Von Hippel-Lindau disease: Ocular manifestations, surveillance, systemic associations, and emerging molecular...

Von Hippel-Lindau disease (VHL) is a rare autosomal dominant hereditary tumour predisposition syndrome affecting multiple organ systems, including the retina, central nervous system, kidneys, pancreas, adrenal glands, and inner ear. It is caused by pathogenic variants in the VHL gene, resulting in loss of functional pVHL, abnormal stabilization of hypoxia-inducible factor (HIF)-α subunits, and activation of downstream transcriptional programmes involved in angiogenesis, metabolism, cell survival, and tumour growth. Clinically, VHL is characterized by a spectrum of benign and malignant neoplasms that require lifelong surveillance and multidisciplinary management. Retinal hemangioblastomas are among the earliest manifestations and may provide the first clue to diagnosis of this multisystem disorder. Historically, management has relied on screening, surveillance, and local treatment according to lesion size, location, symptoms, and malignant potential. The emergence of HIF-2α-targeted therapy, particularly belzutifan, has begun to change this paradigm by offering a mechanism-based systemic treatment option for selected VHL-associated tumours. In this review, we summarize the ocular and systemic manifestations of VHL, its genetic and molecular basis, genotype-phenotype correlations, contemporary surveillance strategies, current local therapies, and the emerging role of HIF-2α inhibition in reshaping management.