PTEN Hamartoma Tumor syndrome (PHTS) is a diagnosis given to someone who has a change (mutation) in the PTEN gene. Many patients diagnosed with either Cowden syndrome or BRRS by their clinical manifestations will be found to have a PTEN mutation. While Cowden syndrome and BRRS were first thought to be completely separate conditions, we now understand that all patients with PTEN mutations (and thus PHTS diagnoses) face similar health risks. Patients with PHTS can develop characteristics associated with both Cowden syndrome and BRRS over their lifetime.
Patients with Cowden syndrome tends to present in adulthood and may result in both benign and cancerous growths, which commonly affect the breasts, uterus, thyroid, gastrointestinal tract, skin, and tongue and gums. A common finding in Cowden syndrome is a large head size (macrocephaly). Cowden syndrome occurs in an estimated 1 out of every 250,000 people. The diagnosis of Cowden syndrome is made when a patient has enough characteristics to meet specific criteria (see below).
BRRS tends to present in childhood. This syndrome is suspected in individuals with fatty tumors (lipomas) on the skin, developmental delays, a large head size (macrocephaly), hamartomatous polyps in the gastrointestinal tract, vascular malformations such as hemangiomas, and, for boys, freckling on the penis.
Much is known about the risks associated with PHTS and Cowden syndrome, but little is known about the cancer risks or appropriate cancer screening for patients with BRRS who do not have a PTEN gene change. Therefore, we have only included information about PHTS and Cowden syndrome below.
Individuals with PHTS/Cowden syndrome require lifelong cancer screening and medical care by a health care team knowledgeable about PHTS/Cowden syndrome. This team may include endocrinologists, gastroenterologists, surgeons, gynecologists, breast health specialists, primary care physicians, geneticists, genetic counselors, hematologists, and oncologists.
What are the Manifestations of PHTS/Cowden Syndrome?
PHTS/Cowden syndrome is a condition that causes multiple benign and cancerous growths in certain organs. The benign growths commonly affect the breasts, uterus, thyroid gastrointestinal tract, skin, tongue, gums, and neurologic system.
Women with PHTS/Cowden syndrome can develop benign growths of many different types in their breasts. Common findings include fibrocystic changes, fibroadenomas, papillomas, and atypical ductal hyperplasia. Women with PHTS/Cowden syndrome can also develop benign fibroid tumors of the uterus. Men and women with PHTS/Cowden syndrome can also develop benign thyroid growths such as a multinodular goiter and/or Hashimito’s thyroiditis, an autoimmune thyroid condition.
An estimated 90% of patients with PHTS/Cowden syndrome will develop gastrointestinal polyps. The number of polyps patients may develop ranges from one to innumerable. Polyps can occur in both the colorectum and the upper gastrointestinal tract. Every microscopic type of polyp has been reported to occur in patients with PHTS/Cowden syndrome, but the most common types are hamartomatous and hyperplastic polyps, which both have low potential to become cancer.
The characteristic skin findings of patients with PHTS/Cowden syndrome are papillomatous papules (benign, skin-colored, raised bumps), trichilemmomas (benign tumors derived from the lower part of the outer sheath of the hair root, most frequently found on the head), and lipomas (benign fatty growths). Many patients develop papillomas on their gums and/or tongue, giving them a ‘cobblestone’ appearance. Men with PHTS/Cowden syndrome can develop freckles on their penis. In addition, many individuals with PHTS/Cowden syndrome have acral and plantar keratoses (dark flat spots on their hands and feet) and some also have hemangiomas or vascular malformations. The skin findings are often present by the time a patient is in their late 20s.
Persons with PHTS/Cowden syndrome also tend to have a large head size (macrocephaly) and a head shape that is longer than wide (dolichocephaly). Patients are also at increased risk to develop Lhermitte-Duclos disease, a benign tumor of the cerebellum (the part of the brain that controls coordination of movement). Autism and developmental delay have also been observed at increased frequency in persons with PHTS/Cowden syndrome.
What Are The Cancer Risks Associated With PHTS/Cowden Syndrome?
Risk for certain cancers is increased for patients with PHTS/Cowden syndrome.
||General population risk
||Lifetime Risk with PHTS
||Lifetime Risk with Cowden syndrome, negative PTEN testing
||~85% (average age of diagnosis in 40s)
||35% (average age of diagnosis in 30s/40s)
||28% (average age of diagnosis in 40s/50s)
||Thought to be increased, but exact risk unknown
|Renal cell (kidney)
||34% (average age of diagnosis in 50s)
||Possibly increased, exact risk unknown
||9% (average age of diagnosis in 40s)
||Possibly increased, exact risk unknown
||6% (average age of diagnosis in 40s)
||Possibly increased, exact risk unknown
How is PHTS/Cowden Syndrome Diagnosed?
PHTS is diagnosed when a change (mutation) is found in the PTEN gene. The International Cowden Consortium has developed criteria to establish a diagnosis of Cowden syndrome. Additionally, both the National Comprehensive Cancer Network and the Cleveland Clinic (www.lerner.ccf.org/gmi/ccscore/) have established genetic testing criteria for PHTS/Cowden syndrome. These criteria are updated frequently based on new research. A PHTS/Cowden syndrome evaluation by a genetics professional should be considered for individuals with adult-onset Lhermitte-Duclos disease, macrocephaly plus autism/developmental delay, numerous and mixed types of gastrointestinal polyps, or a combination of PHTS/Cowden syndrome features, such as thyroid and uterine cancers or breast and kidney cancers.
If a patient is found to meet clinical or testing criteria, testing of the PTEN gene may be offered. Genetic testing is done through a blood sample. Once a mutation is identified in a patient, his or her family members can be tested for that mutation in order to determine who else in the family has PHTS.
How is PHTS/Cowden Syndrome Inherited?
PHTS/Cowden syndrome is inherited in an autosomal dominant manner. Everyone has two copies of the PTEN gene. Individuals with PHTS have a mutation in one copy of their PTEN gene pair. The copy of the gene with the mutation can be passed on to future generations. The chance that a child of someone with PHTS would inherit the copy of the gene with the mutation is 50%. The chance that he or she would not inherit the mutation is also 50%.
Individuals diagnosed with PHTS/Cowden syndrome should inform their family members about their diagnosis and encourage their family members to undergo genetic counseling. For patients with Cowden syndrome who do not have a PTEN gene mutation, family members may need evaluation by a medical geneticist to determine if they also meet the clinical criteria for a diagnosis of Cowden syndrome. This evaluation includes an evaluation of their personal history, exploration of the family history, and genetic testing if a PTEN gene mutation has previously been identified in the family. Recommendations to keep the patient and his or her family healthy and to prevent cancer will also be provided.
How is PHTS/Cowden Syndrome Treated?
Currently, there is no cure for PHTS/Cowden syndrome. Patients undergo lifelong surveillance to monitor for benign and cancerous growths to help detect any problems at the earliest, most treatable point in time.
We recommend that individuals with PHTS/Cowden syndrome have specialized breast cancer screening. This should include breast self-examination every month beginning at age 18, breast examination by a doctor or nurse every 3-6 months beginning at age 20, and mammography/breast MRI once a year beginning at age 25 or 5-10 years earlier than the youngest breast cancer diagnosis in the family. There are men with PHTS/Cowden syndrome who have developed breast cancer. Although the risk is much lower than that for women, we would recommend that the men perform monthly breast self-examination.
Some women at increased risk for breast cancer consider prophylactic mastectomy (removal of the breasts to prevent cancer). This is a consideration especially for women whose breast tissue is so dense that their physicians do not feel comfortable with traditional breast cancer screening techniques, or for those who have had repeated breast biopsies. One study has shown that prophylactic mastectomy reduces the risk for breast cancer by 90% in high-risk women.
Individuals with PHTS/Cowden syndrome should also receive thyroid cancer screening. For persons with PTEN mutations we recommend a baseline thyroid ultrasound at the age of diagnosis with at least yearly follow-up thereafter by an endocrine specialist. For those who are PTEN negative we recommend baseline ultrasound at age 18; if thyroid ultrasound is normal follow-up can be done by physical examination of the thyroid with their primary care provider. Thyroid nodules are often seen on thyroid ultrasound because they are common in PHTS/Cowden syndrome, but an expert will be able to determine whether or not they require biopsy or other further investigation.
In persons who are PTEN positive we also recommend imaging of the kidneys every two years starting at age 40.
A baseline colonoscopy should be done at age 35 or 40 years (or 10 years younger than the earliest colorectal cancer diagnosis in the family), with follow-up dependent on the number and type of polyps found. Both upper gastrointestinal and colorectal polyps are very common in persons with PTEN mutations. Baseline upper endoscopy often is recommended to help establish or confirm the diagnosis and surveillance of the stomach and small bowel is based upon the findings of the baseline exam.
Yearly dermatologic examination is also recommended.
Women who are PTEN positive should also see a gynecologic oncologist to discuss what kind of screening for endometrial cancer should be performed. Transvaginal ultrasounds as well as endometrial biopsies are both options.
For those who are PTEN negative but have a clinical diagnosis of Cowden syndrome, it is not recommend that screening of other organs beyond that mentioned for breast and thyroid cancers, be routinely performed. However, it should be based on a person’s family and personal history . We also recommend that the patient’s healthcare providers be aware of their diagnosis and the possible increase in risk for these cancer types so that appropriate assessment may be performed if the patient has concerning symptoms.
There are no studies that prove that cancer screening is effective for individuals with PHTS/Cowden syndrome. The recommendations are based on the opinion of experts in the field of cancer genetics and PHTS/Cowden syndrome. As with most cancer screening, these recommendations will hopefully help to detect cancers at an earlier stage when they are more treatable, but they cannot prevent the cancer from occurring.
Where Can I Find More Information?