Haemangioblastoma of the central nervous system (CNS) is the most characteristic lesion and the most common presenting manifestation of von Hippel-Lindau (VHL) disease and has a striking tendency to multiple occurrence. Its sites of predilection are the posterior fossa (cerebellum++), and the spinal cord. Haemangioblastoma may cause increased intracranial pressure and/or neurological deficits and remains the main cause of morbidity and mortality in VHL. Treatment of symptomatic haemangioblastoma remains neurosurgical and is often in emergency. Haemangioblastoma appears to be more commonly associated with VHL than previously reported and suggests that all patients with 'sporadic' haemangioblastoma should be investigated for evidence of VHL disease. From a fundamental point of view, haemangioblastoma is a benign neoplastic entity with a double, vascular and cellular differentiation. Mutational inactivation of both copies of the VHL gene plays a major role in the pathogenesis of haemangioblastoma. Over-expression of vascular endothelial growth factor (VEGF) and VEGF-receptors has been recently demonstrated in these tumours, raising the possibility of angioblastic origin, and is of very great interest in view of the direct implication of the VHL gene in negative regulation of VEGF.
Von Hippel-Lindau disease (VHL) is a hereditary cancer syndrome caused by germline mutations of the VHL tumor suppressor gene. Major progress has been made in the last decade in both clinical and fundamental aspects of VHL. The VHL gene product, pVHL, has major and multiple functions: pVHL regulates not only first angiogenesis but also extracellular matrix formation and the cell cycle. A molecular diagnosis of VHL is now available, leading to a transformation in clinical management of patients and their families. Diagnosis of VHL has to be suspected in patients with a VHL-related tumor without familial history and especially in case of hemangioblastoma or endolymphatic sac tumors. Such patients should be systematically investigated for clinical and molecular evidence of VHL disease. Treatment of symptomatic hemangioblastomas remains mainly neurosurgical, often in emergency, but stereotactic radiosurgery is emerging as an alternative therapeutic procedure. In the future, antiangiogenic drugs could represent a potential medical treatment of CNS hemangioblastomas in view of their highly vascular structure. Lastly, visceral manifestations of VHL disease are also of critical importance and require early detection for effective treatment.
Neurofibromatosis type 2 (NF2) is a monogenic dominantly inherited disease that predisposes to the development of tumors of the nervous system, particularly meningiomas and schwannomas. The gene which, when altered, causes NF2, is localized on chromosome 22 and has recently been identified. The NF2 gene is also the site of somatic mutation in tumors, suggesting that it might have a tumor suppressor activity. We here report a screening method for the detection of point mutations in NF2 which takes advantage of denaturing gradient gel electrophoresis (DGGE). This method efficiently screens 95% of the coding sequence and 90% of intron/exon junctions. When applied to 91 unrelated NF2 patients, it enabled the identification of 32 germ-line mutations. Since mutations are found in only one third of the patients, it is expected that mutations or deletions affecting the promoter and/or intronic regions of the NF2 gene occur frequently. The characterized mutations are preferentially located within the 5' half of the gene. Most of them are predicted to lead to the synthesis of a truncated protein. A search for genotype/phenotype correlations showed that, at least in this series of patients, mild manifestations of the disease were associated with mutations which preserve the C-terminal end of the protein.
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