What is von Hippel-Lindau Syndrome?

December 5, 2019

  • Von Hippel-Lindau syndrome is a rare disorder that gives rise to tumors and cysts in different organs and tissues.
  • Although most of these tumors are benign, they can still be dangerous.
  • Dana-Farber research into the syndrome led to discovery of a cellular switch for responding to changes in oxygen levels — and to a Nobel Prize for Institute scientist William G. Kaelin, Jr., MD.

Von Hippel-Lindau syndrome (VHL) is a rare disorder in which tumors and cysts can arise in multiple organs and tissues. It affects about 10,000 people in the United States and is caused by a mutation in the VHL gene. The vast majority of people with the syndrome inherited a mutated copy of VHL from a parent, although some spontaneously developed a mutation in the gene while they were embryos in their mother’s womb.

The tumors and cysts associated with VHL often make their first appearance during young adulthood but can occur throughout life. The most commonly affected parts of the body are the kidneys, adrenal glands, pancreas, eyes, inner ears, brain, spine, reproductive tract, liver, and lungs. Many of these tumors are hemangioblastomas, growths that are tangles of newly formed blood vessels. Most VHL-related tumors are benign — unlikely to spread elsewhere in the body — but they can still be dangerous. As they enlarge, they push into surrounding structures, causing pain and interfering with the function of the affected organ or tissue.

What are symptoms of von Hippel-Lindau syndrome?

Some people with VHL experience no symptoms. When symptoms do occur, they vary from one patient to another, even within the same family. Some of the most common presenting signs are:

  • multiple hemangioblastomas of the brain, spinal cord, or eye
  • a single hemangioblastoma and kidney cancer or cysts in certain organs
  • or, in young individuals, cancer in both kidneys.

People with a family history of VHL may be suspected of having the disorder if they have a single VHL-associated tumor, such as:

  • a hemangioblastoma
  • kidney or pancreatic cysts
  • kidney cancer
  • or tumor of the adrenal gland.

A definitive diagnosis of VHL occurs when genetic testing reveals a mutation in the VHL gene.

Once a VHL diagnosis is made, it’s important for patients to be closely monitored. Most VHL growths are easier to treat when they’re small.

How is von Hippel-Lindau syndrome treated?

Just as symptoms of the syndrome vary, so do treatments, which are based on the organs or tissues affected, the size, type, and growth rate of tumors and their potential to become metastatic, and other factors. Surgery may be necessary to remove some growths.

MyVHL: The National Natural History Study is an online research project exploring how patients can manage the disorder more effectively and how lifestyle might be related to the features of VHL in individual patients. It is open to everyone diagnosed with VHL or with symptoms of the condition.

While VHL is a relatively rare disorder, research into its causes and consequences might have a profound effect on the treatment of a range of diseases. This is exemplified by the work of Dana-Farber’s William G. Kaelin, Jr., MD, who is a co-recipient of the 2019 Nobel Prize in Physiology or Medicine for his work in this area.

William G. Kaelin, Jr., MD.

How is von Hippel-Lindau syndrome related to oxygen regulation?

As a postdoctoral fellow in the late 1980s and early 1990s, Kaelin was studying retinoblastoma, a childhood eye tumor linked to a specific genetic mutation.  In 1993, shortly after starting his own laboratory, researchers in the U.S. and England announced their discovery of the abnormal gene responsible for VHL. Intrigued, Kaelin began creating models to understand the gene’s normal role and why a mutation leads to the formation of cysts and tumors.

In 1996, he and his colleagues found that cells lacking a normal copy of the VHL gene behave as if they’re being starved of oxygen, even if they aren’t. Oxygen is critical to human cell life: When oxygen levels drop, cells switch on certain gene circuits to compensate for the loss. Some of these circuits trigger the growth of new blood vessels to bring more oxygen to the cells. Kaelin showed that cells unable to manufacture normal VHL protein lost some of their ability to respond to changes in oxygen availability. He then set out to trace the exact connection between the VHL protein and oxygen use.

He found that the VHL protein normally helps regulate the levels of an oxygen-sensitive protein called HIF, which can trigger or restrict the production of red blood cells and new blood vessels. Cancer cells with mutated VHL genes seize control of this system to order the construction of new blood vessels to feed their growth.

These findings and those that were to follow enabled Kaelin to show how a subtype of HIF drives certain kidney cancers and how another subtype is involved in triple-negative breast cancer. He is currently developing therapeutic strategies for targeting these subtypes with designer drugs.

The discovery of the switch for sensing and responding to oxygen, and how it sometimes malfunctions, has implications not only for treating cancer but for a range of other diseases as well, including anemia, stroke, and heart conditions.  

Information and support for patients and families affected by von Hippel-Lindau syndrome is available from the VHL Alliance.