Von Hippel-Lindau Syndrome

Von Hippel-Lindau Syndrome

What is von Hippel-Lindau syndrome (VHL)?

Two eye doctors--von Hippel in Germany and Lindau in Sweden--were the first to publish descriptions of tumors in patients' eyes and brains, hallmarks of this genetic condition. In the 1960s, the disease was named von Hippel-Lindau syndrome to recognize their contributions in characterizing the condition.

Von Hippel-Lindau syndrome is a rare genetic disorder characterized by an increased risk of developing the tumors listed below:

  • Hemangioblastomas. Benign (noncancerous) tumors made up of nests of blood vessels of the brain and spine.

  • Hemangioblastomas of the retina

  • Pheochromocytomas. A neuroendocrine tumor, usually benign (noncancerous), within or outside of the adrenal gland

  • Renal cell carcinoma. Cancerous tumor of the kidney that occurs in about 70 percent of individuals with VHL. 

Less commonly, some individuals develop endolymphatic sac tumors (ear tumors that can cause deafness if undetected), pancreatic tumors, and cystadenomas of the epididymis or broad ligament. Other manifestations include cysts (pockets of fluid) of the kidney and pancreas.

The VHL gene is a tumor suppressor gene located on chromosome 3, which usually controls cell growth and cell death. Both copies of a tumor suppressor gene must be altered, or mutated, before a person will develop cancer. In about 80 percent of VHL cases, the first mutation is inherited from either the mother or the father and 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(s) will develop depends on where (in which cell type) the second mutation occurs. 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 requires 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 individuals 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, when, in reality, the mutation is present. Individuals 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 20 percent of VHL cases are new mutations (de novo), and not inherited from a parent.

It is 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 clinically and identifies a mutation in about 90 to 100 percent of affected individuals. Genetic testing is also considered part of the standard management for first-degree relatives (parent, siblings, children) of affected individuals. For persons who are mutation-positive, annual screening to detect 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.