This review and practice guide provides a comprehensive summary of the monogenic causes of IBD-like intestinal

inflammation and a conceptual framework for the diagnostic evaluation of patients with suspected monogenic IBD. We categorize this website known genetic defects into functional subgroups and discuss key intestinal and extraintestinal findings. Based on the enrichment of known causative mutations as well as extreme phenotypes in very young children, we have focused on a practical approach to detect monogenic disorders in patients with VEOIBD and infantile IBD in particular. Because there is only modest biological evidence to support age-specific categorization of IBD above infantile IBD and within the EOIBD subgroup, we also discuss disease- and gene-specific ages of onset of intestinal inflammation (Figure 1). Approximately GSK2126458 supplier 20%

to 25% of patients with IBD develop intestinal inflammation during childhood and adolescence. IBD in children younger than 1 year of age has been reported in approximately 1% and VEOIBD in approximately 15% of pediatric patients with IBD.6 VEOIBD has an estimated incidence of 4.37 per 100,000 children and a prevalence of 14 per 100,000 children.22 The incidence of pediatric IBD is increasing.22 and 23 Some studies have reported that the incidence of IBD is increasing particularly rapidly in young children,24 and 25 although not all studies have confirmed this observation.9 Twin studies have provided the best evidence for a genetic predisposition to IBD,

which is stronger for CD than UC. Conventional IBD is a group of polygenic disorders in which hundred(s) of susceptibility loci contribute to the overall risk of disease. Meta-analyses of (genome-wide) association studies of adolescent- and adult-onset IBD identified 163 IBD-associated genetic loci encompassing approximately 300 potential candidate genes. However, it is important to consider that these 163 Montelukast Sodium loci individually contribute only a small percentage of the expected heritability in IBD.26 This suggests that IBD, including CD and UC, can be regarded as a classic polygenic disorder. Findings from initial genome-wide pediatric association studies focused on adolescents and confirm a polygenic model.27 and 28 There are no well-powered genome-wide association studies of patients with EOIBD or VEOIBD. Although most cases of IBD are caused by a polygenic contribution toward genetic susceptibility, there is a diverse spectrum of rare genetic disorders that produce IBD-like intestinal inflammation.29 The genetic variants that cause these disorders have a large effect on gene function. However, these variants are so rare in allele frequency (many private mutations) that those genetic signals are not detected in genome-wide association studies of patients with IBD.