VHL c.505 T > C mutation confers a high age related penetrance but no increased overall mortality

Background-Germline mutations of the VHL gene cause von Hippel-Lindau syndr ome (VHL). In southern Germany, a specific mutation in this gene, c.505 T>C , is one of the most frequent alterations owing to a founder effect. Methods-This study was conducted to evaluate morbidity, specific clinical r isk profile, and mortality among a series of VHL c.505 T/C mutation carrier s. A total of 125 eligible subjects carrying VHL c.505 T/C underwent ophtha lmoscopy and gadolinium enhanced magnetic resonance imaging of the brain, t he spinal cord, and the abdomen. Age related penetrance, morbidity, and mor tality were assessed. Results-Frequently observed lesions were phaeochromocytoma (47%), retinal a ngiomas (36%), haemangioblastoma of the spine (36%), and haemangioblastoma of the brain (16%). Four patients developed renal cell carcinoma. VHL was s ymptomatic in 47% of subjects; 30% were asymptomatic despite the presence o f at least one VHL related tumour and 23% of the carriers had no detectable VHL lesion. Of the 19 patients who had died (15%), 10 died of symptomatic VHL lesions. Overall penetrance by cumulative incidence functions is estima ted at 48% by 35 years and 88% by 70 years. In contrast to the only existin g published report based on patients with presumably unselected VHL germlin e mutations, the mortality rate for c.505 T/C mutation carriers is comparab le to that of the general population of Germany. Conclusions-Our results are an important example that a specific genotype, at least in the case of VHL c.505 T/C, can favourably impact on mortality d espite a high age related penetrance. Our study also indirectly provides ob jective data which might be useful to the life and health insurance industr y; it would appear that c.505 T>C mutation positive subjects have similar d isease specific mortality to that of the general population owing to a comb ination of phenotype and timely detection of mutation carrier status follow ed by aggressive clinical screening and, if necessary, treatment.