PTEN hamartoma tumor syndrome (Cowden syndrome)
PTEN hamartoma tumor syndrome (Cowden syndrome) is an inherited cancer predisposition caused by a germline mutation in the PTEN tumor suppressor gene, producing macrocephaly, facial trichilemmomas, oral papillomas, lipomas, hamartomatous gastrointestinal polyps, and raised lifetime risks of breast, thyroid, endometrial, colorectal, and kidney cancer and melanoma. Diagnosis is confirmed by germline PTEN testing after genetic counseling, and management is organ-directed surveillance with annual mammography plus breast MRI, annual endometrial biopsy, thyroid evaluation, colonoscopy, and cascade testing of relatives.
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What this article covers
- Overview
Definition: PTEN hamartoma tumor syndrome (PHTS), also called Cowden syndrome, is an inherited cancer predisposition caused by a germline mutation in the PTEN tumor suppressor gene, producing benign…
- Epidemiology
Endometrial cancer risk: lifetime risk of 13% to 19%, compared with 40% to 60% in Lynch syndrome.
- Risk factors
Germline pathogenic PTEN variant: the sole cause; every cell carries the first hit, and a second somatic hit in a target tissue starts tumor formation.
- Pathophysiology
PTEN is a phosphatase brake: it negatively regulates the PI3K/AKT pathway and the mechanistic target of rapamycin (mTOR) pathway, the main drivers of cell growth, proliferation, and survival.
- Clinical features
Macrocephaly: head circumference more than 2 standard deviations above the mean (usually above the 97th percentile), one of the common benign findings.
- Differential diagnosis
Hereditary breast and ovarian cancer (BRCA1/2): 50% to 85% lifetime breast cancer risk plus ovarian cancer, without macrocephaly, trichilemmomas, or hamartomatous polyps (BRCA1 and BRCA2 mutations).
- Diagnosis
Establish the diagnosis by germline PTEN testing: a pathogenic or likely pathogenic PTEN variant confirms PHTS; the clinical pattern that justifies testing is macrocephaly plus characteristic…
- Management
First, confirm the variant and start cascade testing: offer targeted testing for the familial variant to first-degree relatives; gene-positive relatives enter surveillance, gene-negative relatives return to average-risk screening.
- Complications
Breast cancer: the most consequential malignancy and the main reason for intensive imaging.
- Prognosis
Outcome is set by the cancers, not the hamartomas: trichilemmomas, papillomas, lipomas, and polyps are benign, so survival depends on detecting breast, thyroid, endometrial, and colorectal cancer early.
- Prevention
Cascade testing: offer first-degree relatives testing for the familial PTEN variant; a gene-negative relative stops syndrome-specific screening.
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