PTEN Hamartoma Tumor Syndrome

What is PTEN hamartoma tumor syndrome?

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

  • Cowden syndrome (CS)
  • Bannayan-Riley-Ruvalcaba syndrome (BRRS)
  • Proteus and Proteus-like syndrome (PS)

Although CS, BRRS, and PS were once considered to be separate syndromes, any patient found to carry a PTEN mutation, regardless of their clinical features, should be classified as having PHTS.

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

Signs and symptoms of PTEN hamartoma tumor syndrome

Patients with PHTS may develop cancers as well as benign (noncancerous) growths — known as hamartomas — in different areas of the body. In addition, patients may have other clinical features, including:

  • Macrocephaly (larger-than-average head size)
  • Skin and oral mucosal lesions that usually present before age 20, such as:
    • Trichilemmomas (benign skin lesions)
    • Papillomatous papules (small flesh-colored nodules in the skin or mouth)
    • Lipomas (fatty nodules under the skin)
    • Thickened skin of the hands and feet (acral and plantar keratosis)
  • Learning disabilities, developmental delays, hyperactivity (ADHD) and/or autism spectrum disorders
  • Development of hamartomas, such as thyroid adenomas (non-cancerous nodules) and intestinal polyps
  • Development of specific cancers, most commonly cancers of the breast, thyroid and endometrium (lining of the uterus); and less frequently, colorectal cancer, melanoma, and renal cell carcinoma (a type of kidney cancer)

Risk of cancer associated with PHTS

The lifetime risk for developing specific cancers related to PHTS includes:

  • Breast cancer (females only) — up to 85 percent, with an average age of diagnosis between 35 and 45 years old
  • Thyroid cancer — up to 35 percent
  • Endometrial cancer (females) — up to 28 percent
  • Other risks, such as:
    • About 90 percent of patients with PHTS develop gastrointestinal polyps; the lifetime risk of developing colorectal cancer is approximately 9 percent.
    • Up to a 35 percent risk for developing renal cell carcinoma (papillary renal cell carcinoma.
    • Up to a 6 percent risk for developing cutaneous melanoma.
    • The risk of a person with PHTS developing vascular malformations is higher than the general population, but difficult to determine because these are also common as isolated events in the general population. A specific brain tumor, called a cerebellar dysplastic gangliocytoma (Lhermitte-Duclos disease), is a unique form of brain tumor associated with PHTS in adulthood.

PHTS clinical disorders and their features

The clinical features associated with PHTS include four distinct clinical disorders: Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, Proteus syndrome, and Proteus-like syndrome. Recently, all have been linked to the same genetic cause.

Cowden syndrome (CS)

Almost all individuals with Cowden syndrome (CS) have large heads, skin changes, and an increased risk for benign and cancerous tumors of the thyroid gland, breast cancer and endometrium (uterus).

Bannayan-Riley-Ruvalcaba syndrome (BRRS)

Patients with Bannayan-Riley-Ruvalcaba syndrome (BRRS) generally have large heads, polyps of the intestines, lipomas, and freckling of the head of the penis (glans).  Other common features of BRRS include: high birth weight, developmental delays, learning disabilities and/or autism, and weakness of certain muscles.

Proteus syndrome and PTEN-related Proteus-like syndrome

Proteus syndrome (PS) and Proteus-like syndrome are clinically related to PHTS due to similar association with overgrowth features. Both syndromes are associated with a large head, but patients with Proteus syndrome also have disfiguring, segmental or patchy overgrowth of bones, skin and other tissues.

PTEN mutations have been identified in approximately 20 percent of patients with Proteus syndrome and in 50 percent of patients with Proteus-like syndrome, suggesting that a subset of patients with Proteus and Proteus-like syndromes may have PHTS. However, other genes 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.

Causes of PTEN hamartoma tumor syndrome

PHTS is caused by alterations, also known as “mutations," of the PTEN gene on chromosome 10. In some cases, all or part of the gene is deleted. The condition can be inherited or caused by “new” mutations in one of the father’s sperm, mother’s eggs, or in a cell of the developing fetus.

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. When the PTEN gene is mutated within a cell, the affected cell does not produce this enzyme properly and may grow in an uncontrolled fashion. This uncontrolled cell growth can cause tumors to form.

With the exception of egg and sperm cells, each cell of our bodies normally has two working copies of the PTEN gene. However, in individuals with PHTS, each cell contains only one working PTEN gene copy. Although the second copy may be present, it is altered and does not function properly.

The PTEN gene mutation is inherited in an autosomal dominant fashion, meaning that a person carrying a mutation in one copy of the PTEN gene has a 50 percent chance of passing this same alteration onto each of their future children. Children who inherit the altered gene copy have PHTS and will likely develop the clinical features associated with PHTS over the course of their lives.

Between 10 to 50 percent of patients with PHTS inherit a mutated copy of the PTEN gene from a parent who also has the syndrome. 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. Although these individuals will be the first in their family to carry the mutated gene, each of their future children will have a 50 percent chance of inheriting the same genetic alteration.

Testing and diagnosis of 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.

Major clinical features that are distinctly characteristic of PHTS include (NCCN 2018):

  • Macrocephaly (head circumference greater than the 97th percentile for age)
  • Follicular thyroid cancer
  • Breast cancer
  • Malignant tumor of the endometrium (females)
  • Multiple gastrointestinal hamartomas or ganglioneuromas
  • Freckling on the head of the penis (glans)
  • Mucocutaneous lesions: trichilemmomas (facial), acral keratoses, papillomatous lesions, and/or mucosal lesions
  • Adult Lhermitte-Duclos disease (LDD): a hamartomatous overgrowth in a particular area of the brain known as the cerebellum

Minor findings include:

  • Other types of thyroid cancer (papillary or follicular variant of papillary thyroid cancer)
  • Other types of benign thyroid lesions (such as thyroid adenomas or other benign nodules)
  • Intellectual disability (IQ less than 75), hyperactivity (ADHD) and/or autism spectrum disorder
  • Colon cancer
  • Esophageal glycogenic acanthoses (three or more) Lipomas (three or more)
  • Renal cell carcinoma
  • Testicular lipomatosis
  • Vascular anomalies

A clinical diagnosis of PHTS can be made regardless of whether the affected individual has major or minor findings, as long as certain criteria are met. Generally, a geneticist or genetic counselor who specializes in cancer syndromes can help establish a clinical diagnosis that can be confirmed by genetic testing.

If there is any indication your child may have PHTS, they should be referred to a nationally recognized facility that has the experience, expertise and resources to fully evaluate your child. At Children’s Hospital of Philadelphia (CHOP), a diagnosis of PHTS begins with a complete medical and family history, as well as a comprehensive physical exam.

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 genetic counselor will recommend genetic testing be performed. A definitive diagnosis of PHTS is made only when an alteration in the PTEN gene is identified.

In order to determine on a molecular level if your child has PHTS, a genetic test must be completed. A sample of your child’s blood will be collected, then their DNA will be isolated and analyzed to determine if there are any alternations to the PTEN gene. If an alteration is found, the genetic counselor will investigate further to determine if what was found in your child’s DNA has been previously reported in other individuals with PHTS.

Determining the type of mutation may help clinicians better predict the course of your child’s illness and customize treatment plans and long-term monitoring. 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 in order to determine whether they also carry the alteration and could therefore develop the features of PHTS.

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

Treatment of PTEN hamartoma tumor syndrome

Treatment for PHTS-associated tumors is based on the type and location of the tumor. Because there is a higher likelihood of the tumor being benign (not cancerous), a biopsy should be performed to determine if surgery is necessary, as well as the extent of surgery.

Treatment may include:

  • Surgery to remove tumors or growths
  • Laser ablation to destroy cancerous cells
  • Cryosurgery (extreme cold) to destroy affected tissue
  • Medication
  • Topical ointments for skin issues

There is no cure for PHTS, so the focus for most individuals with PHTS is on cancer surveillance and screening to allow clinicians to discover tumors at their earliest, most treatable stages.

Follow-up care and cancer screening for PHTS

Individuals with PHTS will need long-term follow-up care for the rest of their lives. The most serious consequence of PHTS is an increased risk of benign tumors and malignant cancers, so cancer screening for individuals with a mutation or deletion in the PTEN gene is essential to help clinicians identify tumors early, and treat them more effectively.


The risk of tumor development is low during childhood, but children should have an annual physical exam, including a skin exam. Neurodevelopmental evaluation is also recommended. Annual thyroid ultrasound screening should start at age 7 years and should be coordinated by a pediatric endocrinologist with experience in managing patients with thyroid nodules and thyroid cancer (Schultz et al. 2017). If a thyroid nodule is found, a fine-needle aspiration of the nodule should be performed to determine if surgery is necessary or if surveillance can continue.

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 sunblock and a hat when outdoors in the sunlight. As adolescents, they should be discouraged from smoking and should not be exposed to second-hand smoke. Parents should watch for symptoms of illness and have their children evaluated promptly if they occur.


Specific surveillance measures for breast, thyroid and endometrial cancers have been established and are recommended for adults who carry PTEN mutations (NCCN 2018). These include, but are not limited to:

  • A yearly physical examination starting at 18 years old, with particular attention to the breast and thyroid examination.
  • Annual thyroid ultrasound.
  • Evaluation by a dermatologist may be indicated for some patients.
  • Monthly breast self-examinations starting at age 18 years (females), clinical breast examination every six to 12 months by a doctor beginning at 25, yearly mammograms and breast MRI examinations beginning at age 30-35.
  • Patient education about endometrial cancer and prompt response to symptoms. Some clinicians recommend yearly biopsies of the endometrium beginning at age 35-40 (for premenopausal women) and yearly transvaginal ultrasound examination.
  • Colonoscopy starting at age 35 (unless symptoms arise earlier) and then every five to 10 years or more frequently if patient is symptomatic or if polyps are found.
  • A renal ultrasound every one to two years starting at age 40.

Patients who have a family history of a specific type of cancer at an early age should be screened five to 10 years before the earliest diagnosis in the family. For example, if a father developed colon cancer at age 35, his children with PHTS should begin preventative screening for the disease at age 25-30.

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

Reproductive options

As your child with PHTS grows into adulthood, they may consider starting a family of their own. Up to 50 percent of children born to a parent with PHTS may also carry the genetic abnormality in the PTEN gene However, with early detection and surveillance, children can lead healthy, happy and productive lives. For families that are interested, reproductive options exist for individuals with an alteration in the PTEN gene who do not wish to pass this alteration onto future children.

Prenatal diagnosis

DNA is isolated from the cells of the developing baby through one of two procedures (chorionic villus sampling [CVS] or amniocentesis) and is analyzed for alterations in the PTEN gene. With appropriate counseling, a parent can then decide whether to carry the pregnancy to term or to end the pregnancy.

Pre-implantation genetic diagnosis (PGD)

For couples using in vitro fertilization to become pregnant, embryos can be tested for genetic disorders before transferring them into the uterus. Only healthy embryos carrying two working copies of the PTEN gene would be implanted.

Before one can proceed with prenatal testing or PGD, a PTEN mutation must be identified in a parent with PHTS.

Long-term outlook for PHTS

The long-term outlook for patients with PTEN gene mutations is highly variable and depends on the symptoms, severity, and how quickly complications are diagnosed and treated. Life-long monitoring is recommended for all patients with PHTS.

Adults who have PHTS or who would like more information about PHTS may contact the medical genetics experts at the Hospital of the University of Pennsylvania at 215-662-4740. Appointments can also be requested online or by calling 1-800-789-PENN (7366).

Individuals with PHTS have a 50 percent chance of passing along their genetic mutation to their children, so family planning should be carefully considered.

Reviewed by Kristin Zelley, MS, LCGC, Garrett M. Brodeur, MD, Andrew J. Bauer, MD

Providers Who Treat PTEN Hamartoma Tumor Syndrome