Von Hippel-Lindau syndrome

AD; VHL (tumor suppressor, hypoxia sensing)

pVHL is the substrate-recognition arm of an E3 ubiquitin ligase complex, and its job in normal oxygen is to tag hypoxia-inducible factor for destruction. Lose pVHL and that tagging stops, so HIF-2 alpha accumulates and the cell behaves as though it were permanently hypoxic, transcribing the targets that state calls for: VEGF and EPO above all.

That one block explains the entire tumor list. Every lesion is either hypervascular or cystic, because VEGF-driven angiogenesis is what those lesions are built from: hemangioblastomas of retina and CNS, clear cell renal cell carcinoma, and the cysts of the kidney, pancreas, and epididymis. EPO drives the secondary polycythemia that sometimes accompanies a hemangioblastoma.

It also explains the drug. Belzutifan is a HIF-2 alpha inhibitor, so it treats the driver rather than each tumor in turn, which is what makes a systemic option possible in a condition that otherwise means a lifetime of serial surgery.

• CNS hemangioblastomas: Cerebellum, spinal cord, brainstem
• Retinal hemangioblastomas
• Clear cell renal cell carcinoma (40-70%)
• Pheochromocytoma (10-20%)
• Pancreatic cysts, neuroendocrine tumors
• Endolymphatic sac tumors
• Epididymal cystadenomas

• Clinical diagnosis in a simplex case requires more than one characteristic tumor (e.g., two hemangioblastomas, or one hemangioblastoma plus a visceral lesion); with a positive family history a single characteristic lesion suffices
• Confirm with germline VHL testing, including deletion/duplication analysis since large deletions are common; detection rate approaches 100%
• Genotype-phenotype correlation distinguishes type 1 (low pheochromocytoma risk, often truncating variants) from type 2 (high pheochromocytoma risk, typically missense variants)

• Annual ophthalmology, audiology
• Abdominal imaging (MRI)
• CNS imaging
• Blood/urine catecholamines
• Belzutifan, a HIF-2 alpha inhibitor, for renal cell carcinoma, CNS hemangioblastoma, and pancreatic neuroendocrine tumors that do not need immediate surgery. It is the first systemic option in a condition that otherwise means a lifetime of serial operations, and it treats the driver rather than one lesion at a time
• Anemia is the expected on-target effect of belzutifan, not an idiosyncratic reaction: less HIF-2 alpha means less EPO. Check a blood count before starting and monitor on treatment, and watch for hypoxia. It is toxic to a pregnancy and it lowers the efficacy of hormonal contraception, so settle contraception before the first dose in anyone who could become pregnant