The condition is associated with pathogenic variants in the VHL gene, located on chromosome 3. ClinGen classifies the gene-disease validity as definitive. The inheritance pattern is autosomal dominant. According to GeneReviews, about 80% of individuals diagnosed have an affected parent, and about 20% have the condition because of a de novo pathogenic variant, which may include a postzygotic de novo event in a mosaic, apparently unaffected parent. GeneReviews also states that pathogenic variants are highly penetrant, with almost all individuals who carry one symptomatic by age 65 years.

GeneReviews describes certain pathogenic variants as failing to downregulate hypoxia-inducible factor alpha, leading to overexpression of downstream effectors such as vascular endothelial growth factor that contribute to pathogenesis. It also describes four suggested phenotypes (type 1, type 2A, type 2B, and type 2C) based on the likelihood of pheochromocytoma or renal cell carcinoma, while noting that patterns are not clear-cut and that genotype-phenotype correlations have no current diagnostic or therapeutic value.

According to GeneReviews, clinical diagnostic criteria have been proposed that vary slightly between Dutch and Danish guidelines. Findings described as raising suspicion include retinal angioma, 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, multiple pancreatic neuroendocrine tumors, and endolymphatic sac tumors.

A diagnosis can be established clinically under the published criteria, or molecularly by identification of a heterozygous pathogenic or likely pathogenic variant in VHL. GeneReviews notes that a heterozygous variant of uncertain significance neither establishes nor rules out the diagnosis. Molecular approaches described include single-gene sequence analysis with deletion and duplication analysis, multigene panels, and comprehensive genomic testing. GeneReviews also describes evaluations after diagnosis covering the nervous system, eyes, kidneys, pancreas, adrenal glands, blood pressure and catecholamine metabolites, hearing, and genetic counseling, and notes that surveillance guidelines have been assembled by the VHL Alliance and by groups in Denmark and the Netherlands.

For differential diagnosis, GeneReviews discusses isolated hemangioblastoma, retinal angioma, or clear cell renal cell carcinoma without a detectable germline VHL variant, other genetic disorders associated with pheochromocytoma, and familial renal cell carcinoma conditions.

According to GeneReviews, no guidelines exist for the management of VHL lesions. For central nervous system hemangioblastomas, GeneReviews states that most can be surgically removed completely and safely, that some advocate early removal of symptomatic and asymptomatic lesions while others follow asymptomatic lesions with yearly imaging, and that preoperative arterial embolization is described for extensive spinal tumors. Genetic counseling by genetics professionals and assessment of psychosocial needs are among the components GeneReviews lists. GeneReviews also identifies tobacco products, certain chemicals and industrial toxins, and contact sports in the presence of adrenal or pancreatic lesions as exposures and circumstances of concern.

The packet lists one currently active FDA-approved treatment, belzutifan (Welireg), approved through a new drug application on August 13, 2021. GeneReviews describes belzutifan as a targeted oral hypoxia-inducible factor 2 alpha inhibitor. In the phase 2 LITESPARK-004 trial of 61 individuals, GeneReviews reports objective response rates of 49% for renal cell carcinoma, 77% for pancreatic lesions, and 30% for central nervous system hemangioblastoma; 33% had grade 3 or higher adverse events and seven individuals (11.5%) discontinued treatment. Anemia and fatigue are described as the most prominent side effects. GeneReviews states that it is unknown whether belzutifan can prevent tumors in VHL and that it is used in individuals not requiring immediate surgery. A separate orphan drug designation for another compound does not indicate approval.

GeneReviews also describes a single-arm phase 2 study of pazopanib in 31 individuals with VHL, in which 42% achieved a response. Therapies under investigation per GeneReviews include intravitreal ranibizumab and bevacizumab for retinal hemangioblastomas and sunitinib, which it reports as effective for clear cell renal cell carcinoma but not hemangioblastomas.

According to GeneReviews, central nervous system hemangioblastomas remain the main cause of death, although VHL-related survival has improved over time. Renal cell carcinoma is described as a leading cause of mortality, and overall survival with renal cell carcinoma is associated with tumor size and age. GeneReviews reports that growth patterns of central nervous system hemangioblastomas are saltatory (72%), linear (6%), or exponential (22%), and that increased growth was associated with male sex, symptomatic tumors, tumor-associated cysts, and germline VHL intragenic deletions. For retinal lesions, the number of hemangioblastomas does not appear to increase with age, while the probability of vision loss does. A higher age-related incidence of several tumor types is described in individuals with truncating variants than in those with missense variants or single amino acid in-frame deletions.

Several certified active trial records are present. Examples include NCT04924075, a phase 2 study of belzutifan in advanced pheochromocytoma or paraganglioma, pancreatic neuroendocrine tumor, VHL disease-associated tumors, and other solid tumors (recruiting); NCT04074135, a phase 2 natural history and management study of VHL-associated pancreatic neuroendocrine tumors (recruiting); and NCT07405164, a phase 3 extension study for participants in studies that include belzutifan (recruiting). Active clinical trials for this condition are listed on ClinicalTrials.gov.