The impact of molecular genetic analysis of the VHL gene in patients with haemangioblastomas of the central nervous system

Objectives-Haemangioblastoma of the CNS occurs as a sporadic entity and as a manifestation of the autosomal dominant von Hippel-Lindau disease with th e major additional components retinal angioma, renal cancer, and pheochromo cytoma. Genetic testing for germline mutations predisposing to von Hippel-L indau disease has been available since identification of the VHL tumour sup pressor gene. The impact of this testing was evaluated in patients with hae mangioblastomas seen in this centre. Methods-A register and database of patients with symptomatic haemangioblast omas for the last 15 years was evaluated. The VHL gene was analysed by the SSCP method for all exons and Southern blotting for mutations and deletions of the gene. Results-141 patients with haemangioblastoma of the CNS were registered. In 81 patients (57%) there was a disease predisposing germline mutation includ ing eight novel mutations. Population related calculation of patients from the administrative district of Freiburg disclosed VHL germline mutations in 22% of the patients with haemangioblastoma. Analysis of mutation carriers for clinical information suggestive of the syndrome showed (1) a positive f amily history of a brain tumour in 50%, (2) a history for the patient of ex tracranial manifestations in 36% (retinal angioma 30%, pheochromocytoma 6%) , and (3) 19% presenting with multiple brain tumours when first admitted. B y genetic testing of haemangioblastoma patients without any indications of von Hippel-Lindau disease mutation carriers were identified in 14%. Sensiti vity of VHL germline testing was 86%. Conclusions-DNA analysis for VHL germline mutations is clearly superior to clinical information in the diagnosis of von Hippel-Lindau disease. Althoug h the percentage of von Hippel-Lindau disease associated haemangioblastoma decreases after the fourth decade of life and is infrequent in patients wit hout other symptomatic lesions and a negative family history, it is recomme nded that every patient with CNS haemangioblastoma should be screened for v on Hippel-Lindau disease germline mutations. This provides the key informat ion and enables screening for extraneurological tumours of the patients and investigations of the patient's family to ameliorate management of von Hip pel-Lindau disease.