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.