What is Von Hippel-Lindau (VHL) disease?

From the Guidelines

Von Hippel-Lindau disease is a rare genetic disorder that requires prompt diagnosis and management to prevent morbidity and mortality, and genetic testing is recommended for diagnosis and for family members of affected individuals, as stated in the most recent guidelines 1.

Key Points

• Von Hippel-Lindau disease is caused by mutations in the VHL gene, which normally functions as a tumor suppressor.
• People with this condition typically develop benign and cancerous tumors in the brain, spinal cord, eyes, inner ear, adrenal glands, kidneys, pancreas, and reproductive organs.
• Common manifestations include retinal hemangioblastomas (eye tumors), cerebellar hemangioblastomas (brain tumors), renal cell carcinomas (kidney cancer), and pheochromocytomas (adrenal gland tumors).
• Management involves regular surveillance with imaging studies and specialized examinations to detect tumors early, as recommended in the consensus guidelines for ocular surveillance of von Hippel-Lindau disease 1.
• Treatment depends on the location and type of tumors but may include surgery, radiation therapy, or targeted medications.
• The disease is inherited in an autosomal dominant pattern, meaning a person has a 50% chance of passing it to their children.
• Early detection and treatment of tumors can significantly improve outcomes and quality of life for patients with this condition, as shown in a recent cohort study that reported an increase in life expectancy of individuals with VHL disease in recent decades 1.

Diagnosis and Management

• Genetic testing is recommended for diagnosis and for family members of affected individuals, as stated in the guidelines 1.
• Ocular screening should begin within 12 months after birth and continue throughout life, with a frequency of approximately every 6-12 months until 30 years of age and then at least yearly thereafter, as recommended in the guidelines 1.
• Patients should be managed by those with subspecialty training and experience with VHL disease or retinal hemangioblastomas, and ideally within the context of a multidisciplinary center capable of providing multiorgan surveillance and access to genetic testing, as stated in the guidelines 1.

From the Research

Overview of von Hippel-Lindau Disease

• von Hippel-Lindau (VHL) disease is a hereditary, autosomal dominant syndrome characterized by the development of various benign and malignant tumors, including hemangioblastomas, renal cell carcinomas, pheochromocytomas, and pancreatic neuroendocrine tumors 2, 3, 4, 5, 6.
• The disease is caused by a mutation in the VHL gene, leading to the loss of function of the VHL protein and increased expression of hypoxia-inducible factor (HIF) 6.

Clinical Manifestations

• VHL disease can present with a range of clinical manifestations, including retinal angiomas, hemangioblastomas of the central nervous system, pheochromocytomas, and epididymal cystadenomas 4.
• The disease can also cause cysts in various organs, including the kidneys, pancreas, and reproductive organs 5.

Diagnosis and Surveillance

• Diagnosis of VHL disease can be made based on clinical criteria, genetic testing, or a combination of both 2, 3.
• Surveillance programs are essential for early detection and management of VHL-related tumors, and should include regular examination of the retina, central nervous system, kidneys, and other organs 2, 3, 5.
• The Freiburg surveillance protocol recommends starting screening at age 6 for retinal tumors and at age 14 for central nervous system tumors, with biannual examinations until age 18 5.

Treatment and Management

• Treatment of VHL disease typically involves surgical resection of symptomatic tumors, as well as management of related conditions such as hypertension and hormonal imbalances 2, 3, 6.
• Modern neurosurgical techniques, including microsurgery, neuronavigation, and intraoperative neuromonitoring, can help minimize morbidity and improve outcomes for patients with VHL-related tumors 5.
• Belzutifan, a drug that targets HIF-2α, has been approved for the treatment of adult patients with VHL-associated renal cell carcinomas, central nervous system hemangioblastomas, or pancreatic neuroendocrine tumors 2.