Cowden Syndrome

The risk for breast cancer, endometrial (uterine) cancer, gastrointestinal cancers, and thyroid cancer is increased with Cowden syndrome, a rare inherited disorder that is also associated with a number of specific noncancerous features. Cowden syndrome is associated with the following characteristics:

  • Multiple benign, or noncancerous, tumors of normal organ tissue of the skin and other organs, usually present by the late 20s

  • Macrocephaly (increased head size)

  • Noncancerous breast and thyroid diseases are common

  • Intellectual disability

  • A rare, noncancerous brain tumor called Lhermitte-Duclos disease

Additional features can include noncancerous thyroid lesions, intestinal polyps, lipomas (benign fatty tumors), fibromas, uterine fibroids, and fibrocystic disease of the breast.

Cowden syndrome is caused by mutations in a gene on chromosome 10 known as PTEN. Around 20% to 34% of people whose symptoms meet the criteria for a diagnosis of Cowden syndrome will have a PTEN mutation. Mutations in PTEN confer a cumulative lifetime risk for breast cancer of 81% to 85%, a 3% to 35% risk of thyroid cancer, and a 13% to 28% risk of endometrial cancer.

The PTEN gene is a tumor suppressor gene, 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. With Cowden syndrome, the first mutation is inherited from either the mother or the father and is present in all cells of the body. This is called a germline mutation. Whether a person who has a germline mutation will develop cancer and where the cancer(s) will develop depends on where (which cell type) the second mutation occurs. For example, if the second mutation is in the thyroid, then thyroid cancer may develop. If it is in the breast, breast cancer may develop. The process of tumor development actually requires mutations in multiple growth control genes. Loss of both copies of PTEN 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 PTEN mutation never develop cancer 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. People with a mutation, regardless of whether they develop cancer, have a 50/50 chance to pass the mutation on to their children.

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