Cowden Syndrome

Approved by the Cancer.Net Editorial Board, 12/2018

What is Cowden syndrome?

Cowden syndrome (CS) is part of the PTEN hamartoma tumor syndrome. Hamartomas are benign, meaning noncancerous, tumor-like growths. Other clinical syndromes that are part of the PTEN hamartoma tumor syndrome are Bannayan-Riley-Ruvalcaba syndrome (BRR; diagnosed in children), Proteus syndrome, and Proteus-like syndrome. CS is characterized by a high risk of both benign and cancerous tumors of the breast, thyroid, endometrium (uterus), colorectal, kidney, and skin (melanoma).

Other key features of CS are skin changes, such as trichilemmomas (skin tags) and papillomatous papules, and macrocephaly, meaning larger than average head size.

How is CS diagnosed?

The diagnostic criteria for CS are complex and frequently reviewed by geneticists, who are health professionals with specialized training in medical genetics, as new information becomes available. Sometimes CS is difficult to diagnosis. That’s why teams of hereditary cancer risk specialists including oncologists, who are cancer doctors, geneticists, genetic counselors, and nurses certified in hereditary cancer have worked together to create diagnostic categories, termed major and minor criteria, summarized in guidelines from the National Comprehensive Cancer Network (NCCN).

Below are the current major and minor criteria as well as the testing criteria for CS:

Major criteria:

  • Breast cancer
  • Endometrial cancer
  • Follicular thyroid cancer
  • Multiple gastrointestinal hamartomas or ganglioneuromas
  • Macrocephaly  
  • Macular pigmentation of glans penis, meaning a discolored area on the skin
  • Mucocutaneous lesions
  • One biopsy-proven trichilemmoma
  • Multiple palmoplantar keratosis, meaning abnormal thickening of the hands and feet
  • Multifocal or extensive oral mucosal papillomatosis
  • Multiple cutaneous facial papules that are often verrucous, meaning wartlike projections

Minor Criteria:

  • Colon cancer
  • Esophageal glycogenic acanthosis
  • Autism-spectrum disorder
  • Mental retardation
  • Papillary or follicular variant of papillary thyroid cancer
  • Thyroid structural lesions, such as adenoma, nodule(s), or goiter
  • Renal cell carcinoma
  • Vascular anomalies, including (kidney cancer) multiple intracranial developmental venous anomalies
  • Lipomas, meaning benign soft-tissue tumor
  • Single gastrointestinal hamartoma or ganglioneuroma
  • Testicular lipomatosis

Cowden Syndrome PTEN Gene Testing Criteria:

People with a personal history of:

  • A family with a known PTEN gene mutation
  • Meeting clinical diagnostic criteria for CS
  • Bannayan-Riley-Ruvalcaba syndrome (BRR)
  • Adult Lhermitte-Duclos disease (cerebellar tumors)
  • Autism spectrum disorder and macrocephaly
  • 2 or more biopsy-proben trichilemmomas
  • 2 or more major criteria (one must be macrocephaly)

Source: Eng C. Will the real Cowden syndrome please stand up: revised diagnostic criteria. Med Genet 2000;37:828-830.

CS is suspected if a person has either 3 major criteria without macrocephaly, 1 major and 3 minor criteria, 4 minor criteria, or a relative with a clinical diagnosis of CS or BRR.

Research is ongoing to better understand CS. Approximately 80% of the people who meet the current clinical diagnosis of CS have a mutation in the PTEN gene. A blood test can determine if someone has a mutation in the PTEN gene. If a person has a mutation in the PTEN gene, he or she has CS.

How is CS inherited?

Normally, every cell has 2 copies of each gene: 1 inherited from the mother and 1 inherited from the father. CS follows an autosomal dominant inheritance pattern in which a mutation in only 1 copy of the gene can cause the Cowden syndrome. This means that a parent with a gene mutation may pass along a copy of their normal gene or a copy of the gene with the mutation. It takes only 1 copy of the gene with the mutation to have the disease. Therefore, a parent with a mutation in the PTEN gene has a 50% chance of passing the mutation to their child with each pregnancy. A brother, sister, or parent of a person who has a mutation also has a 50% chance of having inherited the same gene mutation. Learn more about genetics.

Options exist for people interested in having a child when a prospective parent carries a gene mutation that increases the risk for this hereditary cancer syndrome. Preimplantation genetic diagnosis (PGD) is a medical procedure done in conjunction with in-vitro fertilization (IVF). It allows people who carry a specific known genetic mutation to have children who do not carry the mutation. A woman’s eggs are removed and fertilized in a laboratory. When the embryos reach a certain size, 1 cell is removed and is tested for the hereditary condition in question. The parents can then choose to transfer embryos that do not have the mutation.  PGD has been in use for over 2 decades, and has been used for several hereditary cancer predisposition syndromes. However, this is a complex procedure with financial, physical, and emotional factors to consider before starting. For more information, talk with an assisted reproduction specialist at a fertility clinic.

How common is CS?

CS is thought to be rare, although it is probably under-diagnosed. It is estimated that CS affects about 1 in every 200,000 individuals.

As testing for hereditary cancer expands to include multi-gene panels, the classical definition of syndromes such as CS may change. Some individuals may have a mutation in the PTEN gene but do not meet any of the criteria listed above for CS. It is not known if these people will have the same risks for developing cancer.

What are the estimated cancer risks associated with CS?

  • The greatest cancer risk for a woman with CS is breast cancer. The lifetime risk for a woman with CS to develop breast cancer is estimated to be in the range of 50% to 85%. Breast cancer may develop earlier in women with CS than the general population. There is also an increased risk for a second breast cancer in the opposite breast and some increased risk of breast cancer in men with CS, but the specific risk is not known.

  • The risk of thyroid cancer in men and women with CS is estimated to be in the range of 30% to 40%. Thyroid cancer in CS is most commonly the follicular type but may also be the papillary type.  

  • The risk to develop kidney cancer is in the range of 30% to 35%, and it is one of the highest cancer risks for those with a PTEN gene mutation.

  • The risk of endometrial cancer in women with CS is in the range of 25% to 30%.

  • The risk for colorectal cancer is in the range of 5% to 10% and often occurs at a younger age than compared to the general population.

  • The risk for melanoma is 6%. It is important to be aware of this risk because prevention can begin in childhood by using sunscreen and protective clothing to reduce the number of blistering burns before age 20. Melanoma is a cancer that is influenced by multiple factors including skin color, and eye and hair color, as well as sun exposure and in some cases, inherited gene mutations. If a person tests negative for a PTEN gene mutation that has previously been identified in their family, they may still have risk factors that increase their risk of melanoma.

  • Many other types of cancer have been seen in people with CS. It is not yet known if the risk of these cancers is increased in people with CS. The list reported includes liver cancer, pancreatic cancer, ovarian cancer, bladder cancerbasal cell and squamous cell skin cancers, Merkel cell skin cancer, brain cancer, liposarcoma, and non-small cell lung cancer.

What are the screening options for CS?

It is important to discuss with your doctor the following screening options, as each person is different.  

At the time of diagnosis:

  • People with CS of all ages: an annual thyroid ultrasound scan and an annual skin exam.

Starting at age 30:

Starting at age 40:

Preventive surgery:

  • Women with CS: The preventive removal of the breasts before cancer develops through a surgery, called a prophylactic mastectomy, may be considered. In addition, there can also be the preventive removal of the woman’s uterus, called a prophylactic hysterectomy.  

Source: Min-Han Tan, Jessica L. Mester, Joanne Ngeow, et al. “Lifetime Cancer Risks in Individuals with Germline PTEN MutationsClin Cancer Res. 2012 January 15; 18(2): 400–407.; and National Comprehensive Cancer Network (http://www.nccn.org).

Surveillance, which means close monitoring by a medical professional, may begin 5 to 10 years earlier than the youngest person diagnosed with a specific cancer in the family, but should begin no later than the ages noted above. The frequency of scheduled colonoscopies may increase based on how many polyps are found.

Screening options may change over time as new technologies are developed and more is learned about CS. It is important to talk with your doctor about appropriate screening tests.

Learn more about what to expect when having common tests, procedures, and scans.

Questions to ask the health care team

If you are concerned about your risk of cancer, talk with your health care team. It can be helpful to bring someone along to your appointments to take notes. Consider asking the following questions:

  • What is my risk of developing cancer?

  • Where can I receive a hereditary cancer risk assessment?

  • What can I do to reduce my risk of cancer?

  • What are my options for cancer screening and prevention?

If you are concerned about your family history and think your family may have CS, consider asking the following questions:

  • Does my family history increase my risk of cancer?

  • Could my family have CS?

  • Will you refer me to a genetic counselor for a cancer risk assessment?

  • Should I meet with a genetic counselor?

Related Resources

The Genetics of Cancer

Genetic Testing

What to Expect When You Meet With a Genetic Counselor

Collecting Your Family Cancer History

Sharing Genetic Test Results with Your Family

Family Genetic Testing Q&A

More Information

Facing Our Risk of Cancer Empowered (FORCE)
Information for women who are at a higher risk of developing ovarian cancer or breast cancer.
www.facingourrisk.org  

National Comprehensive Cancer Network (NCCN)
http://www.nccn.org/members/network.asp

National Cancer Institute
www.cancer.gov  

American Cancer Society
www.cancer.org  

To find a genetic counselor in your area, ask your doctor or visit this website:       

National Society of Genetic Counselors                    
www.nsgc.org