Von Hippel-Lindau Syndrome (VHL)

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 von Hippel-Lindau syndrome. In the 1960s the disease was named VHL, von Hippel-Lindau, to recognize their contributions in characterizing the disease.

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

  • Hemangioblastomas (benign, or noncancerous, tumors made up of nests of blood vessels) of the brain and spine

  • Hemangioblastomas of the retina

  • Pheochromocytomas (a tumor of the chromaffin cells, which are present in the adrenal gland; usually benign, or noncancerous) within or outside of the adrenal gland

  • Renal cell carcinoma (cancerous tumor of the kidney)

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 VHL, the first mutation is inherited from either the mother or the father and is therefore present in all cells of the body. 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 brain, then a hemangioblastoma may develop. The process of tumor development actually requires mutations in multiple growth control genes. Loss of both copies 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 mutation, regardless of whether they develop cancer, however, have a 50/50 chance to pass the mutation on to the next generation. About 20 percent of VHL cases are new mutations, 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 or the father's side of the family.

Genetic testing (in this case for mutations in the VHL gene) is 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.

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