Variable Features of Juvenile Polyposis Syndrome With Gastric Involvement Among Patients With a Large Genomic Deletion of BMPR1A

Juvenile polyposis syndrome (JPS, OMIM 174900) is a rare autosomal dominant disorder, affecting between 1 in 100,000 and 1 in 160,000 (1), characterized by hamartomatous polyps and increased risk of gastrointestinal (GI) cancer. JPS is diagnosed clinically when a person has any one of the following: (i) more than 5 juvenile polyps of the colon or rectum; (ii) juvenile polyps in other parts of the GI tract; or (iii) any number of juvenile polyps and one or more affected family members (National Comprehensive Cancer Network [NCCN] guidelines) (2). Up to 60% of individuals with clinically defined JPS are now found to exhibit mutations in SMAD4 or BMPR1A genes (3). JPS polyps are typically colonic with edematous, markedly inflamed lamina propria, with cystic dilation and smooth muscle proliferation. Although dysplastic polyps may appear with variable histology, one study reported “mixed polyposis syndrome” with polyps containing variable pathology of adenomatous, hyperplastic, and juvenile features caused by small base pair deletions in the BMPR1A gene (4); adenomas comprise less than 10% of JPS polyps (5). JPS can involve the entire GI tract. Although colonic phenotype is similar between patients with SMAD4 and BMPR1A mutations, upper GI and gastric polyposis is much more common in SMAD4 mutation (1,6,7). As reported by Aretz et al. (6), SMAD4 mutation carriers had a significantly higher frequency of gastric polyposis than did patients with BMPR1A mutations (83% vs 8%, respectively). All cases of gastric cancer occurred in families with SMAD4 mutations (6,7). Lifetime risk estimates of GI cancers, mostly colorectal cancer (CRC), are highly variable, ranging from 14% to 55% in different series (1,8,9). Although surveillance guidelines exist, the NCCN guidelines for surveillance recommend referral of patients with JPS to a specialized team due to the rarity of the syndrome and complexities of diagnosis and management (2). The molecular alterations involved in polyp and tumor formation in JPS are attributed to defective BMP signaling, where aberrant BMP signaling disrupts stem cell self-renewal and differentiation, contributing to tumor formation (10). Loss of heterozygosity (LOH) was reported in half of BMPR1A-related polyps, compatible with BMPR1A acting as a tumor suppressor gene (11). However, BMPR1A LOH has not been documented yet in cancerous tumors. Most pathogenic variants in BMPR1A are point mutations or small deletions. Large deletions of BMPR1A are rare, accounting for approximately 6% of cases, many of them are contiguous with PTEN (6,12–14). Contiguous gene deletions may lead to more pronounced manifestations; however, the rarity and variability of BMPR1A deletions not including PTEN have made genotype-phenotype relationships of large BMPR1A deletions difficult to assess (14). We identified a deletion of the entire coding region of the BMPR1A gene among and investigated the clinical features in over 50 individuals from 7 unrelated families. This cohort enables expanding our knowledge about this rare predisposition syndrome.