Description

Von Hippel-Lindau (VHL) disease is a hereditary syndrome with known gene mutations of the VHL gene, which manifests as benign (renal cysts, inner ear, temporal bone) and malignant tumors (renal cell carcinoma [RCC], hemangioblastomas, testicular cancer, others).

Epidemiology

• Median life expectancy: 49 years
• Most common cause of death is either central nervous system (CNS) hemangioblastomas or RCC (1,2).
• 95% penetrance by age 65 years; by age 25 years, most affected individuals have a detectable lesion.
• All individuals who inherit VHL gene mutations or deletions will have some degree of phenotypic expression.
• Asymptomatic VHL gene carriers: 4%
• 40% of patients with VHL have renal lesions, which manifest as multifocal and bilateral with cystic and partially cystic areas.

Incidence
1 in 36,000 to 1 in 45,000 live births

Pathophysiology

• VHL disease results from variations on the VHL gene located on the short arm of chromosome 3 and the 2-hit hypothesis. The VHL gene represents 3 exons that code for the VHL protein, which is thought to regulate the hypoxia-inducible factor (HIF). The cellular response to hypoxia is regulated by HIF (1,2).
• When HIF is produced, it increases the proteins that act to reverse hypoxia, such as vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and erythropoietin. The malfunction of the VHL protein leads to an unregulated increase in HIF. This causes an increase in VEGF, PDGF, and erythropoietin, with the end results being angiogenesis, cell growth, and division, eventually contributing to tumor formation.
• Type I VHL disease is associated with large deletions of the VHL gene, whereas type II VHL disease is associated with missense substitutions of the VHL gene.

Etiology and Pathophysiology

• Autosomal dominant hereditary syndrome caused by mutations or deletions of the VHL gene
• About 20% of people with VHL do not have a family history of the disease and have mutations that occur de novo.

Genetics
Autosomal dominant transmission of VHL gene variations

Risk Factors

Familial

General Prevention

• Although VHL is not a preventable disease, early detection will reduce the burden of morbidity and mortality.
• Screening of asymptomatic family members of those with VHL should be done to look for the family-specific variation in the VHL gene.
• First-line screening for a patient with family history includes genetic testing for VHL gene mutation and then pedigree analysis; a complete history and physical exam, 24-hour urine catecholamines and metanephrines to assess for pheochromocytoma, ophthalmic exam, CT or MRI of abdomen, MRI of neuraxis and skull base, and/or audiogram

Commonly Associated Conditions

• CNS hemangioblastomas: may present in any part of the CNS, most commonly in the cerebellum, spinal cord, brainstem, supratentorial region, and lumbosacral nerve roots (in decreasing order); patients with this manifestation may also present with paroxysmal hypertension without pheochromocytoma, as well as polycythemia, which may require occasional phlebotomy.
• Ocular hemangioblastomas
• Endolymphatic sac tumors (ELSTs) of the ear
• Clear RCC
• Renal cysts
• Pheochromocytoma
• Pancreatic neuroendocrine tumor and cyst
• Epididymal cyst of the testes in men and of the broad ligament in women
• Retinal angioma
• Hypercholesterolemia (due to hypoxic activation of HIF-2α)
• Upper GI bleed, duodenal stenosis, cholangitis