Hereditary Cancer Predisposition Program at the Cancer Center

PTEN Hamartoma Tumor Syndrome

What is PTEN Hamartoma Tumor syndrome?

PTEN Hamartoma Tumor syndrome (PHTS) is a group of disorders caused by alterations in the PTEN gene. This group includes:

Patients with PHTS disorders usually develop multiple benign (noncancerous) growths known as hamartomas in different areas of the body. In addition to hamartomas, patients can have other clinical features, including:

Because PHTS disorders are hereditary, the risk of developing the features associated with each disorder can be passed from generation to generation in a family.

Clinical features associated with Cowden syndrome (CS)

Over 90 percent of people with Cowden syndrome (CS) have macrocephaly and skin changes, such as trichilemmomas, papillomatous papules, and acral or plantar keratoses (thickened skin or callouses on the palms of the hands and soles of the feet), by the time they are in their late 20s. Individuals with CS also have a high risk of developing benign and malignant tumors of the thyroid, breast and endometrium. Polyps may occur in the intestinal tract but these are not thought to increase the risk for development of colorectal cancer.

Clinical features associated with Bannayan-Riley-Ruvalcaba syndrome (BRRS)

Patients with Bannayan-Riley-Ruvalcaba syndrome (BRRS) generally have macrocephaly, polyps of the intestines, lipomas and in boys, freckling of the penis. Some other common features of BRRS include a large birth weight, developmental delay, cognitive abnormalities and weakness of certain muscles. Individuals with BRRS are thought to have the same cancer risks as those with CS.

Proteus syndrome and Proteus-like syndrome

Proteus syndrome (PS) and Proteus-like syndrome are more complex conditions that are less common than CS or BRRS. To learn more about Proteus syndrome and Proteus-like syndrome, please visit  www.proteus-syndrome.org.

What causes PTEN Hamatoma Tumor syndrome (PHTS)?

PHTS is caused by alterations, also known as “mutations," at specific areas in an individual’s genetic information. Each of us has a large amount of genetic information that is organized into smaller segments known as “genes.” Genes provide the instructions the cells of the body need to perform their different functions.

There is a specific gene known as PTEN, located on chromosome 10 at position q23.3, that is altered in patients with PHTS. The role of the PTEN gene is to produce an enzyme that acts as part of a chemical pathway to signal cells to stop dividing and to die under appropriate conditions. When both copies of the PTEN gene are altered within a cell, the affected cell does not produce this enzyme properly. Therefore, the affected cell may divide in an uncontrolled fashion and escape cell death. If this occurs, abnormal cells accumulate, leading to the formation of benign and/or malignant tumors.

How is PTEN Hamartoma Tumor syndrome (PHTS) inherited?

With the exception of egg and sperm cells, each cell of the body normally has two working copies of the PTEN gene. In patients with PHTS, however, each cell contains only one working PTEN gene copy. While the second copy is present, it is altered so that it does not function properly. A person carrying an alteration in one copy of the PTEN gene has a 50 percent (or 1 in 2) chance of passing this same alteration on to each of his or her future children. Children who inherit the altered gene copy have PHTS and will inevitably develop the clinical features associated with PHTS over the course of their lives.

Between 10 percent and 50 percent of patients with PHTS inherit an altered copy of the PTEN gene from a parent who also has PHTS. In the remaining patients, PHTS results from the occurrence of a “new” mutation in the PTEN gene in one of the father’s sperm, mother’s eggs or in a cell of the developing fetus. Therefore, these individuals will be the first ones in their family to carry this genetic change. Since they carry an altered gene copy, each of their future offspring will have a 50 percent chance of inheriting the same genetic alteration.

How do you diagnose PTEN Hamartoma syndrome (PHTS)?

The diagnosis of PHTS disorders may be suspected based on the presence of a certain number and type of clinical features in an affected individual. The clinical criteria of CS include the following:

Pathognomonic criteria (clinical findings that are distinctly characteristic of CS)

Major criteria

Minor criteria

A clinical diagnosis of Cowden syndrome can be made regardless of whether an affected individual has major or minor findings, as long as certain published criteria are met. Generally a geneticist or genetic counselor who specializes in cancer syndromes can help in establishing the diagnosis of CS.

Criteria for BRRS have not been established but the diagnosis is suspected based on the presence of physical findings including macrocephaly, hamartomatous intestinal polyps, lipomas, and pigmented areas of the penis. Because of the variable and often subtle clinical signs of CS and BRRS, it is believed that many individuals with these conditions are never diagnosed.

A detailed review of an individual’s medical and family history can also be important when diagnosing PHTS. A doctor or genetic counselor may construct a pedigree, or a multi-generation family tree, that indicates which members of the family have developed certain clinical findings or cancer, taking note of the types of cancer and the ages of onset. If the pattern of clinical features and/or cancers is suggestive of PHTS, the physician or counselor may recommend that genetic testing be performed.

How does one test for PTEN Hamartoma Tumor syndrome (PHTS)?

A definitive diagnosis of PHTS is made only when an alteration in the PTEN gene is identified through the process of genetic testing.

It is important to remember that not all patients with PHTS carry a detectable alteration in PTEN. Therefore, the failure to identify an alteration in the PTEN gene does not exclude a diagnosis of PHTS.

PTEN genetic test results can also provide important information for other family members. Knowing the specific alteration that is present in an individual with PHTS allows for other family members to undergo testing to determine whether they also carry the alteration and could therefore develop the features of PHTS. 

Reproductive options

Reproductive options exist for an individual with an alteration in the PTEN gene who does not wish to pass this alteration on to future children:

What are the cancer risks in individuals with PTEN Hamartoma Tumor syndrome (PHTS)?

Regardless of whether an individual with a PTEN gene mutation carries a diagnosis of CS or BRRS, they are currently thought to have similar cancer risks. By and large, the majority of cancers occurring in PHTS develop in adults, not children.

Adults with PTEN gene abnormalities have a high risk to develop:

For example, in women with CS, the lifetime risk of developing breast cancer is approximately 25 percent to 50 percent with the average age of breast cancer diagnosis being between 38 and 46 years. Breast cancer can involve one or both breasts. Breast cancer has also been reported in men with PTEN alterations. The lifetime risk for thyroid cancer is approximately 10 percent and the risk for endometrial cancer may approach 5 percent to 10 percent. Patients are also known to develop skin cancers, renal cell carcinoma, brain tumors and vascular abnormalities such as hemangiomas. Although polyps may occur in the gastrointestinal tract, it is felt that the risk for colorectal cancer is not significantly increased by their presence.

The most serious consequences of PHTS are due to the increased risk of cancer. Thus, it is important that adults with PTEN mutations follow recommended surveillance guidelines and be on the look out for signs or symptoms of illness that cannot otherwise be easily explained. If such features occur, individuals should be evaluated promptly by their doctors to examine for the presence of a possible underlying cancer.

Recommended cancer screening protocol for children

Because the risk for tumor development is low during childhood, there are no specific recommendations for cancer surveillance in children harboring PTEN gene abnormalities, however children should continue to have regular check-ups by their physicians.

Children should be encouraged to lead as healthy a lifestyle as possible. They should eat a balanced diet, avoid excess sun exposure and always wear sun block and a hat when outdoors in the sunlight. As adolescents, they should be discouraged from smoking cigarettes or cigars and should not be exposed to second hand smoke. Parents should watch for symptoms of illness and have their children evaluated promptly if these occur.

Recommended cancer screening protocol for adults

Specific surveillance measures for breast, thyroid and endometrial cancers have been established and are recommended for adults who carry PTEN mutations. These include, but are not limited to:

For families with known PTEN mutations, screening for specific cancers is started either at the recommended ages, or at least 5 years before the earliest known diagnosis of that specific cancer in affected family members (for example, if an affected family member developed breast cancer at 35 years of age, it is recommended that additional affected family members begin breast cancer surveillance at age 30 years).

Support resources for PTEN Hamartoma Tumor syndrome (PHTS)

Clinical services

Adults who have PTEN hamartoma tumor syndrome or who would like more information about PTEN hamartoma tumor syndrome may contact the Medical Genetics Team at the Hospital of the University of Pennsylvania at 215-662-4740. Appointments can also be requested online at http://www.uphs.upenn.edu/penngenn or by calling 1-800-789-PENN(7366).

Resources

Cowdens Syndrome & Bannayan-Riley-Ruvalcaba Syndrome Foundation
1394 Wedgewood Drive
Saline, MI 48176
Phone: 734-944-8313
E-mail: rosilita@comcast.net
http://groups.msn.com/cowdenssyndrome

American Cancer Society
1599 Clifton Road NE
Atlanta, GA 30329
Phone: 1-800-227-2345
www.cancer.org

CancerCare
275 Seventh Avenue
New York, NY
10001
Phone: 1-800-813-HOPE (1-800-813-4673) or 212-712-8400
Fax: 212-712-8495
E-mail: info@cancercare.org
www.cancercare.org

Proteus Syndrome Foundation
www.proteus-syndrome.org

National Library of Medicine Genetics Home Reference - Cowden syndrome
GeneReviews - PTEN Hamartoma Syndrome
 

Reviewed by: Kim Nichols, MD, The Children's Hospital of Philadelphia
Date: January 2011

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