Juvenile polyposis (JP) is an autosomal dominant syndrome characterized by multiple hamartomatous polyps of the gastrointestinal (GI) tract. Patients may have juvenile polyps of the stomach, small intestine, and/or colon. The diagnosis of JP is made by having more than five juvenile polyps in the colon, juvenile polyps throughout the GI tract, or one or more juvenile polyps in the setting of a family history of JP. Patients with other genetically distinct syndromes may also have hamartomatous polyps, and these conditions need to be excluded by careful history and physical examination. Due to the association of juvenile polyps with several heterogeneous syndromes, it is likely that there are multiple genes that predispose to JP.
Approximately 20 to 50 percent of JP cases are familial, with the remainder arising de novo. As many as 20 percent of patients may have associated anomalies, which are more common in sporadic cases. Patients with JP are at approximately 50 percent risk for the developing GI cancers, the majority of which are colorectal cancers, but they are also at risk for upper GI cancers.
The pathologic features of juvenile polyps are dilated, cystic glands, infiltration of the lamina propria by inflammatory cells, and an overabundance of stroma. Larger polyps may also contain adenomatous areas; adenocarcinoma has also been described within juvenile polyps. Although the exact mechanism of carcinogenesis is unclear, it has been suggested that the changes seen in the lamina propria are brought about through landscaper defects, where changes in this tissue layer lead to an environment predisposing to neoplastic transformation of the overlying epithelium.
Loss of heterozygosity studies have revealed a tumor-suppressor locus for JP on chromosome 10q22, with the minimal region of overlap defining a 3-cM region approximately 7 cM centromeric to the PTEN gene. Germ line PTEN mutations have been described in four unrelated patients with JP, but it is possible that some of these patients had Cowden syndrome.
A gene for JP has been mapped to chromosome 18q21.1 by genetic linkage analysis, within an interval containing the two tumor-suppressor genes DCC and DPC4 (Smad4). Germ line mutations in one of these genes, Smad4, have been found in 6 of 10 familial and sporadic JP patients. In familial cases, these mutations segregated with the JP phenotype, and all were predicted to cause truncation of the Smad4 protein, resulting in loss of its C-terminus required for oligomerization.
The Smad4 gene consists of 11 exons and encodes for 552 amino acids. Smad4 is a common mediator for the transforming growth factor-β, activin, and bone morphogenetic protein signaling pathways. The Smad4 protein associates with other Smad proteins following their phosphorylation by activated receptors, then translocates to the nucleus where it regulates transcription through direct binding to specific DNA sequences. Smad4 is required for differentiation of the mesoderm and visceral endoderm during embryogenesis; transgenic mice with Smad4 and Apc mutations have polyps with stromal proliferation reminiscent of juvenile polyps.