The Great Imposter: Three Cases of Inflammatory Bowel Disease Associated with Innate Immune Defects

Abstract

Pediatric inflammatory bowel disease associated with inborn errors of immunity represents a diagnostic and therapeutic challenge, particularly in cases of early-onset, severe disease, extraintestinal manifestations, or refractoriness to treatment. We present three pediatric cases with an aggressive clinical course, multisystemic involvement, and an inadequate response to multiple therapeutic lines of therapy, in whom the persistent presence of warning signs prompted genetic testing. In one of these patients, exome sequencing identified a pathogenic variant in FOXP3, confirming the diagnosis of IPEX syndrome. In the other two patients, who were siblings, an alteration in XIAP was identified, consistent with a diagnosis of X-linked lymphoproliferative syndrome type 2. In the index patient with XIAP deficiency, the initial exome sequencing did not identify any causative variants. Subsequently, genome sequencing established the molecular diagnosis, which subsequently led to the cascade diagnosis of his sibling. These cases highlight the importance of early recognition of phenotypes suggestive of monogenic disease, maintaining diagnostic suspicion despite initially negative genetic test results, and conducting a timely multidisciplinary evaluation. Identification of an underlying inborn error of immunity can substantially modify the therapeutic approach, allow for the consideration of potentially curative options such as hematopoietic stem cell transplantation, and facilitate family genetic counseling.