Genotype-phenotype correlation in von Hippel-Lindau disease with retinal angiomatosis

Abstract

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.

Figure 1

Prevalences of retinal angiomatosis in VHL patients in 3 genotypic mutational categories of single amino-acid substitutions, protein-truncating mutations, and complete deletion of VHL protein. Asterisk (*) indicates that the prevalence for complete deletions were significantly lower than those for amino-acid substitutions and protein truncations (p<0.0001).

Figure 2

Mean ages of VHL patients with ocular angiomatosis according to genotypic categories (n = 310 patients). Square symbols and adjacent notation indicate mean age in each category. Vertical error bars indicate 95% confidence limits. Mean age for amino acid substitutions is significantly higher than for protein truncations (asterisk *).

Figure 3

Prevalence of retinal angiomatosis at a juxtapapillary location (in at least one eye) in each of the 3 genotypic categories. The prevalence of juxtapapillary RCHs is significantly lower for protein truncations than for amino-acid substitutions.

Figure 4

Mean visual acuities in each of 3 genotypic categories. A. Mean visual acuity in the better-seeing eye. There were no detectable significant differences between the means (p > 0.10 for all 3 pair-wise comparisons). B. Mean visual acuity in the worse-seeing eye. Mean visual acuity for complete deletions were significantly higher than those for amino-acid substitutions and protein truncations (p = 0.01).