Phenotypic differences in Juvenile Polyposis Syndrome with or without a disease-causing SMAD4/BMPR1A variant.

Juvenile polyposis syndrome (JPS) is a clinically diagnosed hamartomatous polyposis syndrome that increases the risk of gastrointestinal cancer. Approximately 40-50% of JPS is caused by a germline disease-causing variant (DCV) in the SMAD4 or BMPR1A genes. The aim of this study is to characterize the phenotype of DCV-negative JPS and compare it to DCV-positive JPS. Herein we analyze a cohort of 145 individuals with JPS from nine institutions, including both pediatric and adult centers. Data analyzed included age at diagnosis, family history, cancer history, need for colectomy/gastrectomy, and polyp number and location. Compared to DCV-positive JPS, DCV-negative JPS was associated with younger age at diagnosis (p<0.001), lower likelihood of having a family history of JPS (p<0.001), and a lower risk of colectomy (p=0.032). None of the DCV-negative individuals had gastric or duodenal polyps, and polyp burden decreased after the first decade compared to DCV-positive JPS. Subgroup analysis between SMAD4 and BMPR1A carriers showed that SMAD4 carriers were more likely to have a family history of JPS and require gastrectomy. Taken together, these data provide the largest phenotypic characterization of individuals with DCV-negative JPS to date, showing that this group has distinct differences compared to JPS due to a SMAD4 or BMPR1A variant. Better understanding of phenotype and cancer risk associated with JPS both with and without a DCV may ultimately allow for individualized management of polyposis and cancer risk.