VHLrelated

VHL-related refers to conditions arising from pathogenic variants in the VHL gene, most notably von Hippel-Lindau disease, an autosomal dominant hereditary tumor syndrome characterized by a predisposition to multiple highly vascular tumors. The condition results from inactivation of the VHL tumor suppressor gene on chromosome 3p25-26, encoding the pVHL protein, which is part of an E3 ubiquitin ligase complex that targets hypoxia-inducible factors for degradation. Loss of pVHL leads to stabilization of HIF and increased expression of angiogenic and growth-promoting factors.

Clinical features include central nervous system and retinal hemangioblastomas; clear cell renal cell carcinoma and cysts; pheochromocytomas and paragangliomas; pancreatic cysts and neuroendocrine tumors; endolymphatic sac tumors causing hearing loss; and, less commonly, epididymal cystadenomas or other benign lesions. The penetrance is high but presentation is variable, even within families.

Traditionally VHL disease is classified into types: Type 1 (low risk of pheochromocytoma) and Type 2 (risk of pheochromocytoma), with further subdivisions (2a, 2b, 2c) reflecting specific tumor risks. Inheritance patterns and genotype-phenotype correlations inform counseling and surveillance strategies.

Diagnosis relies on genetic testing for VHL variants in individuals with a suggestive family history or tumors typical of VHL, along with regular surveillance imaging and biochemical screening for pheochromocytoma. Surveillance typically includes MRI of the brain and spine, renal imaging, retinal examinations, and periodic assessment for pheochromocytoma.

Management is multidisciplinary and individualized, balancing monitoring with timely treatment of progressive lesions. Treatments include surgical resection or radiosurgery for brain/spinal and retinal tumors, nephron-sparing approaches for RCC, and biochemical control for pheochromocytoma. Belzutifan, a HIF-2α inhibitor, has emerged as a systemic therapy for VHL-associated tumors in selected patients.