Somatic mosaicism and common genetic variation contribute to the risk of very-early-onset inflammatory bowel disease

Abstract: Very-early-onset inflammatory bowel disease (VEO-IBD) is a heterogeneous phenotype associated with a spectrum of rare Mendelian disorders. Here, we perform whole-exome-sequencing and genome-wide genotyping in 145 patients (median age-at-diagnosis of 3.5 years), in whom no Mendelian disorders were clinically suspected. In five patients we detect a primary immunodeficiency or enteropathy, with clinical consequences (XIAP, CYBA, SH2D1A, PCSK1). We also present a case study of a VEO-IBD patient with a mosaic de novo, pathogenic allele in CYBB. The mutation is present in ~70% of phagocytes and sufficient to result in defective bacterial handling but not life-threatening infections. Finally, we show that VEO-IBD patients have, on average, higher IBD polygenic risk scores than population controls (99 patients and 18,780 controls; P < 4 × 10−10), and replicate this finding in an independent cohort of VEO-IBD cases and controls (117 patients and 2,603 controls; P < 5 × 10−10). This discovery indicates that a polygenic component operates in VEO-IBD pathogenesis

Micro-RNAs as regulators and possible diagnostic bio-markers in inflammatory bowel disease

Not fully defined pathophysiologic mechanisms of inflammatory bowel disease (IBD) involve an array of genetic, epigenetic, infectious, physiological and immunological factors. Nowadays, an inadequate activation of the innate immune system to a luminal factor occurring in genetically predisposed subjects is the most widely accepted today. Micro-autoimmune diseases, a group of small, single-stranded, non-coding RNA molecules act as potent negative gene regulators. Beyond cancer and various autoimmune diseases, their impact on IBD has recently been the focus of research. Differential expression of various micro-RNAs has been documented in active and inactive ulcerative colitis, while micro-RNA profile appears to differ between ileal and colonic Crohn&apos;s disease. Except for tissue samples, attempts have been made to estimate similar differences at patients&apos; blood samples. Apart from offering new directions in related research, these molecules arise as useful diagnostic tools and potential therapeutic targets. This review focuses on micro-RNA alterations in IBD and their potential implication on immunologic deregulation. © 2011 European Crohn&apos;s and Colitis Organisation

ABC des polypes coliques [Abecedary of colonic polyps]

Colonic polyps are very common in the general population. Some polyps present a cancerization risk and their screening and management by endoscopy reduce the risk of colorectal cancer. Other polyps do not need specific follow-up. There are different types of polyps whose classification has been updated over the last ten years. Serrated polyps now intersect hyperplastic polyps, sessile serrated adenomas and traditional serrated adenomas. Current recommendations are to resect and histologically analyze each colonic polyp to define a personalized endoscopic surveillance strategy. Some colonic polyposis syndromes require management in a specialized center

Glucocorticoids in Pediatric Gastrointestinal Disorders

3Pediatric Inflammatory Bowel Disease Inflammatory bowel diseases (IBDs) are the most frequent chronic gastrointestinal disorders in pediatric age. They include two disease entities – Crohn’s disease (CD) and ulcerative colitis (UC) – which, although different in their pathogenesis, show common clinical characteristics such as chronic inflammation at different levels of the gastrointestinal tract and alternation between active and inactive phases. The incidence of IBD is increasing in recent years, particularly among children and adolescents, and it is currently estimated that 20–30 % of patients with IBD experience the onset of symptoms when they are under 20 years of age [1–3]. In childhood, IBDs are gener- ally more extended, more severe, and progress more rapidly than in adulthood. Moreover, therapy in children with IBD is more aggressive than in adults: Indeed, about 80 % of children need steroids, and about 30 % are subjected to an intestinal resection during a 5-year follow-up. Quality of life is severely affected in IBD, espe- cially for pediatric patients, owing to the chronic character of the disease that implies frequent hospitalizations and aggressive therapies, with a significant risk of side effects and a considerable impact on health care costs. IBD can result in loss of education and difficulty in gaining employment or insurance; overall, 15 % of patients with IBD are unable to work after 5–10 years of disease. Depressive disorders and low social func- tioning are also common among these patients, and the disease can also cause growth failure or retarded sexual development in young people [4–7]. It was recently reported that the mean individual annual costs in European countries amount to US$6,000 for CD and$4,600 for UC, and pediatric cases cost even more than adult ones [8].nonenoneDe Iudicibus, Sara; Martelossi, Stefano; Decorti, GiulianaDE IUDICIBUS, Sara; Martelossi, Stefano; Decorti, Giulian

Somatic mosaicism and common genetic variation contribute to the risk of very-early-onset inflammatory bowel disease

Very-early-onset inflammatory bowel disease (VEO-IBD) is a heterogeneous phenotype associated with a spectrum of rare Mendelian disorders. Here, we perform whole-exome-sequencing and genome-wide genotyping in 145 patients (median age-at-diagnosis of 3.5 years), in whom no Mendelian disorders were clinically suspected. In five patients we detect a primary immunodeficiency or enteropathy, with clinical consequences (XIAP, CYBA, SH2D1A, PCSK1). We also present a case study of a VEO-IBD patient with a mosaic de novo, pathogenic allele in CYBB. The mutation is present in ~70% of phagocytes and sufficient to result in defective bacterial handling but not life-threatening infections. Finally, we show that VEO-IBD patients have, on average, higher IBD polygenic risk scores than population controls (99 patients and 18,780 controls; P &lt; 4 × 10-10), and replicate this finding in an independent cohort of VEO-IBD cases and controls (117 patients and 2,603 controls; P &lt; 5 × 10-10). This discovery indicates that a polygenic component operates in VEO-IBD pathogenesis