Early-onset inflammatory bowel disease starting within the first months of life could be due to a particular genetic defect. We set up the GENetically determined ImmUne-mediated enteropathieS (GENIUS) network and collected infants with a proven defect of the IL10 axis for accurate phenotyping of disease presentation and evolution.
Ten patients with early-onset inflammatory bowel disease with confirmed mutations in IL10, IL10RA, or IL10RB genes were characterized on clinical, endoscopic–histological, immunobiological, and radiological findings. Functional assays to confirm defective responses to IL10 were performed on peripheral blood mononuclear cells.
A functional defect in IL10 signaling was confirmed in all IL10R patients tested. Disease started with severe diarrhea within the first 12 weeks in all patients. All infants showed Crohn's disease–like ulcerations limited to the colon with marked perianal inflammation (fissures, abscess, and fistula); disease progression to the small bowel occurred in only 1 patient. Four of the 10 patients had granulomata on histology, and all patients showed Crohn's disease–like mesenteric infiltration on imaging. Disease pattern was indistinguishable between IL10R alpha or beta chain or IL10 defects; autoimmunity was not observed. Mutations in IL10 were more frequently associated with bacterial and viral infections. Patients responded partially to treatment with steroids or anti–tumor necrosis factor drugs, whereas hematopoietic stem cell transplantation proved efficacious.
The importance of the IL10 pathway within the colonic mucosa is highlighted by the development of severe colitis within a few weeks in infants with mutations in IL10, IL10RA, or IL10RB. Immunosuppression failed to correct the defect in this pathway, which seems to be a key to controlling inflammation in the colon.