Cowden Syndrome: A Guide for patients and their families

This material supplements information provided by physicians, nurses, genetic counselors, and other members of your health care team about Cowden syndrome. It does not replace regular medical care or discussions with your health care team. If you see an unfamiliar term, please see the Glossary of Terms at the end of this material.

That's Not the Name My Doctor Gave Me

Cowden syndrome (CS)--first described in 1963--was named after Rachel Cowden, the young woman who had the features reported. However, Cowden syndrome is not the only name used for this condition. It is also known as the PTEN hamartoma syndrome (PHTS), or less commonly as the multiple hamartoma syndrome. Other related, but not identical, conditions include Bannayan- Ruvalcaba-Riley syndrome, Ruvalcaba-Myhre syndrome, Riley-Smith syndrome, or Bannayan-Zonana syndrome.

The use of different names can be confusing. The problem started when several different groups of physicians and researchers began describing collections of features they observed in their patients. Each group believed that they were describing a new condition. Because CS consists of various features that occur at different times, or not at all, different people will show different features even though they have the same genetic condition. That was enough to make researchers at the time believe they were describing different conditions.

In 1996, the overlap of features in CS and Bannayan-Ruvalcaba-Riley syndrome (BRRS) was recognized and shortly after it was shown that CS and BRRS were caused by harmful changes (called mutations) in the same gene. Since then, many names have been added to the list of related syndromes. Below are several other names that you may encounter as well.

  • Ruvalcaba-Myhre-Smith syndrome
  • Bannayan syndrome
  • PTEN Hamartoma Tumor syndrome
  • Autism disorders with macrocephaly
  • Proteus-like syndrome

What is Cowden Syndrome?

Cowden syndrome is a hereditary condition which causes multiple types of benign tissue overgrowth (called hamartomas) and a risk of breast, thyroid, and uterine cancers. The most consistent features of CS are small flesh-colored bumps on the skin involving a hair follicle (trichilemmomas) and small wart-like growths (papillomatous papules) on the face, hands and mouth. CS is also often associated with a large head size (macrocephaly) and hamartomatous polyps of the small and large intestine. Thyroid adenomas, goiter, and nodules are also seen at increased frequency. Women are at increased risk for benign breast conditions, such as ductal hyperplasia, papillomatosis, fibrocystic breast disease, or fibroadenomas. Less commonly seen are benign fatty tumors (lipomas), blood vessel growths (hemangiomas), and other changes.

The breast, thyroid and uterus are the most common sites for cancer development in CS. About 30-50 percent of women with CS will develop breast cancer, often at a much younger age than average. This is compared to a risk of about 12 percent for women without CS. It is also common for women with CS to eventually develop cancer in both breasts. Only two men with CS have been reported with breast cancer, so it is not clear if men with CS have an increased risk for developing breast cancer. Studies have suggested that uterine (endometrial) cancer is also increased in CS, with a risk currently estimated at six to eight percent (compared to about 2.5 percent in women with average risk). Men and women with CS have about a three to 10 percent lifetime risk for developing thyroid cancer (compared to one percent for an average risk person). Recent data suggests that the risk for colon cancer may also be increased. Cancers of the skin, kidney, small bowel and others have been reported, but it is has not been proven if the risks for these cancers are increased for people with CS.

Although it is not certain at what age the features of Cowden syndrome begin to appear, we believe that more than 90 percent of people with CS have some features by the age of 20. However, people diagnosed with CS do not necessarily have all the same features. For example, most individuals with CS have some skin feature, up to 75 percent have a breast-related problem, and about 80 percent have a large head (macrocephaly), but they may have only some or none of the other features. Table 1 lists the features that have been associated with Cowden syndrome and the approximate percentage of people that develop each feature (incidence).

Common Characteristics of Cowden Syndrome

Table 1: Common Characteristics of Cowden Syndrome
Class Feature Incidence
Skin and mouth lesions Trichilemmomas, acral keratoses, and papillomatous papules 90-100%
Head Macrocephaly 80%
Development Mental retardation/developmental delay 15-20%
Thyroid problems Goiter, adenomas, nodules 40-60%
Breast Problems (females) Fibroadenomas, fibrocystic disease 40%
Gastrointestinal Hamartomatous polyps, ganglioneuromas 80%
Gynecologic problems Uterine fibroids (multiple and early onset) 25%
Other benign growths

Lipomas
Hemangiomas

40-50%
10-40%

Cancer

Thyroid Cancer
Breast Cancer
Endometrial Cancer

3-10%
25-50%
6-8%

How is Cowden Syndrome Diagnosed?

Physicians diagnose Cowden syndrome using a combination of criteria that were originally set by the International Cowden Syndrome Consortium and have been slightly revised over time. The various features are grouped into three categories: the pathognomonic criteria, the major criteria, and the minor criteria. Pathognomonic criteria are the most likely features to be associated with a condition. The major and minor criteria consist of related features that are not as specific to CS. The categories help to define when a patient really has CS instead of another condition that may have similar features. Your doctor, or a genetic specialist, can look at the features you have and compare them to the diagnostic criteria when deciding if CS is a likely possibility. An individual does not need to have all the features in every category to be diagnosed with CS, nor does someone necessarily have CS when they have only one feature from any or all of the categories. When making this diagnosis, it is more important to look at all of the features an individual experiences over time.

CS Categories:

  • Pathognomonic criteria
  • Mucocutaneous lesions
  • Facial trichilemmomas
  • Acral keratoses
  • Papillomatous lesions

Major criteria

  • Breast cancer
  • Thyroid cancer
  • Macrocephaly
  • Lhermitte-Duclos disease
  • Uterine (endometrial) cancer

Minor criteria

  • Structural thyroid diseases (such as goiter or adenomas)
  • Mental retardation/developmental delay
  • Gastrointestinal hamartomas or benign tumors
  • Fibrocystic Breast Disease
  • Lipomas
  • Fibromas

Are Tests for Cowden Syndrome Available?

Genetic testing of the PTEN gene can identify if someone has a mutation causing Cowden syndrome. There is a charge for these services when provided by clinically approved laboratories. These charges may or may not be covered by insurance and should be discussed with your doctor or genetic counselor.

The usual test for CS is called gene sequencing. In sequencing, the individual components (“letters”) of the PTEN gene are examined in detail looking for a mutation. This test is very accurate, but only about 40-80 percent of people meeting the criteria for CS have an identifiable mutation. This means that 20-60 percent of people who meet the criteria for CS will not have an identifiable mutation and will have a normal test result even though they do have CS. This could be due to a limitation in the test, and some labs offer additional testing to detect rare mutations missed by sequencing. It may also be possible, although this has not been proven, that CS could be cause by a mutation in another gene that has not been identified yet.

PTEN testing may also be available to you through a research study. Unlike clinical testing, research-based testing may take many months or years, but it is usually done without any cost to you. It may also provide information and results that are not available on a clinical basis. You may want to consider these issues as you decide whether you wish to pursue either clinical or research-based testing. Your physician and genetic counselor can help you if you are interested in participating in a research study.

What Should I Be Doing About This Condition?

Recommendations for cancer screening for people with Cowden syndrome are updated and published each year by the National Comprehensive Cancer Network (NCCN). In many cases, screening can help manage benign growths and detect any cancer at an early stage, when it is best treated. The recommended screenings for people with CS are summarized in Table 2.

Because of the risk for breast cancer, women with CS should have increased breast cancer screening. Currently this includes performing monthly breast self-examination, getting a breast exam from your doctor every 6 months beginning at 25 years of age, and an annual mammogram and breast MRI beginning at 30 to 35 years of age (or 5-10 years before the earliest known breast cancer in the family; whichever comes first). For some women with dense breast tissue that can make it harder to detect breast cancers, preventative mastectomy may be an option. Women should also be aware of the signs and symptoms of possible uterine cancer, such as abnormal vaginal bleeding, pelvic pain, pain during intercourse and painful urination.

Both men and women should receive thyroid cancer screening that includes an ultrasound of the thyroid at age 18 and annual thyroid palpation (having a doctor feel the thyroid) after that. You might also consider having an annual ultrasound. Because thyroid nodules can be a common feature, an experienced endocrinologist should evaluate any thyroid nodules to determine if they require follow-up, such as a biopsy.

Skin cancer screenings should also be considered. Yearly visits to a dermatologist can help manage the CS skin findings and also screen for skin cancer.

There is some recent evidence that the risk for colon cancer may be increased in people with CS. Currently it is recommended that people with CS have colonoscopy every 10 years beginning at age 50 like anyone in the general population. However, these recommendations could change and it is important to ask your doctor or genetic counselor about the most current guidelines.

Check Yourself: Are You Getting the Screening You Need?

Women
Beginning Age Recommended Screenings Frequency
18 Thyroid palpation and ultrasound Annual for palpation consider annually for ultrasound
18 Breast self-examination Monthly
18* Comprehensive physical exam Annually
25* Clinical breast examination Every six months
30-35*

Mammography
Breast MRI

Annual
Annual

30-35 Endometrial cancer screening Consider annually
Adults Dermatology Consider annually
50 Colonoscopy Every 10 years, if normal
Men
Beginning Age Recommended Screenings Frequency
18* Thyroid palpation and ultrasound Annual for palpation consider annually for ultrasound
18* Thyroid ultrasound and palpation Annual for palpation and consider for ultrasound
18* Comprehensive physical exam Annual
Adults Dermatology Consider annually
50 Colonoscopy Every 10 years, if normal

* or 5-10 years before the earliest related cancer in the family.

Resources and Support Groups

Because Cowden syndrome can be complicated to diagnose, it is important to address your questions and concerns with your physician and genetic counselor. Remember that no two people with this diagnosis will have exactly the same symptoms. Pay particular attention to physical changes and discuss them with your physician regularly. Living with any type of genetic condition can be a challenge, but living with CS is a challenge you can face with a good medical team as your partner.

Remember that different people deal with this diagnosis in different ways. For some the path may be long and difficult while others adjust in a shorter time with less difficulty. Just remember to give yourself time to acknowledge your feelings. The members of your health care team--physicians, genetic counselors, and nurses--serve as an excellent resource and you should discuss your situation with them. Another valuable resource can be other people who have been in similar situations. Support groups can connect people who are dealing with similar issues and bring them together in a supportive environment. Here are several groups that may benefit you or someone you know.

American Cancer Society
1599 Clifton Road NE
Atlanta, GA 30329
800-ACS-2345
www.cancer.org
Genetic Alliance4301 Connecticut Avenue NW Suite 404
Washington, DC 20008-2369
202-966-5557
www.geneticalliance.org
National Society of Genetic Counselors – NSGC
401 N. Michigan Avenue
Chicago, IL 60611
312-321-6834
www.nsgc.org (includes a search tool to find a genetic counselor in your area)

Patient run support groups*:

* These sites are for personal support for individuals and families with Cowden syndrome and are not monitored by medical professionals.

Glossary of Terms

Acral keratoses:
small callous (thickening of the skin) usually located on the extremities
Adenoma:
a type of benign tumor in which the cells form glands
Angiolipomas:
benign growth of fat cells found in blood vessels
Baseline:
normal background level used for comparisons
Benign:
term describing a growth that is not cancerous
Benign Breast Disease:
a variety of conditions characterized by benign growths in breast tissue. See fibrocystic breast disease, ductal hyperplasia, intraductal papillomatosis, , fibrocystic breast disease, and fibroadenoma
Chromosomes:
the structures made of DNA chains that contain genes
Colonoscopy:
examination of the colon using a long flexible scope (camera)
Cutaneous:
relating to the skin
DNA:
the genetic information that cells need for growth and development
Ductal Hyperplasia:
overgrowth of cells lining the ducts in the breast. This is a common change in fibrocystic disease. Changes can range in severity from a benign growth to a pre-malignant condition that is associated with an increased risk for cancer development
Endometrium:
cells that line the inside of the uterus
Fibroadenomas:
a common benign growth that can occur in many different organs
Fibrocystic Breast Disease:
condition where the breast has lumpy and cystic fibrous tissue that is not due to tumor development.
Fibromas:
benign growth made of fibrous or fully developed connective tissue
Ganglioneuroma
: a benign tumor composed of nerve (ganglion) cells.
Gastrointestinal:
relating to the stomach and intestine
Gene:
the smallest units of heredity
Goiter:
enlargement of the thyroid gland.
Hamartoma:
benign growth of disorganized cells from normal tissue that stops itself from growing once the cells have reached maturity
Hamartomatous Polyp:
a benign growth of disorganized cells from normal tissue that is found on a mucosal membrane (ie: inside lining of colon, mouth, nose, etc.). These polyps have a low chance of being malignant
Hemangioma:
common benign growth developed from blood vessels
Hereditary:
the genetic transmission of a particular trait from parent to child
Hyperextensibility:
extension of a part of the body beyond the usual limit
Hypotonia:
decreased or low muscle tone
Lhermitte-Duclos Disease (LDD): a benign tumor (called a dysplastic gangliocytoma)
in the part of the brain known as the cerebellum (found at the back of the head toward the base of the skull). LDD is believed to be a hamartomatous growth
Lipoma:
benign tumor made of fat tissue
Malignant:
cancerous growth that tends to become progressively worse and often invades other tissues.
Mammograms:
low-dose x-ray that can detect breast cancer up to two years before a woman or a health professional can feel any signs of it
Macrocephaly:
larger head size
Mucocutaneous:
affecting the skin and inside of the mouth
Myopathic:
a muscle problem
Pectus excavatum:
depression of the breastbone and rib cartilage.
Papillomatous:
multiple benign growth arising from specific types of cells (epithelial cells) which line many organs and tissues in the body.
Pathognomonic Criteria:
characteristic or indicative of a disease, i.e. one or more symptoms, findings, or pattern of findings specific for a given condition that are usually not found in any other condition
Pedigree:
pictorial relation of yourself and your family history, see page 7
Palpation:
light touch by a clinician to feel structures under the skin
Papillomatous Lesions:
benign growth that is wart-like (but are not warts)
Prophylactic tissue and organ removal (mastectomy):
surgical removal of tissue or organ used as a method of risk reduction for cancer
PTEN:
tumor suppressor gene located on chromosome 10 that when mutated can cause Cowden syndrome and other conditions.
Scoliosis:
curvature of the spine
Sequencing:
a detailed laboratory test that can detect very small changes in a gene
Syndrome:
set of features that occur together
Trichilemomas:
hamartoma of the lower outer root and sheath of the hair root.
Tumor Suppressor Gene:
a gene whose function is to monitor and control cell growth
Ultrasound:
technique that uses sound waves to visualize internal structures of the body

Robert Pilarski, MS, CGC, MSW, LSW Ohio State University
Joy Larsen Haidle, MS, CGC, Humphrey Cancer Center
Heather Hampel, MS, CGC, Ohio State University

References

  1. Eng C. Will the real Cowden syndrome please stand up: revised diagnostic criteria. J Med Genet 2000: 37(11): 828-30.
  2. Heald, B, Mester, J., Rybicki, L., Orloff, M.S., Burke, C.A, and Eng, C. Frequent Gastrointestinal Polyps and Colorectal Adenocarcinomas in Prospective Series of PTEN Mutation Carriers. Gastroenterology, epub 27 Jun 2010.
  3. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology - Genetic/Familial High-Risk Assessment: Breast and Ovarian. http://www.nccn.org/professionals/physician_gls/PDF/genetics_screening.pdf
  4. Nelen, M. R., G. W. Padberg, et al. (1996). "Localization of the gene for Cowden disease to 10q22-23." Nature Genetics 13: 114-116
  5. Pilarski, R. Cowden syndrome: a Critical Review of the Clinical Literature. J Genet Counsel 2009;18:13-27.
  6. Pilarski, R., Stephens, J., Noss, R., Fisher J.L. and Prior, T (2011). Predicting PTEN mutations: an evaluation of Cowden syndrome and Bannayan-Ruvalcaba-Riley syndrome clinical features.

Credits

2010 Revisions by:
Joy Larsen Haidle, MS, CGC, Genetic Counselor, Humphrey Cancer Center
Heather Hampel, MS, CGC, Genetic Counselor, Clinical Cancer Genetics Program and Division of Human Genetics, The Ohio State University
Robert Pilarski, MS, CGC, MSW, LSW, Genetic Counselor, Clinical Cancer Genetics Program and Division of Human Genetics, The Ohio State University
Original Version Written by:
Sarah Burton, University of Iowa Health Care
Joy Larsen Haidle, MS, CGC
Heather Hampel, MS, CGC
Charis Eng, MD, PhD
Illustrations by Terry Demmer
Special Thanks to:University of Iowa Health Care Division of Medical Genetics

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