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

Abstract

Objectives-Haemangioblastoma of the CNS occurs as a sporadic entity and as a manifestation of the autosomal dominant von Hippel-Lindau disease with the major additional components retinal angioma, renal cancer, and pheochromocytoma. Genetic testing for germline mutations predisposing to von Hippel-Lindau disease has been available since identification of the VHL tumour suppressor gene. The impact of this testing was evaluated in patients with haemangioblastomas seen in this centre. Methods-A register and database of patients with symptomatic haemangioblastomas 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 including 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 family history of a brain tumour in 50%, (2) a history for the patient of extracranial manifestations in 36% (retinal angioma 30%, pheochromocytoma 6%), and (3) 19% presenting with multiple brain tumours when first admitted. By genetic testing of haemangioblastoma patients without any indications of von Hippel-Lindau disease mutation carriers were identified in 14%. Sensitivity 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. Although the percentage of von Hippel-Lindau disease associated haemangioblastoma decreases after the fourth decade of life and is infrequent in patients without other symptomatic lesions and a negative family history, it is recommended that every patient with CNS haemangioblastoma should be screened for von Hippel-Lindau disease germline mutations. This provides the key information and enables screening for extraneurological tumours of the patients and investigations of the patient´s family to ameliorate management of von Hippel-Lindau disease. (J Neurol Neurosurg Psychiatry 1999;67:758-762)

Prevalence, birth incidence, and penetrance of von Hippel–Lindau disease (vHL) in Denmark

“…Previous reports suggest that up to 15% of patients fulfilling the diagnostic criteria have no identifiable VHL variants. 17,20,21 Some might be phenocopies, mosaics, or have alterations in other genes that give rise to a vHL-like phenotype. Better knowledge about the risk of additional manifestations in such families is needed to facilitate appropriate surveillance measures.…”

Risk of new tumors in von Hippel–Lindau patients depends on age and genotype

“…23,24 Even though missense mutation carriers are known to have a higher pheochromocytoma risk, their overall milder phenotype is most likely due to a resulting pVHL that is defective in fibronectin matrix assembly, associated with pheochromocytoma development, 25 but retains some function in the HIF pathway. Because faulty HIF regulation is a key step in RCC and hemangioblastoma development, 24,[26][27][28] missense mutation carriers are likely to have a slighter, possibly age-delayed, rate of new hemangioblastoma and RCC development. The higher adulthood manifestation rate in truncating mutation carriers seems to result from higher rates of new CNS lesions.…”

Germline mutations of the VHL gene in seven Chinese families with von Hippel-Lindau disease

“…Two unrelated stemma, D and F were found to have the same nonsense mutation (646C>T) in exon 2 that had been previously reported by Gläsker et al (14). The splice mutation (553+5G>C) had also been previously detected in a papillary type 2 RCC patient with a family history of VHL disease (19).…”

“…In familial hemangioblastomas patients, the VHL gene mutation detection rate has been reported to reach between 82-100% (13)(14)(15)(16). Germline VHL mutations have been classified among three groups: large deletions, which account for ~40% of all mutations; intragenic missense mutations (~30%); and, protein truncating mutations, including nonsense, frameshift insertions and deletions, and splice site mutations (~30%) (17).…”