NORD gratefully acknowledges Charis Eng, MD, PhD, Chair and Director, Genomic Medicine Institute, and Director, Center for Personalized Genetic Healthcare, Cleveland Clinic; Professor and Vice Chairman, Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Shreya Malhotra, MS, LGC, Cleveland Clinic Genetic Counselor and PTEN Study Coordinator and Jessica Mester MS, CGC Genetic Counselor at GeneDx for assistance in the preparation of this report.
The primary findings in PHTS include increased risk for certain types of cancer, benign tumors and tumor-like malformations (hamartomas), and neurodevelopmental disorders. The symptoms of PHTS vary greatly from person to person and can develop at any age.
Cancer in PHTS
Previous data, which focused only on patients with a clinical diagnosis of Cowden syndrome without understanding whether an underlying PTEN mutation was present, estimated lifetime breast cancer risk to be 25-50% and risk for non-medullary thyroid cancer to be 10%. Risks for endometrial (uterine) and renal cell (kidney) cancer were thought to be increased, but an exact risk level was undetermined.
Current data focusing on patients known to have PHTS provide the following lifetime risk estimates, with the majority of diagnoses occurring after age 30:
Lifetime Risk with PHTS (%)
Average Age at presentation
*Earliest age for thyroid cancer in PHTS is as early as 7 years old
Benign tumors in PHTS
Benign skin or oral lesions are very common and tend to appear in early adulthood. The most common types of benign skin lesions seen in PHTS include:
·Lipomas – benign fatty tumors which can appear just under the skin or elsewhere (breast area, GI tract)
·Acral keratosis – rough patches of skin most often seen on the extremities (arms, hands, legs, feet)
·Papillomatous skin papules – wart-like lesions which can appear anywhere, with feet and hands commonly being affected
·Mucosal papillomas – Benign overgrowth of tissue affecting the tongue, gums, or inside the nose
·Trichilemmomas – Benign tumor of the hair follicle
·Fibromas – another kind of overgrowth involving the skin and other connective tissue; may also affect tissue covering organs, such as the ovaries.
Gastrointestinal polyps are very common in adults with PHTS. Among patients who had undergone colonoscopy as part of their clinical care, >90% were found to have polyps with a mix of histological subtypes. The most common types of polyps found are hyperplastic or hamartomatous, which rarely develop into malignancy; however, adenomas, which may develop into a cancer, were also identified. Many polyps were very small and did not cause noticeable symptoms such as pain or rectal bleeding. Supported by this evidence, colorectal surveillance should be offered to any PTEN mutation carrier.
Benign breast, thyroid, and uterine lesions are also common in persons with PHTS. Some women have severe fibrocystic disease or changes which lead to multiple breast biopsies and complications with imaging. Multinodular goiter and Hashimoto’s thyroiditis may develop in children and adults. Uterine fibroids may appear and cause bleeding or discomfort to the extent that a hysterectomy is indicated without an underlying cancer diagnosis.
Vascular tumors, including hemangiomas, arteriovenous malformations, and developmental venous anomalies, have also been observed in patients with PHTS. Treatment of some lesions has been complicated by tendency for regrowth and scarring.
A small percentage of adults develop a rare tumor known as a cerebellar dysplastic gangliocytoma (Lhermitte-Duclos syndrome). Symptoms of Lhermitte-Duclos syndrome include increased intracranial pressure, impaired ability to coordinate voluntary movements (ataxia), and seizures. It is rare when a person with adult-onset Lhermitte-Duclos does not have an underlying PTEN mutation, and observing this tumor type is an automatic indicator for PTEN testing.
Neurodevelopmental concerns in PHTS
Macrocephaly (large head size) is found in 94% of measured patients with PHTS and can be a helpful screening tool to identify patients for PTEN testing. In most patients, large head size is caused by overgrowth of brain tissue. The head shape also tends to be longer than wide (dolicocephaly).
Autism and other developmental disorders, such as intellectual disability and developmental delays, have been observed in patients with PHTS. In previous case series, up to 17% of children presenting with macrocephaly and an autism spectrum disorder alone were found to have an underlying PTEN mutation.
PHTS is caused by a germline mutation of PTEN, a tumor suppressor gene. PTEN stands for phosphatase tensin homologue. A tumor suppressor is a gene that slows down cell division, repairs damage to the DNA of cells, and tells cells when to die, a normal process called apoptosis. Mutations in a tumor suppressor gene often lead to cancer. The PTEN gene regulates the production of an enzyme (protein tyrosine phosphatase) which is believed to be important in stopping cell growth and starting apoptosis. Researchers believe that the PTEN gene plays a broad role in the development of human malignancies.
PHTS is inherited in an autosomal dominant pattern. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a mutated (changed) gene in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.
Cowden syndrome was estimated to affect 1 in 200,000 individuals; this study was conducted just as PTEN was discovered. However, because the disorder is difficult to recognize, researchers believe it is under-diagnosed, making it difficult to determine its true frequency in the general population. Men and women are affected equally with PHTS. PHTS is not more commonly found in persons of a particular racial or ethnic group.
A diagnosis of PHTS may be suspected based upon a thorough clinical evaluation, a detailed patient history and the presence of characteristic findings. Recently, a mutation risk calculator has been developed which can estimate the risk for adults to have a PTEN mutation based on their personal history characteristics; this tool is available online at http://www.lerner.ccf.org/gmi/ccscore/. The diagnosis can only be confirmed when a mutation of the PTEN gene is identified.
Individuals with PTEN mutations should undergo cancer surveillance and screening at the time of diagnosis as follows to enable healthcare providers to detect any tumors at the earliest, most treatable stages. Current suggested screening by age includes:
Pediatric (below age 18)
·Yearly thyroid ultrasound starting at the time of diagnosis
·Yearly skin check with physical examination
·Consider neurodevelopmental evaluation
·Monthly breast self-examination
·Yearly thyroid ultrasound and dermatologic evaluation
·Women: breast screening (at minimum mammogram) yearly beginning at age 30; MRI may also be incorporated
·Women: annual transvaginal ultrasound and/or endometrial biopsy beginning at age 30
·Colonoscopy beginning at age 35-40; frequency dependent on degree of polyposis identified
·Biannual (every other year) renal imaging (CT or MRI preferred) beginning at age 40
For patients with a family history of a particular cancer type, screening may be considered 5-10 years prior to the youngest diagnosis in the family. For example, a patient whose mother developed breast cancer at 30 may begin breast surveillance at age 25-30.
Additional treatment for PHTS is symptomatic and supportive. Various techniques may be used to treat the mucocutaneous symptoms of Cowden syndrome including topical agents, the use of extreme cold to destroy affected tissue (cryosurgery), the removal of tissue or growths by through a process called curettage, in which a surgical tool shaped like a spoon (curette) is used to scrape away affect tissue, or destroying affected tissue by exposing it to laser beams (laser ablation). Genetic counseling may be of benefit for affected individuals and their families.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Clinical trial information may also be found at www.clinicaltrials.gov.
Some current clinical trials also are posted on the following page on the NORD website:
For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
Contact for additional information about PTEN hamartoma tumor syndrome:
Charis Eng, MD, PhD, FACP
Sondra J. & Stephen R. Hardis Chair in Cancer Genomic Medicine
Chair and Director, Genomic Medicine Institute
Director, Center for Personalized Genetic Healthcare
American Cancer Society Clinical Research Professor
Cleveland Clinic Lerner Research Institute
9500 Euclid Avenue, Mailstop NE-50 (Rm NE5-314)
Cleveland, OH 44195
Tel +1 216 444 3440
Fax +1 216 636 0655
Shreya Malhotra MS, LGC
PTEN Study Coordinator
9500 Euclid Ave. NE50
Cleveland, OH 44195
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