by Dr. C.H. Weaver M.D. updated 8/2021
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.2 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.
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In July 2020 the U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy designation to MK-6482. This was updated to a "priority review" in March, and full approval in August 2021.
MK-6482 will be developed under the name Belzutifan (pronounced bell-ZOO-ti-fan) and the data leading to FDA approval was released.
In an open-label clinical trial in 61 patients with VHL-associated RCC (VHL-RCC) diagnosed based on a VHL germline alteration and with at least one measurable solid tumor localized to the kidney. An overall response rate of 49% was reported in patients with VHL-associated RCC and 56% of responders had a response duration greater than 12 months.
In patients with other VHL-associated non-RCC tumors, 24 patients with measurable CNS hemangioblastomas had a response rate of 63% and 12 patients with measurable pNET had a respone rate of 83%.4
Belzutifan is currently being evaluated in Phase 3 trials as part of a combination regimen in previously treated patients and as part of a combination regimen as a first-line treatment for advanced clear cell RCC.
About Belzutifan (MK-6482)
Belzutifan (MK-6482) is a novel, potent and selective inhibitor of HIF-2α. Proteins known as hypoxia-inducible factors, including HIF-2α, can accumulate in patients when VHL, a tumor-suppressor protein, is inactivated. If not properly regulated, the accumulation of HIF-2α can stimulate several oncogenes associated with cellular proliferation, angiogenesis and tumor growth, leading to the growth 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.
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 "priority review" 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.
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- 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.