SMAD4-related Familial Juvenile Polyposis Syndrome with Colon Cancer

Juvenile polyposis syndrome (JPS) is a rare autosomal dominant disorder characterized by the development of multiple hamartomatous polyps in the gastrointestinal tract with an increased risk of malignancy. SMAD4 germline mutations account for about a third of JPS.

We describe, in the same family, the morphological and genetic aspects of two cases of JPS with colon cancer in one patient.

Both cases were characterised by diffuse colorectal and gastric involvement by typical juvenile polyps as well as "atypical" multilobulated and densely epithelial polyps with some dysplastic areas. A germline mutation of SMAD4 was demonstrated in both cases. SMAD4 protein and DNA analyses were performed on the colonic adenocarcinoma showing a lack of expression of SMAD4 protein and loss of heterozygosity at the SMAD4 locus.

These two exceptional familial cases underline the fact that the morphological features of JPS associated with SMAD4 mutations are different from those found in non SMAD4 mutated cases: polyps are more widespread in the upper GI tract with massive gastric polyposis and they have a dense epithelial component. This study also confirmed that SMAD4 genetic analysis is useful for the diagnosis of JPS and may be predictive of an increased risk of malignancy through inactivation of both alleles of SMAD4.