Clinical Information

Inflammatory bowel disease (IBD) is a term encompassing numerous disorders featuring chronic intestinal inflammation. These conditions are typically classified as either Crohn disease or ulcerative colitis based on clinical features, colonoscopy findings, histologic changes, and the anatomical distribution of disease. However, some cases are not readily classified or may have overlapping features and are classified as IBD-unspecified (IBD-U). The incidence of IBD has rapidly increased in children and adults over the past few decades. Common symptoms include diarrhea, abdominal pain, fatigue, and failure to thrive or unintentional weight loss.

IBD is caused by a combination of dysregulated immune response, microbial dysbiosis, and environmental triggers and occurs in individuals with genetic susceptibility. Most IBD is thought to be either polygenic or multifactorial. However, in rare cases, IBD or IBD-like intestinal inflammation can be attributed to disease-causing variants in a single gene (ie, monogenic inheritance) that result in a highly penetrant condition that presents early in life. Many monogenic forms of IBD are disorders of immune deficiency or dysregulation. Genes associated with IBD continue to be identified with advances in sequencing technology. However, 70% to 80% of patients have IBD without a known genetic etiology.

While the peak age of onset of IBD is between the ages of 20 and 40 years, the incidence of IBD in pediatric patients is increasing. When IBD presents in children younger than 6 years old, it is described as very early onset IBD (VEO-IBD). IBD that presents in children younger than 2 years old is described as infantile-onset IBD. VEO-IBD differs from IBD in older patients in that it is more likely to be IBD-U and have a monogenic cause, particularly among those with infantile-onset IBD.

Conditions associated with VEO-IBD can be grouped into the following broad, sometimes overlapping categories: disorders of general immune dysregulation (eg,. IL-10 signaling defects, IPEX syndrome, STAT3 gain-of-function); T- and B-cell defects (eg,. LRBA deficiency, CTLA4 deficiency, Wiskott Aldrich syndrome, severe combined immunodeficiency [SCID]/Omenn syndrome); phagocytic defects (eg,. chronic granulomatous disease); hyper- or auto-inflammatory disorders (eg,. familial Mediterranean fever, familial hemophagocytic lymphohistiocytosis); epithelial barrier dysfunction (eg, TTC7A deficiency, nuclear factor kappa B essential modulator [NEMO] deficiency); and syndromic conditions (eg, trichohepatoenteric syndrome, CHAPLE [CD55 deficiency with hyper-activation of complement, angiopathic thrombosis, and severe protein-losing enteropathy] syndrome).

Previous reports indicate patients with a monogenic form of IBD may not respond as well to conventional treatment modalities. Identification of the genetic cause of disease in these individuals is important as it may change their treatment plan. Depending on the genetic cause, targeted therapies or allogeneic hematopoietic stem cell transplantation may be beneficial. Therefore, early diagnosis and identification of the specific underlying genetic alteration is important in order to inform treatment, such as medical therapy, surgery, and stem cell transplant and to reduce the high morbidity and mortality associated with these conditions.

Individuals with polygenic or monogenic IBD may have other family members affected with IBD. A family history of IBD is more common among those with VEO-IBD. If a monogenic cause is identified in an individual, family members may be tested for the genetic variant to assess their risk of developing IBD or to guide therapy for those who are affected.