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

• multiple hamartomatous lesions (benign, or noncancerous, tumors of normal organ tissue) of the skin and other organs, usually present by the late 20s
• macrocephaly (increased head size)
• increased risk of breast cancer, with an average age of onset ranging from 38 to 46 years
• increased risk of thyroid cancer
• increased risk of endometrial cancer

Additional features can include noncancerous thyroid lesions, hamartomatous 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. About 80 percent of people whose symptoms meet the criteria for a diagnosis of Cowden syndrome will have a PTEN mutation. Mutations in PTEN confer a 25 percent to 50 percent lifetime risk for breast cancer, about a 10 percent risk of thyroid cancer, and potentially up to a 5 percent to 10 percent risk of endometrial cancer, although this risk is still being evaluated.

Whether a person who has a germline mutation will develop cancer and where the cancer(s) will develop depends upon 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 to be acquired is unknown. Possible causes include chemical, physical, or biological environmental exposures or chance errors in cell replication.

Some individuals 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. Persons with a mutation, regardless of whether they develop cancer, however, have a 50/50 chance to pass the mutation on to the next generation.

It is also 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.