Evaluating the Role of Genetic Testing for Inborn Errors of Immunity in Pediatric Patients with Very Early-Onset and Early-Onset Inflammatory Bowel Disease

The incidence of inflammatory bowel disease (IBD) has significantly increased in developing countries over the last decade with a rising prevalence among the pediatric population. Very early-onset IBD (VEOIBD), defined as IBD in children younger than 6 years, requires a comprehensive diagnostic approach including clinical history, physical examination, laboratory tests, endoscopy, and genetic evaluation. Literature indicates that 8–20% of pediatric patients diagnosed with VEOIBD have identifiable genetic causes, often involving monogenic mutations related to inborn errors of immunity (IEI), namely those that play a role in intestinal barrier function, innate and adaptive immunity, and autoinflammatory disorders. Identifying these mutations can offer insights into potential therapeutic targets. This study examines our cohort of VEOIBD and early-onset IBD patients referred to the Stanford immunology clinic, with a focus on the prevalence of monogenic diseases and their clinical implications.

Among the 31 pediatric patients referred for immunologic evaluation at Stanford, targeted genetic testing for primary immune deficiency revealed pathogenic mutations in 7 patients (22%). These included mutations in DUOX2, NOD2, CTLA4 (2), CARD11, and NEMO (Table I). The median age of IBD onset was 6.25 years, with a slight female predominance. Crohn’s disease was more prevalent than ulcerative colitis in this VEOIBD cohort. As a note, one 11-year-old female diagnosed with Crohn’s was found to be a carrier for LRBA, inherited from her asymptomatic mother. Patients with identified monogenic causes showed significant improvement with targeted therapies, such as abatacept for CTLA-4 haploinsufficiency.

Predicting which patients have an underlying monogenic disease remains challenging, emphasizing the importance of genetic evaluation.

Genetic screening plays a crucial role in the management of VEOIBD, providing insights and guiding treatment decision. Targeted therapies should be considered whenever available. The effective management of these complex conditions relies on multidisciplinary teams, underscoring their pivotal role in comprehensive care.