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Key Points

  • Disease summary:

    • The PTEN syndromes or PTEN hamartoma tumor syndromes (PHTS) include all disorders that have germline PTEN mutations.

    • PHTS includes Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS), Proteus syndrome (PS), and Proteus-like syndrome.

    • Typically, PHTS is characterized by hamartomas that can affect derivatives of all three germ layers and a high risk of breast and thyroid cancers.

      • CS is a multiple hamartoma syndrome with a high risk of benign and malignant tumors of the thyroid, breast, and endometrium.

      • BRRS is a congenital disorder characterized by macrocephaly, intestinal polyposis, lipomas, and pigmented macules of the glans penis.

      • PS is a complex, highly variable disorder involving congenital malformations and overgrowth of multiple tissues.

      • Proteus-like syndrome is undefined but refers to individuals with significant clinical features of PS who do not meet the diagnostic criteria for PS.

  • Hereditary basis:

    • PHTS is an autosomal dominant condition with incomplete penetrance and variable expressivity.

    • PHTS can be seen in isolated individuals or in segregating families.

    • Germline PTEN mutations are found in approximately 85% of CS, approximately 65% of BRRS, 20% PS, 50% of PS-like, and 5% in individuals with CS-like features.

    • Germline SDHB and SDHD variants are found in approximately 10% of CS or CS-like individuals without germline PTEN mutations.

    • Germline epimutation (promoter hypermethylation) of KLLN are found in approximately 35% of CS or CS-like individuals without germline PTEN mutations.

  • Differential diagnosis:

    • The primary differential diagnoses to consider are other hamartoma syndromes, including juvenile polyposis syndrome (JPS) and Peutz-Jeghers syndrome (PJS), both inherited in an autosomal dominant manner.

    • JPS is characterized by predisposition for hamartomatous polyps in the gastrointestinal tract, specifically in the stomach, small intestine, colon, and rectum. The term “juvenile” refers to the type of polyp, not the age of onset of polyps. Juvenile polyps are hamartomas that show a normal epithelium with a dense stroma, an inflammatory infiltrate, and a smooth surface with dilated, mucus-filled cystic glands in the lamina propria. Approximately 70% of JPS is caused by germline mutations and large deletions in SMAD4 and BMPR1A. Germline deletions involving BMPR1A and PTEN (both on 10q) are particularly associated with juvenile polyposis of infancy.

    • PJS is characterized by the association of gastrointestinal polyposis and mucocutaneous pigmentation. PJS-type hamartomatous polyps are most prevalent in the small intestine, but also occur in the stomach and large bowel in the majority of affected individuals. The Peutz-Jeghers polyp has a diagnostic appearance and is quite different from the hamartomatous polyps seen in CS or JPS. Clinically, Peutz-Jeghers polyps are often symptomatic (intussusception, rectal bleeding), whereas CS polyps are rarely so.

      • Perioral region pigmented macules are pathognomonic, particularly if it crosses the vermilion border. Hyperpigmented macules on the fingers are also common.

      • Approximately 70% of PJS are accounted for by germline mutations in STK11.

    • Less likely genetic differential diagnoses include

      • Birt-Hogg-Dubé syndrome (BHD) is characterized by typical cutaneous findings including fibrofolliculomas, trichodiscomas, and acrochordons; pulmonary cysts or history of pneumothorax; ...

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