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Wai T. Wong, MD, PhD; Elvira Agrón, MS; Hanna R. Coleman, MD; George F. Reed, PhD; Karl Csaky, MD, PhD; James Peterson, PhD; Gladys Glenn, MD, PhD; W. Marston Linehan, MD; Paul Albert, PhD; Emily Y. Chew, MD

Arch Ophthalmol. 2007;125(2):239-245.

Objectives  To characterize the germline mutations found in a large population of persons having von Hippel-Lindau (VHL) disease mutations with the clinical characteristics of associated retinal capillary hemangioblastomas (RCHs), to measure the prevalence of RCHs among patients with VHL disease generally and specifically for each genotype category, to establish genotype-phenotype correlations between genotype category and phenotypic features of ocular VHL disease, and to establish genotype-phenotype correlations between genotype category and visual function.

Methods  Cross-sectional and molecular genetic study. Of 890 patients with VHL disease, 335 had ocular involvement in the form of RCHs. Statistical analysis was used to correlate the structure of the mutated VHL protein with the ocular phenotype.

Results  Three genotype categories (amino acid substitutions, protein-truncating mutations, and complete deletions of VHL protein) were defined in all patients. The prevalence of RCHs was lowest (14.5%) among patients with complete deletions; the overall prevalence of retinal angiomatosis was 37.2%. Genotype category had no correlation with the unilaterality or bilaterality of ocular disease or with the number or extent of peripheral RCHs. The prevalence of RCHs at the juxtapapillary location was lower among patients with protein-truncating mutations compared with those with amino acid substitutions. Complete deletions were associated with the highest mean visual acuity compared with the other 2 genotype categories.

Conclusion  Patients with complete deletions of VHL protein have the lowest prevalence of ocular disease and the most favorable visual outcome.

Clinical Relevance  The VHL mutation genotype may be used to predict the prevalence and outcome of ocular VHL disease and to guide ophthalmic follow-up.

Author Affiliations: Division of Epidemiology and Clinical Research (Drs Wong, Coleman, Reed, and Chew and Ms Agrón), Office of the Scientific Director, National Eye Institute (Dr Csaky), and Urologic Oncology Branch, Center for Cancer Research (Drs Peterson, Linehan, and Albert), and Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics (Dr Glenn), National Cancer Institute, National Institutes of Health, Bethesda, Md.

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