Von Hippel-Lindau disease

Von Hippel-Lindau (VHL) disease is a rare hereditary cancer predisposition syndrome caused by pathogenic variants in the VHL tumor suppressor gene located on chromosome 3p25.3. Also known as VHL syndrome or familial cerebello-retinal angiomatosis, this condition predisposes affected individuals to the development of both benign and malignant tumors in multiple organ systems throughout their lifetime. The hallmark features include hemangioblastomas of the central nervous system (particularly the cerebellum, spinal cord, and brainstem) and retina, clear cell renal cell carcinomas, pheochromocytomas and paragangliomas, pancreatic neuroendocrine tumors, pancreatic cysts, endolymphatic sac tumors of the inner ear, and epididymal or broad ligament cystadenomas. The VHL protein plays a critical role in the cellular oxygen-sensing pathway by regulating the degradation of hypoxia-inducible factors (HIFs). When VHL function is lost, HIF accumulates and drives the expression of genes involved in angiogenesis, cell proliferation, and metabolism, leading to the highly vascular tumors characteristic of this disease. VHL disease is classified into subtypes (Type 1, Type 2A, 2B, and 2C) based on the likelihood of developing pheochromocytoma and renal cell carcinoma, which correlates with the type of underlying VHL gene mutation. Management of VHL disease centers on lifelong surveillance with regular imaging and clinical assessments to detect tumors early, when they are most amenable to treatment. Screening protocols typically include annual ophthalmologic examinations, MRI of the brain and spine, abdominal imaging, audiologic assessments, and biochemical testing for catecholamines. Surgical intervention remains the primary treatment for symptomatic or growing tumors. In 2021, the HIF-2α inhibitor belzutifan (Welireg) was approved by the FDA for the treatment of VHL-associated renal cell carcinoma, hemangioblastomas, and pancreatic neuroendocrine tumors not requiring immediate surgery, representing a significant advance in targeted therapy for this condition. Genetic counseling is recommended for affected individuals and at-risk family members.

Data sourced from FDA regulatory filings and ClinicalTrials.gov. Updated periodically.

Common questions about Von Hippel-Lindau disease