Hereditary Cancer Predisposition Program at the Cancer Center

PTEN Hamartoma Tumor Syndrome

What is PTEN hamartoma tumor syndrome?

PTEN hamartoma tumor syndrome (PHTS) includes a group of disorders caused by alterations in the PTEN gene. In the past, these disorders were called by one of several names, such as:

Although CS, BRRS, and PS were once considered to be separate syndromes, it is now suggested that any patient found to carry a PTEN mutation, regardless of his or her clinical features, should be classified as having PTEN hamartoma tumor syndrome.

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

Because PTEN hamartoma tumor syndrome 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 what was previously known as 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 are also at increased risk to develop benign and malignant tumors, mainly of the thyroid, breast and endometrium. Less commonly, kidney cancer and melanoma have also been reported. Polyps of the intestinal tract are reported to be common in individuals with PTEN hamartoma tumor syndrome who have undergone upper or lower endoscopy, and the risk for colorectal cancer is also reported to be increased (Heald et al., 2010).

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. PTEN mutations have been identified in approximately 20 percent of patients with Proteus syndrome and 50 percent of patients with Proteus-like syndrome (Eng. 2003), suggesting that a subset of patients with Proteus and Proteus-like syndromes may be considered to have PHTS. Other genes most likely contribute to the development of Proteus or Proteus-like syndrome in patients who test negative for PTEN mutations.Recently, alterations in another gene, known as AKT1, have been identified in 90 percent of individuals with Proteus syndrome (Lindhurst et al., 2011). To learn more about Proteus syndrome and Proteus-like syndrome, please visit

What causes PTEN hamartoma tumor syndrome (PHTS)?

PTEN hamartoma tumor syndrome 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, which is altered in patients with PTEN hamartoma tumor syndrome. 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 individuals with PTEN hamartoma tumor syndrome, 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 PTEN hamartoma tumor syndrome 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 PTEN hamartoma tumor syndrome inherit an altered copy of the PTEN gene from a parent who also has PTEN hamartoma tumor syndrome. In the remaining patients, PTEN hamartoma tumor syndrome 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 PTEN hamartoma tumor syndrome 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 PHTS)

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 PTEN hamartoma tumor syndrome 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 PTEN hamartoma tumor syndrome 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 PTEN hamartoma tumor syndrome 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 benign tumors or malignant cancers occurring in PTEN hamartoma tumor syndrome develop in adults, not children.

Adults with PTEN gene abnormalities are at increased risk to develop:

In women with CS, the lifetime risk of developing breast cancer is approximately 25 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 a few men with PTEN alterations. The lifetime risk for thyroid cancer is approximately 10 percent and the risk for endometrial cancer may approach 5 to 10 percent. Skin cancers, renal cell carcinoma, and vascular abnormalities such as hemangiomas and arterio-vascular malformations (AVM) have also been reported in individuals with PTEN hamartoma tumor syndrome, but to a lesser extent. One study showed that polyps of the gastrointestinal tract were a common finding in individuals with PHTS who had undergone at least one upper or lower endoscopy, and an increased risk for colorectal cancer in individuals with PTEN hamartoma tumor syndrome was also reported (Heald et al., 2010).

The most serious consequences of PTEN hamartoma tumor syndrome 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.

As children with PTEN hamartoma tumor syndrome can develop thyroid adenomas, and in rare cases thyroid cancer, thyroid ultrasound could be considered at 10-12 years of age, and should be coordinated by a pediatric endocrinologist with experience in managing patients with PHTS. At the latest, a baseline ultrasound should be performed at age 18 years, with consideration of annual thyroid ultrasound thereafter.

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:

Screening recommendations may be updated over time as new information or screening methods become available. Individuals with PTEN hamartoma tumor syndrome should follow up regularly with a doctor who is knowledgeable about PHTS for the most up to date screening recommendations.

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).


Eng C. PTEN: one gene, many syndromes. Hum Mutat. 2003 Sep;22(3):183-98. Review. Cited in PubMed; PMID 12938083. Read the abstract

Heald B, Mester J, Rybicki L, Orloff MS, Burke CA, Eng C. Frequent gastrointestinal polyps and colorectal adenocarcinomas in a prospective series of PTEN mutation carriers. Gastroenterology. 2010 Dec;139(6):1927-33. Epub 2010 Jun 27. Cited in PubMed; PMID 20600018. Read the abstract

Lindhurst MJ, Sapp JC, Teer JK, Johnston JJ, Finn EM, Peters K, et al. A mosaic activating mutation in AKT1 associated with the Proteus syndrome. N Engl J Med. 2011 Aug 18;365(7):611-9. Epub 2011 Jul 27. Cited in PubMed; PMID 21793738. Read the article

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 or by calling 1-800-789-PENN(7366).


Cowdens Syndrome & Bannayan-Riley-Ruvalcaba Syndrome Foundation
1394 Wedgewood Drive
Saline, MI 48176
Phone: 734-944-8313

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

275 Seventh Avenue
New York, NY
Phone: 1-800-813-HOPE (1-800-813-4673) or 212-712-8400
Fax: 212-712-8495

Proteus Syndrome Foundation

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

Reviewed by: Kim Nichols, MD, Kristin Zelley, MS
Date: September 2012

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