Von Hippel-Lindau Syndrome

What is von Hippel-Lindau syndrome (VHL)?

Two physicians—Eugen von Hippel, a German opthalmologist and Arvid Lindau, a Swedish pathologist—were the first to describe tumors in people's eyes and brains, hallmarks of this genetic condition. In the 1960s, the disease was named von Hippel-Lindau syndrome to recognize their contributions.

Von Hippel-Lindau syndrome is a rare genetic disorder. A person with VHL has an increased risk of developing pockets of fluid (cysts) or tumors in many parts of the body. The more common tumors to occur are:

• Hemangioblastomas. These are noncancerous (benign), slow-growing tumors made up of nests of blood vessels of the brain and spine.

• Hemangioblastomas of the retina. These benign tumors are found in the retina of the eye.

• Pheochromocytomas. This neuroendocrine tumor is usually benign. It occurs within or outside of the adrenal gland.

• Clear cell renal cell carcinoma. This cancerous tumor of the kidney happens in about 7 in 10 people with VHL. 

Less often, people develop endolymphatic sac tumors. These are ear tumors that can cause deafness if undetected. People with VHL may also develop pancreatic tumors and cystadenomas of the epididymis (males) or broad ligament (females). Other signs include cysts in the kidney and pancreas.

The VHL gene is a tumor suppressor gene located on chromosome 3. This usually controls cell growth and cell death. Both copies of a tumor suppressor gene must be changed, or mutated, before a person will develop cancer. In about 4 in 5 VHL cases, the first mutation is inherited from either the mother or the father. It is present in all cells of the body at birth. This is called a germline mutation. Whether a person who has a germline mutation will develop a tumor and where the tumor or tumors will develop depends on where (in which cell type) the second mutation happens. For example, if the second mutation is in the retina, then a retinal hemangioblastoma may develop. If it is in the adrenal gland, then a pheochromocytoma may develop. The process of tumor development actually needs mutations in multiple growth control genes. Loss of both copies of the VHL gene is just the first step in the process. What causes these additional mutations is unknown. Possible causes include chemical, physical, or biological environmental exposures or chance errors in cell replication.

Some people who have inherited a germline VHL mutation never develop cancer. This is because they never get the second mutation necessary to knock out the function of the gene and start the process of tumor formation. This can make the cancer appear to skip generations in a family. But, in reality, the mutation is present. People with a VHL mutation, regardless of whether they develop cancer, have a 50/50 chance to pass the mutation on to each of their children. About 1 in 5 VHL cases are new mutations, and not inherited from a parent.

It's also important to remember that the VHL gene is not located on the sex chromosomes. Therefore, mutations can be inherited from either the mother's side or the father's side of the family.

Molecular genetic testing of VHL is available and can find a mutation in about 9 in 10 to 10 in 10 affected people. Genetic testing is also considered part of the standard management for first-degree relatives (parent, siblings, children) of affected people. For people who are mutation-positive, annual screening to find tumors before severe complications develop is recommended. Genetic testing of unaffected relatives is useful only if a germline mutation has already been identified in an affected family member.