Phenotypic expression in von Hippel-Lindau disease correlations with germline VHL gene mutations

Purpose: To investigate the association between germline mutation and the major complications of von Hippel Lindau (VHL) syndrome. Method: We analysed 138 VHL kindreds for VHL mutations using single strand conformation polymorphism, heteroduplex, Southern analysis and direct sequencing and calculated the age-related risks for each major VHL complication. To further investigate retinal angiomatosis, 111 affected individuals from 54 pedigrees underwent detailed ophthalmic examination by a single observer. Results: We identified a germline VHL gene mutation in 101 families (73%) further increased by direct sequencing of the VHL coding region to 81%. Large deletions and mutations predicted to cause a truncated protein were associated with a lower risk of phaeochromocytoma (6% and 9% at 30 and 50 years respectively) than missense mutations (40% and 59% respectively). Median survival and the cumulative probabilities of renal cell carcinoma, retinal and CNS haemangioblastomas did not differ significantly between these two classes of mutation. Of 111 examined affected patients, 69% had incurred one or more retinal angioma, 32% had visual loss related to angiomatosis with 16% seeing hand movements or less in one or both eyes. The mean age of patients affected and not affected by retinal angiomatosis did not significantly differ. Conclusion: This data shows that VHL mutations may be associated with different tumour susceptibilities providing valuable data for counselling families, suggests that the VHL protein may have tissue specific functions and that the development of retinal angiomatosis may be determined at an early age. Further analysis of the data may yet reveal more subtle associations between severity of retinal angiomatosis and VHL genotype.