus, occurring rarely at the posterior pole (1% of retinal tumors) and commonly on the optic disc (8% of eyes) and supratemporal retina. Complications of ocular angiomatosis included disc and retinal neovascularization; secondary angioma formation; retinal detachment, exudation, and membrane; and retinal and vitreous hemorrhage. Germ-line VHL mutations were detected in 161 of 183 patients and 69 (85%) of 81 pedigrees and included deletions (n=16), missense (mutations causing 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 ocular angiomatosis.

Conclusions  A systematic clinical description of a large cohort of VHL gene carriers further defines the ocular phenotype. There is no general influence of germline mutation on severity of ocular disease in VHL.

Clinical Relevance  The ophthalmic and molecular genetic description of patients with VHL disease.

From the Department of Ophthalmology, Addenbrooke's Hospital (Drs Webster and Moore), and the Department of Pathology, Cambridge University (Drs Webster and Maher), Cambridge; and the Division of Medical and Molecular Genetics, Department of Paediatrics and Child Health, University of Birmingham, Birmingham (Dr Maher), England.

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