PTEN Hamartoma Tumor Syndrome

National Organization for Rare Disorders, Inc.

Skip to the navigation


It is possible that the main title of the report PTEN Hamartoma Tumor Syndrome is not the name you expected. Please check the synonyms listing to find the alternate name(s) and disorder subdivision(s) covered by this report.


  • PHTS

Disorder Subdivisions

  • None

General Discussion

The PTEN hamartoma tumor syndrome (PHTS) is a spectrum of disorders caused by mutations of the PTEN gene. These disorders are characterized by multiple hamartomas that can affect various areas of the body. Hamartoma is a general term for benign tumor-like malformation composed of mature cells and tissue normally found in the affected area that have grown in a disorganized manner.

Individuals with a variety of clinical diagnoses who ultimately have been found to carry a germline PTEN mutation as the underlying cause are said to have PHTS. When the strictest diagnostic criteria are used, patients with a personal and family history of Cowden syndrome (CS) features have up to an 85% chance to have a PTEN mutation. Patients with features of Bannayan-Riley-Ruvalcaba syndrome (BRRS) and with features reminiscent of but not meeting diagnostic criteria for Proteus syndrome (called Proteus-like syndrome) have also been found to have an underlying PHTS diagnosis. 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

Once thought to be completely separate conditions, patients with features of CS or BRRS and an underlying PTEN mutation are unified as all having PHTS, with CS being a diagnosis traditionally given to adults and BRRS being first described in the pediatrics literature. This makes sense given that many of the characteristics first associated with CS tend to not appear until adulthood. PHTS is inherited as an autosomal dominant trait, which means it can be passed down in a 50-50 fashion. The symptoms vary greatly from patient to patient, even among individuals in the same family. For more information on Bannayan-Riley-Ruvalcaba syndrome and Proteus syndrome, see NORD's individual reports on these disorders in the Rare Disease Database.


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:

·Breast cancer: 85%

·Thyroid cancer: 35%

·Renal cell cancer: 34%

·Endometrial cancer: 28%

·Colorectal cancer: 9%

·Melanoma: 6%

Benign tumors in PHTS

Benign skin or oral lesions are very common and most commonly appear in 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 endoscopy, 93% were found to have polyps. The kinds of polyps found most often were 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 symptoms to make their presence known such as pain or rectal bleeding.

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 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.

A minority 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 of need for PTEN testing.

Neurodevelopmental concerns in PHTS

Macrocephaly (large head size) is found in 94% measured patients with PHTS and can be a helpful screening tool to identify patients at increased risk for PTEN mutation. In most patients large head size is caused by overgrowth of brain tissue as opposed to hydrocephalus. The head shape also tends to be longer than wide (dolicocephaly).

Autism and other developmental disorders, such as mental retardation and developmental delays, have been observed in patients with PHTS. In previous case series, up to 12% of children presenting with macrocephaly and an autism spectrum disorder alone were found to have an underlying PTEN mutation.


PHTS is inherited as an autosomal dominant trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.

Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.

PHTS is caused by germline mutations of PTEN, a tumor suppressor gene. PTEN stands for phosphatase, tensin homologue, deleted on chromosome 10. 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 mediate cell growth arrest and apoptosis. Researchers believe that the PTEN gene plays a broad role in the development of human malignancies.

The PTEN gene is located on the long arm (q) of chromosome 10 (10q23). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated "p" and a long arm designated "q". Chromosomes are further sub-divided into many bands that are numbered. For example, "chromosome 10q23" refers to band 23 on the long arm of chromosome 10. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

Affected Populations

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.

Standard Therapies


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 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

·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 at age 30; MRI may also be incorporated

·Women: annual transvaginal ultrasound or endometrial biopsy beginning at age 30

·Colonoscopy beginning at age 35-40; frequency dependent on degree of polyposis identified

·Biannual renal imaging (CT or MRI preferred) beginning at age 40

For patients with a family history of a particular cancer type at a very early age screening for the patient 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.

Investigational Therapies

Information on current clinical trials is posted on the Internet at 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

For information about clinical trials sponsored by private sources, 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



Jessica Mester, MS, CGC

PTEN Study Coordinator

Cleveland Clinic

9500 Euclid Ave. NE50

Cleveland, OH 44195

Phone: 216.636.5535

Fax: 216.445.6935





Hodgson SV, Foulkes WD, Eng C, Maher ER. A Practical Guide to Human Cancer Genetics. 3rd ed. Cambridge, UK: Cambridge University Press; 2007: 169, & 179-182.

Behrman RE, Kliegman RM, Jenson HB. Eds. Nelson Textbook of Pediatrics. 17th ed. Philadelphia, PA: Elsevier Saunders; 2005:1230.

Pilarski R, Hampel H, Eng C. PTEN Hamartoma Tumor Syndrome. NORD Guide to Rare Disorders. Philadelphia, PA: Lippincott Williams & Wilkins; 2003:240.

Cohen MMJr, Nori G, Weksberg R. Overgrowth Syndromes. 1st ed. New York, NY: Oxford University Press; 2002:66-72.

Gorlin RJ, Cohen MMJr, Hennekam RCM. Eds. Syndromes of the Head and Neck. 4th ed. New York, NY: Oxford University Press; 2001:432-7.


Tan MH, Mester J, Ngeow J, Rybicki LA, Orloff MS, Eng C. Lifetime Cancer Risks in Individuals with Germline PTEN Mutations. Clin Cancer Res. 2012;18:400-7.

Tan MH, Mester J, Peterson C et al. A clinical scoring system for selection of patients for PTEN mutation testing is proposed on the basis of a prospective study of 3042 probands. Am J Hum Genet. 2011;88:42-56.

Ngeow J, Mester J, Rybicki LA, Ni Y, Milas M, Eng C. Incidence and clinical characteristics of thyroid cancer in prospective series of individuals with Cowden and Cowden-like syndrome characterized by germline PTEN, SDH, or KLLN alterations. J Clin Endo Metab. 2011;96:E2063-71.

Greene AK, Orbach DB. Management of arteriovenous malformations. Clin Plast Surg. 2011;38:95-106.

Mester J, Tilot AK, Rybicki LA, Frazier TW, Eng C. Analysis of prevalence and degree of macrocephaly in patients with germline PTEN mutations and of brain weight in Pten knock-in murine model. Eur J Hum Genet. 2011;19:763-8.

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. Gastro. 2010;139:1927-33.

Varga EA, Pastore M, Prior T, Herman GE, McBride KL. The prevalence of PTEN mutations in a clinical pediatric cohort with autism spectrum disorders, developmental delay, and macrocephaly. Genet Med. 2009;11:111-7.

Tan WH, Baris NH, Burrows PE et al. The spectrum of vascular anomalies in patients with PTEN mutations: implications for diagnosis and management. J Med Genet. 2007;44:594-602.

Zbuk KM, Eng C. Cancer phenomics: RET and PTEN as illustrative models. Nature Rev Cancer. 2007;7:35-45.

Robinson S, Cohen AR. Cowden disease and Lhermitte-Duclos disease: an update. Neurosurg Focus. 2006;20:E6.

Sarquis MA, Agrawal S, Shen L, Pilarski R, Zhou XP, Eng C. Distinct expression profiles for PTEN transcript and its splice variants in Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome. Am J Hum Genet. 2005;79:23-30.

Pilarski R, Eng C. Will the Cowden syndrome please stand up (again)? Expanding mutational and clinical spectra of the PTEN hamartoma tumor syndrome. J Med Genet. 2004;41:323-6.

Sansal I, Sellers WR. The biology and clinical relevance of the PTEN tumor suppressor pathway. J Clin Oncol. 2004;22:2954-63.

Merks JHM, de Vries LS, Zhou XP, et al., PTEN hamartoma tumour syndrome: variability of an entity. J Med Genet. 2003;40:e111.

Zhou XP, Hampel H, Thiele H, et al., Association of germline mutation in the PTEN tumor suppressor gene and Proteus and Proteus-like syndromes. Lancet. 2001;358:210-1.

Marsh DJ, Kum JB, Lunetta KL, et al., PTEN mutation spectrum and genotype-phenotype correlations in Bannayan-Riley-Ruvalcaba syndrome suggest a single entity with Cowden syndrome. Hum Mol Genet. 1999;8:1461-72.


Eng C. (Updated July 21, 2011). PTEN Hamartoma Tumor Syndrome (PHTS). In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2012. Available at Accessed March 14, 2012.

Adkisson K, Fiala KH. Cowden Syndrome (Multiple Hamartoma Syndrome. Emedicine. Updated April 26, 2012. Accessed March 14, 2012.


March of Dimes Birth Defects Foundation

1275 Mamaroneck Avenue

White Plains, NY 10605

Tel: (914)997-4488

Fax: (914)997-4763


American Cancer Society, Inc.

250 Williams NW St

Ste 6000

Atlanta, GA 30303


Tel: (404)320-3333

Tel: (800)227-2345

TDD: (866)228-4327


National Cancer Institute

6116 Executive Blvd Suite 300

Bethesda, MD 20892-8322


Tel: (301)435-3848

Tel: (800)422-6237

TDD: (800)332-8615



Rare Cancer Alliance

1649 North Pacana Way

Green Valley, AZ 85614



Genetic and Rare Diseases (GARD) Information Center

PO Box 8126

Gaithersburg, MD 20898-8126

Tel: (301)251-4925

Fax: (301)251-4911

Tel: (888)205-2311

TDD: (888)205-3223


Madisons Foundation

PO Box 241956

Los Angeles, CA 90024

Tel: (310)264-0826

Fax: (310)264-4766



FORCE: Facing Our Risk of Cancer Empowered

16057 Tampa Palms Blvd. W.

PMB #373

Tampa, FL 33647

Tel: (954)827-2200

Fax: (954)827-2200

Tel: (866)288-7475



PTEN World



PTEN Hamartoma Tumor Syndrome Foundation

Tel: 256-520-8529



For a Complete Report

This is an abstract of a report from the National Organization for Rare Disorders, Inc.® (NORD). Cigna members can access the complete report by logging into For non-Cigna members, a copy of the complete report can be obtained for a small fee by visiting the NORD website. The complete report contains additional information including symptoms, causes, affected population, related disorders, standard and investigational treatments (if available), and references from medical literature. For a full-text version of this topic, see