However, there are clear gene-specific differences in the age of onset. The reported time of onset of IBD-like immunopathology in subgroups with, for example, IL-10 signaling defects, WAS, or IPEX, is infancy and early childhood. However, atypical late onset BGB324 in vivo of IBD has been reported in patients with WAS122 and 123

as well as IPEX.124, 125 and 126 The age is variable in neutrophil defects, B-cell defects, and XIAP deficiency. Indeed, XIAP deficiency caused by identical genetic defects within families can be associated with VEOIBD or adult-onset IBD. 68, 73 and 127 Other diseases, such as GUCY2C deficiency, typically develop during adulthood ( Figure 1). Phenotypes of many monogenic forms of IBD change over time; gastrointestinal problems can present as an initial or a later finding. Some candidate disorders will be recognized by their pathognomonic symptom combinations. Because there are no specific and fully reliable endoscopic and histological

features of monogenic VEOIBD, patients with VEOIBD and multiple other features (listed in Table 3) should be considered to have increased likelihood to carry disease-causing mutations. The degree of suspicion should dictate the extent of functional and genetic exploration for an underlying cause. It is important to emphasize that in the majority of patients with infantile IBD or VEOIBD, no genetic defect has currently Epigenetic inhibitors library been discovered that would explain the immunopathology. This fraction of causative defects will increase as our knowledge expands and with a growing number of patients undergoing whole-exome sequencing (WES). Although young age of IBD onset is a strong indicator, a strong suspicion for a monogenic cause should lead to limited functional or genetics screening irrespective of age. Laboratory tests, upper and lower gastrointestinal endoscopy with histological analysis of multiple

biopsy specimens, and imaging should be performed for every patient with VEOIBD according to guidelines.13, 18, 19, 20, 21 and 128 Histological investigation is paramount not only to differentiate IBD-like features but also to exclude other Oxalosuccinic acid established pathologies such as eosinophilic or allergic gastrointestinal disease and infection. Cow’s milk protein allergy is common and can cause severe colitis that resembles UC and even requires hospitalization. It manifests typically within the first 2 to 3 months of exposure to cow’s milk protein. This may be apparent with breast-feeding or only after introducing formula feeding. Colitis resolves after cow’s milk is removed from the diet, so a trial of exclusive feeding with an amino acid–based infant formula is a customary treatment strategy for all VEOIBD diagnosed when the patient is younger than 1 year of age.