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Phenotypic Characterization of Very Early-onset IBD Due to Mutations in the IL10, IL10 Receptor Alpha or Beta Gene: A Survey of the GENIUS Working Group

Pigneur, Bénédicte MD*,†; Escher, Johanna MD, PhD; Elawad, Mamoun MD§; Lima, Rosa MD; Buderus, Stephan MD; Kierkus, Jaroslaw MD**; Guariso, Graziella MD††; Canioni, Danielle MD, PhD‡‡; Lambot, Karen MD§§; Talbotec, Cécile MD; Shah, Neil MD§; Begue, Bernadette‖‖; Rieux-Laucat, Frédéric PhD¶¶; Goulet, Olivier MD*,†,‖‖; Cerf-Bensussan, Nadine MD, PhD‖‖; Neven, Bénédicte MD, PhD*,¶¶; Ruemmele, Frank M. MD, PhD*,†,‖‖

doi: 10.1097/01.MIB.0000435439.22484.d3
Original Basic Science Articles

Objective: 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.

Design: 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.

Results: 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.

Conclusion: 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.

Article first published online 7 November 2013

*Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, Paris, France;

Assistance Publique-Hôpitaux de Paris, Hôpital Necker-Enfants Malades, Service de Gastroentérologie pédiatrique, Paris, France;

Department of Pediatric Gastroenterology, ErasmusMC-Sophia Children's Hospital, Rotterdam, the Netherlands;

§Department of Gastroenterology, Great Ormond Street Hospital for Sick Children and Institute of Child Health, London, United Kingdom;

Pediatric Gastroenterology Unit, Centro Hospitalar do Porto, Porto, Portugal;

Marienhospital, Bonn, Germany;

**Department of Gastroenterology, Hepatology and Feeding Disorders, The Children's Memorial Health Institute, Warsaw, Poland;

††Gastroenterologia, Endoscopia Digestiva, Epatologia e Cura del Bambino con Trapianto di Fegato, Dipartimento Salute della Donna e del Bambino, Padova, Italy;

‡‡Assistance Publique-Hôpitaux de Paris, Hôpital Necker-Enfants Malades, Service d'anatomopathologie, Paris, France;

§§Assistance Publique-Hôpitaux de Paris, Hôpital Necker-Enfants Malades, Service de radiologie, Paris, France;

‖‖INSERM U989, Paris, France; and

¶¶INSERM U768, Paris, France.

Reprints: Frank M. Ruemmele, MD, PhD, Pediatric Gastroenterology, Hôpital Necker-Enfants Malades, INSERM U989, Université Paris Descartes, Sorbonne Paris Cité, 149 Rue de Sèvres, Paris F-75015, France (e-mail:

The experimental work performed at Necker-Enfants Malades Hospital was supported by research grants from INSERM, the French Ministry (PHRC grant AOM08087), and a grant from the association François Aupetit, Paris, France. In addition, a grant concerning the genetic causes of EO-IBD of the Université Sorbonne Paris Cité (to F.M.R.) was helpful for the initial work-up of patients. A network grant from ESPGHAN was provided to support this research.

B. Pigneur, J. Escher, M. Elawad, and R. Lima contributed equally.

The authors have no conflicts of interest to disclose.

Received April 01, 2013

Accepted September 06, 2013

© Crohn's & Colitis Foundation of America, Inc.
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