VHL is caused by pathogenic variants in the VHL tumor suppressor gene on chromosome 3. The ClinGen Curation Expert Panel has classified the VHL gene-VHL disease association as DEFINITIVE. The disorder follows autosomal dominant inheritance, in which a single pathogenic variant in one copy of the VHL gene confers elevated susceptibility to the characteristic tumor types. As described by GeneReviews, the VHL protein regulates hypoxia-inducible factor alpha (HIF-alpha), and loss of VHL function leads to constitutive HIF-alpha activity and overexpression of downstream effectors including vascular endothelial growth factor (VEGF). This HIF-pathway dysregulation drives hemangioblastoma formation and clear cell renal tumor development. GeneReviews identifies genotype-phenotype correlations across the four VHL phenotype classes, with the molecular distinction between pheochromocytoma-prone alleles and those primarily associated with renal cell carcinoma representing a clinically significant pattern. A de novo mutation rate of approximately 4.4 x 10-6 gametes per generation is noted by GeneReviews.

GeneReviews describes clinical diagnostic criteria for VHL developed by Dutch and Danish guidelines. Suggestive findings include retinal angioma, particularly in a young individual; multiple spinal or cerebellar hemangioblastomas, or a single hemangioblastoma diagnosed at age 50 years or younger; adrenal or extra-adrenal pheochromocytoma; renal cell carcinoma diagnosed at age 40 years or younger; multiple renal and pancreatic cysts; and multiple neuroendocrine tumors. Definitive diagnosis requires identification of a pathogenic variant in the VHL gene through molecular genetic testing. GeneReviews highlights comprehensive evaluations following initial diagnosis, encompassing neurologic examination, ophthalmologic assessment, abdominal imaging, and audiologic review. OMIM (entry 193300) and Orphanet document the genetic basis and published diagnostic criteria for VHL. Cascade genetic testing of first-degree relatives is an established component of VHL clinical management, given the autosomal dominant inheritance pattern and high penetrance of pathogenic variants in the VHL gene.

Belzutifan (brand name Welireg) is the only FDA-approved systemic agent documented in this packet for VHL disease. Approved August 13, 2021, via New Drug Application, belzutifan is a HIF-2alpha inhibitor that addresses the HIF pathway dysregulation underlying VHL pathogenesis. The approved indication encompasses VHL disease-associated renal cell carcinoma, central nervous system hemangioblastomas, and pancreatic neuroendocrine tumors not requiring immediate surgery. GeneReviews describes the first VHL multidisciplinary care pathway, recently published by a Dutch team, providing structured guidance for disease management following initial diagnosis. GeneReviews further identifies circumstances associated with elevated risk for individuals with VHL: tobacco products are recognized as a risk factor for kidney cancer; chemicals and industrial toxins affecting VHL-involved organs carry heightened concern; and contact sports present elevated risk when adrenal or pancreatic lesions are present. Under therapies under investigation, GeneReviews describes ranibizumab, an intravitreal VEGF receptor inhibitor, in individuals with retinal hemangioblastomas not amenable to local therapy, and bevacizumab, another intravitreal anti-VEGF agent explored for the same indication.

GeneReviews states that VHL pathogenic variants are highly penetrant, with nearly all carriers exhibiting symptoms by age 65 years. The clinical course is shaped primarily by the type and location of tumors that develop, with renal cell carcinoma and central nervous system hemangioblastomas representing the leading sources of morbidity in VHL. The four proposed phenotypic subtypes, types 1, 2A, 2B, and 2C, reflect distinct patterns of RCC and pheochromocytoma risk that influence long-term clinical outlook, as described in GeneReviews. Surveillance protocols assembled by the VHL Alliance in the United States and complementary guidelines from Denmark and the Netherlands support early detection of evolving lesions and timely clinical intervention, per GeneReviews. Clinical expression is substantially variable, including among individuals carrying the same pathogenic variant.

VHL disease has an active clinical research portfolio. The packet documents 10 registered clinical trials involving drug therapy, medical devices, and other investigational approaches, with sponsors including Merck Sharp & Dohme LLC and academic institutions. An extension study for participants in prior belzutifan trials (NCT07405164) is currently recruiting. GeneReviews describes ongoing investigation into experimental agents targeting the HIF/VEGF pathway, given its central role in VHL pathogenesis. Bevacizumab and additional intravitreal anti-VEGF approaches are among the modalities under active investigation for retinal hemangioblastomas per GeneReviews. The Kisho literature tracker documents 324 classified publications related to VHL, including 116 case reports and case series and 82 reviews, with literature encompassing biomarker research, gene therapy publications, and coverage of recent trial results. The defined molecular target in VHL, the HIF pathway, and the availability of an approved targeted agent provide a foundation for continued therapeutic development.