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PTEN hamartoma tumor syndrome

From SNPedia

Mutations in the PTEN gene can cause many different disorders, including Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba syndrome (BRRS). They can also cause autism spectrum disorders with macrocephaly, congenital malformations, and/or increased risks for cancer; the major classifications include [1];:

  • CS is a multiple hamartoma syndrome with a high risk for benign and malignant tumors of the thyroid, breast, and endometrium. Affected individuals usually have macrocephaly, trichilemmomas, and papillomatous papules, and present by the late 20s. The lifetime risk of developing breast cancer is 85%, with an average age of diagnosis between 38 and 46 years. The lifetime risk for thyroid cancer (usually follicular, rarely papillary, but never medullary thyroid cancer) is approximately 35%. The risk for endometrial cancer may approach 28%.
  • BRRS is a congenital disorder characterized by macrocephaly, intestinal hamartomatous polyposis, lipomas, and pigmented macules of the glans penis.
  • PTEN-related Proteus syndrome (PS) is a complex, highly variable disorder involving congenital malformations and hamartomatous overgrowth of multiple tissues, as well as connective tissue nevi, epidermal nevi, and hyperostoses.
  • Proteus-like syndrome is undefined but refers to individuals with significant clinical features of PS who do not meet the diagnostic criteria for PS.


From Rare Diseases.org:

The PTEN hamartoma tumor syndrome (PHTS) is a spectrum of disorders caused by germline 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 http://www.lerner.ccf.org/gmi/ccscore/. 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.

Signs & Symptoms

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.