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Patients with VHL disease have an increased risk of developing characteristic VHL disease-associated lesions such as clear cell renal cell carcinoma, retinal angioma, central nervous system hemangioblastoma, pancreatic neuroendocrine tumors and pheochromocytomas. Loss of the\n                    <jats:italic>VHL<\/jats:italic>\n                    gene results in increased levels of the \u03b1-subunits of the heterodimeric hypoxia inducible factor (HIF). This drives transcription of HIF target genes which are involved in, amongst others: angiogenesis, erythropoiesis and iron metabolism. HIFs have been recognized as major drivers of VHL disease pathology and based on this notion, the HIF-2\u03b1 inhibitor belzutifan was developed, which has marked a major breakthrough in the treatment of this disease. Belzutifan has now been approved for the treatment of a variety of VHL disease-associated lesions by the Food and Drug Administration and the European Medicines Agency. Interestingly, recent studies suggest that pVHL has functions beyond controlling HIF levels, and loss of these HIF-independent functions may further contribute to tumorigenesis in VHL disease. This review summarizes the most recent advances in pathophysiology, genotype\u2013phenotype correlation, treatment guidelines, and potential future treatment options related to VHL disease.\n                  <\/jats:p>","DOI":"10.1007\/s10689-026-00579-8","type":"journal-article","created":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T09:48:54Z","timestamp":1781776134000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Von Hippel-Lindau disease: pathophysiological and clinical advances"],"prefix":"10.1007","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-8565-5791","authenticated-orcid":false,"given":"S. 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