Von Hippel-Lindau (VHL) disease is a rare hereditary autosomal dominant tumor syndrome caused by germline mutations of the VHL tumor suppressor gene leading to cancerous and noncancerous growths in various organs. These include hemangioblastomas of the central nervous system (CNS). Mutations in this gene result in elevated levels of hypoxia-inducible factor (HIF) in hypoxic cells, activating transcription of multiple growth factors leading to tumor formation. Belzutifan, a small molecular inhibitor of HIF-2α prevents the binding to transcription factor HIF-1B. The inhibition of this complex prevents further transcription of downstream genes, arresting the growth of VHL-associated tumors. Belzutifan was FDA approved on August 13, 2021.

We describe a case of a 61-year-old woman with VHL-associated CNS hemangioblastomas. She presented with progressive headaches, diplopia, and significant ataxia impairing her ability to ambulate independently. MRI demonstrated increase in size of multiple enhancing cerebellar lesions with associated vasogenic edema, effacement of the 4^th ventricle, and hydrocephalus. The possible need for CSF diversion was discussed, but the decision was made to first trial systemic treatment with belzutifan. Patient received belzutifan 120mg once daily for 10 months. Complete resolution of neurologic symptoms and marked radiographic improvement was observed by 3 months. Utilizing volumetric analysis, the 3-month MRI demonstrated 73% tumor volume reduction, 6-month MRI demonstrated 81% tumor volume reduction, and 9-month MRI demonstrated continued stability.

This case highlights (1) the measurement of tumor volume reduction rate as a valuable parameter for monitoring response to treatment, prompting consideration for use in clinical practice and (2) the clinical benefits of belzutifan in the real-world setting, supporting continued use in this patient population.