Von Hippel-Lindau Disease: A Genetic and Clinical Review

Background: Von Hippel-Lindau Disease (VHL) is an autosomal dominant inherited systemic cancer syndrome that gives rise to cystic and highly vascularized tumors in many organs, including the eye. Recent studies have contributed to the understanding of VHL pathophysiology, genetics, and the role of the VHL protein. This article reviews recent studies on VHL clinical findings, genetics and tumorigenesis. Methods: Literature review of articles on VHL genetics with correlation to clinical findings. Results: Genotype-phenotype correlation studies show that patients with a complete deletion mutation of the VHL gene, relative to participants with a missense or protein-truncating mutation, had better visual acuity and decreased tumorigenesis incidence of retinal hemangioblastomas. It has also been documented that higher levels of vascular endothelial growth factor (VEGF), hypoxia induced factor (HIF), and ubiquitin are found in ocular hemangioblastomas. The stromal foamy vacuolated cells seem to be the true tumor cells of the disease acting on the surrounding endothelial cells in ocular hemangioblastomas. Tumor cells and ocular lesions have shown increased levels of Erythropoietin (Epo), Epo receptor (EpoR), and CD133. Also, CXCR4, a CXC chemokine receptor, is expressed in retinal VHL hemangioblastomas. Recent studies suggest that the VHL mutation alone may not be sufficient to develop VHL-associated neoplasms. Studies suggest that targeting various proteins along with anti-angiogenesis molecules may be a better therapeutic approach than targeting VEGF alone. Conclusion: Understanding of the mechanisms and genetics underlying VHL and its associated retinal hemangioblastomas has increased substantially in recent years. This knowledge suggests that future advances may include better identification of individuals at higher risk of vision loss and the development of novel individualized therapies.