The Clinical Research Of Double-balloon Enteroscopy In The Treatment Of Peutz-jeghers Syndrome And The Screening Of STK11/LKB1Gene Mutation

OBJECTIVEPeutz-Jeghers syndrome (PJS) is a rare hereditary syndrome characterized bymucocutaneous pigmentation and hamartomatous polyps of the gastrointestinal tract,especially in the small intestine. PJS causes not only higher cancer risk of the digestivetract, but is also an age-dependent increased risk for development of extra-intestinalmalignancies compared to the general population, such as breast cancer and pancreaticcarcinoma. The cancer risk of the PJS patients ups to37%-93%in their lifetime. Multiplegastrointestinal polyps of the PJS patients often caused intussusception, intestinalobstruction and gastrointestinal bleeding in adolescence. The cancer tendency and thecomplications of the PJS can lead to repeated hospitalization and substantial hazard.Double-balloon enteroscopy (DBE) is a new endoscopic technique that enables bothendoscopic of the entire small bowel and the therapeutic interventions in a singleprocedure.Germline mutations in the serine/threonine kinase11(STK11) genes have beenreported as a major cause of PJS. STK11/LKB1mutation causes inactivation of proteinkinase STK11/LKB1which can cause various diseases, including the occurrence of PJS.Currently, more than200kinds of STK11/LKB1mutations have been detected in PJS andother sporadic tumors. However, the exact pathogenesis of STK11/LKB1is complex andhas not been fully illuminated. Different STK11/LKB1mutations may act on differentcell-activity stages. Therefore, safety and efficacy study of the intestinal polypectomy bythe DBE and further screening of STK11/LKB1mutation have extraodinary significance.In this study, we evaluate the safety and efficacy of endoscopic ma nagement ofsmall-bowel polyps in PJS patients by using DBE and attempt to explore the related genesof PJS.METHODSPartⅠ: We retrospectively analysised38consecutive patients who were referred tochanghai hospital, Gastroenterology Department, with the diagnosis of PJS between2009and2014. We reviewed all valuable clinical information during their hospitalizations and followed the patients by telephone. The main content included clinical characteristics (age,sex, history of surgery), results (the number of resected polyps of any size in eachhospitalization, number of resected polyps≥20mm in each hospitalization, maximum sizeof resected polyps in each hospitalization), complications and surgeries after procedures.Quantitative values were summarized as the mean (standard deviation, SD). Differencesbetween hospitalizations of numerical variables were performed by using the Friedman’stest. Differences were considered significant at P <0.05.PartⅡ: Peripheral blood genomic DNA samples from18PJS patients from17unrelated families (1PJS family and16sporadic families) were investigated for STK11mutations using a combination of conventional direct DNA sequencing and the multiplexligation-dependent probe amplification (MLPA) assay. Phenotypic correlations wereinvestigated.ResultsPartⅠ: Thirty-eight patients (14males, mean age30.5±11.1years) were included inthis study from January2010to January2014. The average hospitalization was1.4±0.6and the number of DBE was102. The mean number of resected polyp larger than20mmsignificantly decreased as hospitalizations advanced (first,3.4; second,0.4; third,0.1; P <0.001). The maximum size of resected polyps also significantly decreased at eachhospitalization:36.5,5.5and1.3mm (P <0.001). One patient had a delayed bleeding andwas managed endoscopicly with hemostatic clipsclip. Three patients had perforation. Onewas managed conservatively and the other two turned to surgery. Only2patientsunderwent surgery for intussusception during the study period.1patient died ofsmall-bowel polyp’s cancerization.PartⅡ:STK11/LKB1gene point mutations: we identified germline point mutations in8of17(47.1%) of the index cases. We detected3missense mutations and4truncating mutations.Two mutations are associated with cancer in the index patients in relatives with PJS. Allthe mutations are in line with the international coverage.STK11/LKB1gene large genomic deletions: we nest tested for the presence of exonicrearrangements by using MLPA in the9PJS probands in whom no mutations was identified by Sanger sequencing. The overall frequency of large deletions was3/9(33.3%).Conclusion1. Endoscopic management of small-bowel polyps in PJS patients by using DBE issafe and effective. Polypectomies made in the small intestinal can decrease thecomplication rate due to those polyps and avoid the need for surgery.2. Measured by Sanger sequencing and MLPA detection technology, the STK11/LKB1gene mutation rate in PJS patients up to64.7%. All the screened gene mutations are in linewith international coverage.