Disease expression in juvenile polyposis syndrome: a retrospective survey on a cohort of 221 European patients and comparison with a literature-derived cohort of 473 SMAD4/BMPR1A pathogenic variant carriers

Abstract

Purpose: Juvenile polyposis syndrome (JPS) is a rare, autosomaldominantly inherited cancer predisposition caused in approximately 50% of cases by pathogenic germline variants in SMAD4 and BMPR1A. We aimed to gather detailed clinical and molecular genetic information on JPS disease expression to provide a basis for management guidelines and establish open access variant databases. Methods: We performed a retrospective, questionnaire-based European multicenter survey on and established a cohort of SMAD4/ BMPR1A pathogenic variant carriers from the medical literature. Results: We analyzed questionnaire-based data on 221 JPS patients (126 kindreds) from ten European centers and retrieved literature-based information on 473 patients. Compared with BMPR1A carriers, SMAD4 carriers displayed anemia twice as often (58% vs. 26%), and exclusively showed overlap symptoms with hemorrhagic telangiectasia (32%) and an increased prevalence (39% vs. 13%) of gastric juvenile polyps. Cancer, reported in 15% of JPS patients (median age 41 years), mainly occurred in the colorectum (overall: 62%, SMAD4: 58%, BMPR1A: 88%) and the stomach (overall: 21%; SMAD4: 27%, BMPR1A: 0%). Conclusion: This comprehensive retrospective study on genotype-phenotype correlations in 694 JPS patients corroborates previous observations on JPS in general and SMAD4 carriers in particular, facilitates recommendations for clinical management, and provides the basis for open access variant SMAD4 and BMPR1A databases.

Phenotypic diversity among juvenile polyposis syndrome patients from different ethnic background

“…As expected, we did not find any difference between BMPR1A and SMAD4 carriers in terms of colonic phenotype and polyp burden. Surprisingly, in contrast to previous series which showed higher gastric polyp rate and more severe gastric phenotype among SMAD4 mutation carriers [ 9 , 17 , 26 ], we did not find such an association. Apparently, the reason for this finding is the dominance of the BMPR1A Bukharin mutation among our BMPR1A mutation carriers.…”

“…The reason for our lower rate of cancer diagnosis in our cohort is most probably due to the relatively higher representation of young patients (median age of JPS diagnosis in our cohort was 13 years with 5 years follow up, while in the two cohorts that were recently published the median age was 25 and 27 years, respectively [ 5 , 26 ]). The median age of cancer diagnosis was 41–47 years in previous studies [ 5 , 15 , 26 ]; however, only 12 patients from our cohort (24%) have reached this age range. Another study from Israel described only one JPS patient with cancer (2.8%).…”

“…All besides one family had the BMPR1A Bukharin mutation. According to a recent publication from Europe [ 26 ] the rate of large deletions in the SMAD4 is reported to be higher in SMAD4 and lower in BMPR1A (6.7–21.4% large deletions in SMAD4 and 13.5–16.4% in BMPR1A ). This reflects the specific ethnicity background in Israel which is different from that in Europe.…”

“…All of them had colonic polyps as well. In two recent publications the rate of SB involvement was even lower (4.5–5.7%) [ 26 , 27 ]; however older data showed 14% of JPS patients to have SB polyps [ 4 , 5 , 7 , 8 , 27 ]. Although we did not have any case of SB cancer, SB cancer has been previously described [ 27 ].…”

mTOR inhibitors reduce enteropathy, intestinal bleeding and colectomy rate in patients with juvenile polyposis of infancy with PTEN-BMPR1A deletion

“…Hamartomatous polyps typically develop in JPS by 14–20 years of age ( 11 , 15 , 16 ). Endoscopic surveillance is recommended starting at age 12 or earlier if there are gastrointestinal symptoms ( 14 , 17 ).…”