Stage II: Summary Report Secondary Findings in Adults Non-diagnostic, excludes newborn screening & prenatal testing/screening Stage I Survey Update History Stage 2 Status (Adult):Complete (Actionability curation complete.)

Condition: PTEN Hamartoma Tumor Syndrome - Cowden Syndrome
Narrative Description of Evidence
1. What is the nature of the threat to health for an individual carrying a deleterious allele?
Prevalence of the Genetic Disorder
The true prevalence of Cowden syndrome (CS) is unknown.
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Clinical Features
(Signs / symptoms)
CS is part of the PTEN hamartoma tumor syndrome (PHTS) spectrum. CS is a cancer syndrome associated with a high risk of hamartomas and/or cancerous lesions in various organs and tissues, including the skin, mucous membranes, breast, thyroid, endometrium, and brain. Macrocephaly is a common manifestation. Hamartomatous polyps of the colon and other intestines also occur. Renal cell carcinoma and malignant melanoma may be minor component neoplasias of CS.
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Natural History
(Important subgroups & survival / recovery)
More than 90% of individuals with CS have some clinical manifestation of the disorder by the late 20s. By the third decade, 99% of affected individuals develop the mucocutaneous stigmata, as well as acral and plantar keratoses. The average age of breast cancer diagnosis is between 38 and 46 years. The median age of epithelial thyroid cancer onset is 37 years. Elevated risk for endometrial cancer, colorectal cancer, and renal cell carcinoma starts in the late 30s and early 40s.
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2. How effective are interventions for preventing harm?
Information on the effectiveness of the recommendations below was not provided unless otherwise stated.
Patient Management
Information on the effectiveness of the patient management recommendations below was not available.
At diagnosis: individuals should undergo a physical examination, paying particular attention to skin, mucous membranes, thyroid, and breasts; urinalysis; and medical genetics consultation. Individuals diagnosed after ages 35 and 40 should undergo colonoscopy and renal imaging, respectively. Women diagnosed after age 30 should undergo breast screening and transvaginal ultrasound. (Tier 4)
Dermatologic management may be indicated for some patients. (Tier 2)
Risk-reduction mastectomy and hysterectomy should be discussed on a case-by-case basis. (Tier 2)
CS patients should be educated about the signs and symptoms of cancer. (Tier 2)
CS patients should undergo annual comprehensive examinations. (Tier 2)
Women should be breast aware starting at age 18, including periodic, consistent breast self-exam. Clinical breast exam, every 6-12 months, should begin at age 25, or 5-10 years before the earliest known breast cancer in the family. (Tier 2)
Women should undergo annual mammography and breast MRI screening starting at age 30-35 or individualized based on earliest age of onset in the family. (Tier 2)
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Women should consider annual random endometrial biopsies and/or ultrasound beginning at age 30-35. (Tier 2)
Individuals with CS should receive annual thyroid ultrasounds starting at age 18 or 5-10 years before the earliest known thyroid cancer in the family, whichever is earlier. (Tier 2)
Individuals with CS should undergo colonoscopy, starting at age 35, then every 5 years, or more frequently if patient is symptomatic or polyps are found. (Tier 2)
Consider renal ultrasound starting at age 40, then every 1-2 years. (Tier 2)
Family Management
Genetic counseling and consideration of genetic testing is recommended for at-risk relatives. An individual with a known deleterious PTEN mutation in a close family member who does not undergo gene testing should be followed according to the same guidelines as a carrier of a PTEN mutation. (Tier 2)
Circumstances to Avoid
Because of the propensity for rapid tissue regrowth, it is recommended that cutaneous lesions be excised only if malignancy is suspected or symptoms are significant. (Tier 4)
3. What is the chance that this threat will materialize?
Mode of Inheritance
Autosomal Dominant
Prevalence of Genetic Mutations
Information on the prevalence of PTEN mutations was not available.
Relative Risk
(Include any high risk racial or ethnic subgroups)
More than 90% of individuals with CS have some clinical manifestation of the disorder by the late 20s. By the third decade, 99% of affected individuals develop the mucocutaneous stigmata. (Tier 3)
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Among individuals meeting the diagnostic criteria for CS, the cumulative lifetime risk of any cancer is 89%. (Tier 3)
The lifetime risk of breast cancer for females with a PTEN pathogenic variant is 77-85%, with 50% penetrance by age 50. (Tier 3)
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Lifetime risk of epithelial thyroid cancer ranges from 21-38%. (Tier 3)
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Information on relative risk was not available.
The high variability in disease expression is highlighted by the fact that clinical diagnosis in an individual is based on three of eight possible major diagnostic criteria, or two major criteria and three of eleven possible minor criteria. (Tier 2)
4. What is the Nature of the Intervention?
Nature of Intervention
Management of CS includes regular invasive and non-invasive screening tests and the possible recommendation of prophylactic organ removal for affected women.
5. Would the underlying risk or condition escape detection prior to harm in the settting of recommended care?
Chance to Escape Clinical Detection
Given the age of development of cancers in CS patients, general population screening would not allow for prophylactic measures to be taken. The increased cancer surveillance in this population will allow detection of tumors at the earliest, most treatable stages. (Tier 4)

Final Consensus Scores
Outcome / Intervention Pair
Nature of the
Breast cancer / Regular screening
Thyroid cancer / Thyroid ultrasounds
To see the scoring key, please go to:
Description of sources of evidence:
Tier 1: Evidence from a systematic review, or a meta-analysis or clinical practice guideline clearly based on a systematic review.
Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.
Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.
Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.
Tier 5: Evidence from a non-systematically identified source.
Reference List
1. Genetic/familial high-risk assessment breast and ovarian. Other. (2013) Website:
2. Hall JE, Abdollahian DJ, Sinard RJ. Thyroid disease associated with cowden syndrome: a meta-analysis. Head Neck. (2013) 35(8):1189-94.
3. Pten hamartoma tumor syndrome (phts). Gene reviews. (2014) Website:
4. Eng C. Will the real cowden syndrome please stand up: revised diagnostic criteria. J Med Genet. (2000) 37(11):828-30.
5. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. Cowden syndrome 1; cws1. MIM: 158350: 2016 Aug 18. World Wide Web URL:
6. Pten hemartoma tumor syndrome. Orphanet. (2014) Website:
7. Magnetic resonance imaging for breast cancer screening, pre-operative assessment, and follow-up. Ncg. (2012) Website:
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