PHENOTYPIC-EXPRESSION IN VON HIPPEL-LINDAU DISEASE - CORRELATIONS WITH GERMLINE VHL GENE-MUTATIONS

Von Hippel-Lindau disease is an autosomal dominantly inherited familia l cancer syndrome predisposing to retinal and central nervous system h aemangioblastomas, renal cell carcinoma, and phaeochromocytoma. VHL di sease shows variable expression and interfamilial differences in predi sposition to phaeochromocytoma. In a previous study of 65 VHL kindreds with defined VHL mutations we detected significant differences betwee n VHL families with and without phaeochromocytoma such that missense m utations were more common and large deletions or protein truncating mu tations less frequent in phaeochromocytoma positive families. To inves tigate the significance and cause of this association further, we stud ied 138 VHL kindreds for germline mutations and calculated the age rel ated tumour risks for different classes of VHL gene mutations. Using S SCP, heteroduplex and Southern analysis we identified a germline VHL g ene mutation in 101 families (73%). Direct sequencing of the VHL codin g region further increased the mutation detection rate to 81%. In addi tion to precise presymptomatic diagnosis, identification of a VHL gene mutation can provide an indication of the likely phenotype. We found that large deletions and mutations predicted to cause a truncated prot ein were associated with a lower risk of phaeochromocytoma (6% and 9% at 30 and 50 years, respectively) than missense mutations (40% and 59% , respectively) and that missense mutations at codon 167 were associat ed with a high risk of phaeochromocytoma (53% and 82% at ages 30 and 5 0 years). Cumulative probabilities of renal cell carcinoma did not dif fer between the two groups (deletion/ truncation mutations: 8% and 60% , and missense mutations: 10% and 64% at ages 30 and 50 years, respect ively). Age related risks for haemangioblastoma were similar in the tw o mutation groups, with the age related risks of cerebellar haemangiob lastoma slightly less (35% and 64% v 38% and 75% at ages 30 and 50 yea rs) and retinal haemangioblastoma slightly higher (45% and 72% v 37% a nd 64% at ages 30 and 50 years) in the missense mutation group than in the deletion/protein truncation group. These results provide valuable data for counselling VHL families and indicate that specific VHL muta tions may be associated with different tumour susceptibility risks. Th ere was no evidence of a generalised increase in age related tumour ri sks for missense mutations, suggesting that missense mutations predisp osing to phaeochromocytoma have tissue specific effects, possibly beca use the VHL protein has several functions, the importance of which var ies from tissue to tissue, or because the proteins which interact with VHL differ between different tissues.