Von Hippel Lindau (VHL) Disease
by Dr. C.H. Weaver M.D. updated 8/2020
Von Hippel-Lindau (VHL) disease is a rare inherited disorder characterized by the abnormal growth of both benign and cancerous tumors and cysts in many parts of the body. Von Hippel-Lindau disease affects one in 36,000 people (200,000 cases worldwide and 10,000 cases in the U.S.). The tumors usually first appear in young adulthood and tumors associated with VHL disease include;
- Hemangioblastomas (slow-growing tumors of the central nervous system)
- Kidney Cysts
- Clear Cell Renal Cancer
- Pancreatic Neuroendocrine tumors
- Pheochromocytomas (noncancerous tumors of the adrenal glands)
- Endolymphatic sac tumors
Signs and Symptoms of VHL Disease
The symptoms of von Hippel-Lindau (VHL) disease are wide ranging and many depend on the size and location of the tumors. (3,4)
- Headaches, vomiting, weakness, and a loss of muscle coordination may be caused by hemangioblastomas in the brain.
- Vision loss can occur from retinal angiomas.
- High blood pressure may occur from pheochromocytoma tumors in the adrenal glands.
- Hearing loss in one or both ears and tinnitus and problems with balance can occur in about 10% of people with VHL disease due to endolymphatic sac tumors in the inner ear.
Individuals with VHL disease are also at a higher risk than normal fir developing kidney cancer which occurs in about 70% of individuals with VHL disease by age 60 and is the leading cause of death.
Cause of VHL
VHL disease is caused by a mutation in the VHL gene. Early detection and treatment of VHL disease is important, and usually involves surgical removal of tumors. (1,2) VHL is a tumor suppressor gene, which helps to regulate cell growth. Mutations in the VHL gene lead to defective regulation and uncontrolled cell growth resulting in the formation of the tumors associated with VHL disease.
VHL gene mutations are inherited in an autosomal dominant manner. This means that having a mutation in only one copy of the VHL gene in each cell is enough to increase a person's risk of developing VHL disease. In most autosomal dominant conditions, having one mutated copy of the responsible gene is sufficient to cause the condition. In VHL disease however, a mutation in the other copy of the gene must occur or VHL doesn't develop.
Almost everyone who is born with one VHL mutation will eventually acquire a mutation in the second copy of the gene and develop VHL disease. In most cases, an affected person inherits the first mutated gene from an affected parent. However, in about 20% of cases, the mutation occurs for the first time in a person with no family history of the condition. This is called a de novo mutation. When a person with a mutation that can lead to VHL disease has children, each of their children has a 50% (1 in 2) chance to inherit that mutation.
The diagnosis of von Hippel-Lindau disease is confirmed when molecular genetic testing detects a mutation in the VHL gene.
Treatment of VHL usually involves surgery to remove the tumors before they become harmful. Certain tumors can also be treated with focused high-dose irradiation. Individuals with VHL need careful monitoring by a physician and/or medical team familiar with the disorder.
MK-6482 (formerly PT2977) is an oral precision cancer medicine that inhibits HIF-2α. Proteins known as hypoxia-inducible factors, including HIF-2α, can accumulate in patients when VHL tumor-suppressor protein is inactivated. The accumulation of HIF-2α can lead to the formation of both benign and malignant tumors. This inactivation of VHL has been observed in more than 90% of clear cell RCC tumors. Research into VHL biology that led to the discovery of HIF-2α was awarded the Nobel Prize in Physiology or Medicine in 2019.
In July 2020 the U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy designation to MK-6482, a novel investigational medication for the treatment of patients with VHL disease-associated renal cell carcinoma with nonmetastatic RCC tumors less than three centimeters in size, unless immediate surgery is required. The FDA also granted orphan drug designation to MK-6482 for VHL disease.
Certain patients with von Hippel-Lindau disease, who currently have limited treatment options and face an increased risk for benign tumors as well as several types of cancer, including renal cell carcinoma.” The FDA’s Breakthrough Therapy designation is granted to expedite the development and review of medicines that are intended to treat serious or life-threatening conditions and that have demonstrated preliminary clinical evidence indicating that the medicine may provide a substantial improvement over available therapy on at least one clinically significant endpoint.
Frantzen C, Klasson TD, Links TP, Giles RH. Von Hippel-Lindau Syndrome. 2000 May 17 [updated 2015 Aug 6]. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, Bird TD, Ledbetter N, Mefford HC, Smith RJH, Stephens K, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017. Available from http://www.ncbi.nlm.nih.gov/books/NBK1463/
Ganeshan D, Menias CO, Pickhardt PJ, Sandrasegaran K, Lubner MG, Ramalingam P, Bhalla S. Tumors in von Hippel-Lindau Syndrome: From Head to Toe-Comprehensive State-of-the-Art Review. Radiographics. 2018 May-Jun;38(3):849-866. doi: 10.1148/rg.2018170156. Epub 2018 Mar 30. Review. Erratum in: Radiographics. 2018 May-Jun;38(3):982.
Shuin T, Yamasaki I, Tamura K, Okuda H, Furihata M, Ashida S. Von Hippel-Lindau disease: molecular pathological basis, clinical criteria, genetic testing, clinical features of tumors and treatment. Jpn J Clin Oncol. 2006 Jun;36(6):337-43.
Von Hippel-Lindau Syndrome
Von Hippel-Lindau (VHL) syndrome is characterized by hemangioblastomas of the brain, spinal cord, and retina; renal cysts and clear cell renal cell carcinoma; pheochromocytoma, pancreatic cysts, and neuroendocrine tumors; endolymphatic sac tumors; and epididymal and broad ligament cysts. Cerebellar hemangioblastomas may be associated with headache, vomiting, gait disturbances, or ataxia. Spinal hemangioblastomas and related syrinx usually present with pain. Sensory and motor loss may develop with cord compression. Retinal hemangioblastomas may be the initial manifestation of VHL syndrome and can cause vision loss. Renal cell carcinoma occurs in about 70% of individuals with VHL and is the leading cause of mortality. Pheochromocytomas can be asymptomatic but may cause sustained or episodic hypertension. Pancreatic lesions often remain asymptomatic and rarely cause endocrine or exocrine insufficiency. Endolymphatic sac tumors can cause hearing loss of varying severity, which can be a presenting symptom. Cystadenomas of the epididymis are relatively common. They rarely cause problems, unless bilateral, in which case they may result in infertility.