Hamartomatous polyposis syndromes: Molecular genetics, neoplastic risk, and surveillance recommendations

Hamartomatous polyposis syndromes are characterized by an overgrowth of cel ls or tissues native to the area in which they normally occur. Juvenile pol yposis syndrome (JPS) results from germ-line mutations in the SMAD-4 gene ( 18q21.1) that encodes for an enzyme involved in transforming growth factor beta(TGF-P) signal transduction. The increased neoplastic risk may result f rom SMAD-4 mutations in the stromal component, which stimulate epithelial d ysplasia and progression to invasive malignancy. Peutz-Jeghers syndrome (PJ S) is associated with germ-line mutations in the LKB1 gene (19p13.3) that e ncodes a multifunctional serine-threonine kinase. These mutations occur in the epithelial component, suggesting a direct tumor suppressor effect. Pati ents are at an increased risk of intestinal and extraintestinal malignancie s, including breast, pancreatic, ovarian, testicular, and cervical cancer. Cowden's disease is associated with germ-line mutations in the PTEN gene (1 0q22-23) and an increased risk of breast and thyroid malignancies. Ruvalcab a-Myhre-Smith syndrome is less common; controversy suggests that it may rep resent a variant of Cowden's disease. Conclusions: Genetic alterations unde rlying hamartomatous polyposis syndromes are diverse. Carcinogenesis may re sult from either germ-line mutations in the stroma (JPS) or as a direct res ult of functional deletion of tumor suppressor genes (PJS). Diagnosis depen ds on clinical presentation and patterns of inheritance within families. Su ggested surveillance guidelines for the proband and first-degree relatives are outlined.