Clinical Information

von Hippel-Lindau (VHL) disease is an autosomal dominant cancer predisposition syndrome with a prevalence of approximately 1 in 36,000 livebirths. It predisposes affected individuals to the development of mainly 5 different types of neoplasms: retinal angioma (approximately 5%-70% penetrance), cerebellar hemangioblastoma (CHB) (44%-72% penetrance), clear-cell renal cell carcinoma (cRCC) (approximately 25%-60% penetrance), spinal hemangioblastoma (SHB) (approximately 13%-50% penetrance), and pheochromocytoma (PC) (approximately 10%-20% penetrance). Angiomas in other organs, pancreatic cysts/adenomas/carcinomas, islet cell tumors, and endolymphatic sac tumors can also occur. VHL-related tumors typically present in the second to third decade of life, but sometimes earlier, particularly for retinal angiomas. For each tumor type, the incidence rates rise steadily, albeit at different slopes, throughout life.

VHL disease is caused by heterozygous germline loss-of-function sequence variants, small deletions or insertions (approximately 80% of cases), or large germline deletions (approximately 20% of cases) of the VHL gene. Approximately 20% of cases are due to new (de novo) pathogenic variants, which in some cases result in disease mosaicism. This presents a diagnostic challenge for individuals who present with clinical signs of VHL disease, but test negative genetically because the pathogenic variant is not present in all peripheral leukocytes.

VHL encodes the VHL protein, a tumor suppressor protein that is involved in ubiquitination and degradation of a variety of other proteins, most notably hypoxia-inducible factor (HIF). HIF induces expression of genes that promote cell survival and angiogenesis under conditions of hypoxia. It is believed that diminished HIF degradation due to inactive VHL protein causes the tumors in VHL disease. Tumors form when the remaining intact copy of VHL is somatically inactivated in target tissues (2-hit model). Sporadic cRCC, unrelated to VHL disease, also shows somatic deletions, sequence variants, or aberrant methylation in 80% to 100% of cases.

Retinal angioma, CHB, and SHB cause morbidity and some mortality through pressure on adjacent structures and through retinal or subarachnoid hemorrhages. VHL-related cRCC and PC follow a similar clinical course as their sporadic counterparts, with substantial morbidity and mortality. Early detection of VHL-related tumors can reduce these adverse outcomes, and surveillance of affected individuals is, therefore, widely advocated. Genetic testing is the most accurate way to identify presymptomatic individuals, who can then be entered into a surveillance program.

Research has suggested that certain combinations of VHL tumors cluster in VHL families, and this may be driven by the type of VHL gene variant present in the family. This observation has led to a phenotype-based classification of VHL syndrome. However, it should be noted that these patterns are not clear cut, and should not necessarily be used for diagnostic or therapeutic purposes.

VHL Type 1: Retinal angioma, central nervous system (CNS) hemangioblastoma, renal cell carcinoma, pancreatic cysts, and neuroendocrine tumors. Low risk for pheochromocytoma. Associated with pathogenic truncating or missense variants that are predicted to grossly disrupt the folding of VHL protein.

VHL Type 2: Pheochromocytoma, retinal angiomas, and CNS hemangioblastoma. High risk for pheochromocytoma. Associated with pathogenic missense variants.

VHL Type 2 is further subdivided:

-Type 2A: Pheochromocytoma, retinal angiomas, and CNS hemangioblastomas; low risk for renal cell carcinoma

-Type 2B: Pheochromocytoma, retinal angiomas, CNS hemangioblastomas, pancreatic cysts, and neuroendocrine tumor; high risk for renal cell carcinoma

-Type 2C: Risk for pheochromocytoma only

Additionally, pathogenic sequence variants distinct from those associated with VHL syndrome can cause hereditary erythrocytosis or polycythemia. Cases of VHL disease and erythrocytosis are largely mutually exclusive, and patients who present with erythrocytosis do not typically develop the neoplasms discussed above, although they are sometimes associated with varicose veins and vertebral hemangiomas. Erythrocytosis due to VHL is caused by germline homozygous or compound heterozygous pathogenic sequence variants, and is inherited in an autosomal recessive manner. These patients usually have a markedly high erythropoietin level in the presence of an elevated hematocrit. Erythrocytosis due to a germline homozygous missense variant at nucleotide c.598C->T, p.R200W in the VHL gene has been found endemically in the Chuvash region of Russia, leading individuals with this variant to be labeled as having Chuvash polycythemia (CP), although further studies have determined that this variant can be found in other ethnic groups as well. These patients are at an increased risk to develop cerebrovascular and embolic complications. Heterozygous carriers are typically unaffected.