Inflammatory bowel disease in patients with congenital chloride diarrhoea

J Crohns Colitis. 2021 Mar 26;jjab056. doi: 10.1093/ecco-jcc/jjab056. Online ahead of print.

Lorenzo Norsa 1 2, Roberto Berni Canani 3 4 5, Remi Duclaux-Loras 6 7, Emeline Bequet 8, Jutta Köglmeier 9, Richard K Russell 10, Holm H Uhlig 11, Simon Travis 11, Jennifer Hollis 11, Sibylle Koletzko 12 13, Giusi Grimaldi 3, Giuseppe Castaldo 4, Astor Rodrigues 11, Jaques Deflandre 14, Lukasz Dembinski 15, Neil Shah 9, Peter Heinz Erian 16, Andreas Janecke 16, Saara Leskinen 17, Satu Wedenoja 18, Ritva Koskela 19, Alain Lachaux 6, Kaija-Leena Kolho 20, Frank M Ruemmele 1


Author information

  • 1Assistance Publique - Hôpitaux de Paris, Hôpital Necker Enfants Malades, Pediatric Gastroenterology Hepatology and Nutrition, Paris, France, Université de Paris, Faculté de Médecine, Paris, France.
  • 2Pediatric Gastroenterology Hepatology and Transplantation, ASST Papa Giovanni XXIII, Bergamo, Italy.
  • 3Department of Translational Medical Science - Pediatric Section, University "Federico II", Naples, Italy.
  • 4CEINGE Advanced Biotechnologies, University Federico II, Naples, Italy.
  • 5European Laboratory for the Investigation of Food Induced Diseases University "Federico II", Naples, Italy.
  • 6Department of Paediatric Gastroenterology Hepatology and Nutrition, Hospices Civils de Lyon, Hôpital Femme Mère Enfant, Bron, France.
  • 7CIRI unité Inserm U1111, ENS Lyon, France.
  • 8Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University Hospital Liège, Belgium.
  • 9Pediatric Gastroenterology Hepatology and Nutrition, Great Ormond Street Hospital for Sick Children, London, UK.
  • 10Pediatric Gastroenterology Hepatology and Nutrition, Royal Hospital for Children, Glasgow, Scotland.
  • 11Translational Gastroenterology Unit and Biomedical Research Centre, University of Oxford, Oxford, United Kingdom.
  • 12Division of Gastroenterology and Hepatology, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, Munich, Germany.
  • 13Department of Paediatrics, School of Medicine Collegium Medicum University of Warmia and Mazury, Olsztyn, Poland.
  • 14Department of Gastroenterology, CHR Citadelle, Liège, Belgium.
  • 15Department of Paediatrics, Gastroenterology and Nutrition, Medical University of Warsaw, Warsaw, Poland.
  • 16Department of Pediatrics I, Medical University of Innsbruck, Innsbruck, Austria.
  • 17Department of Paediatric Gastroenterology, Kuopio University Hospital, Kuopio, Finland.
  • 18Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
  • 19Department of Internal Medicine, Oulu University Hospital, Oulu, Finland.

20Department of Paediatric Gastroenterology, Children's Hospital and University of Helsinki, Helsinki, Finland and Tampere University, Tampere, Finland


Introduction: Congenital chloride diarrhoea (CLD) is a rare autosomal recessive disease caused by mutations in the solute family carrier 26 member 3 (SLC26A3) gene. Patients suffer from life-long watery diarrhea and chloride loss. Inflammatory bowel disease (IBD) has been reported in individual patients with CLD and in scl26a3-deficient mice.

Methods: We performed an international multicentre analysis to build a CLD cohort and to identify cases with IBD. We assessed clinical and genetic characteristics of subjects and studied the cumulative incidence of CLD-associated IBD.

Results: In a cohort of 72 patients with CLD caused by 17 different SLC26A3 mutations, we identified 12 patients (17%) diagnosed with IBD. Nine patients had Crohn's disease, two ulcerative colitis, and one IBD-unclassified (IBD-U). Prevalence of IBD in our cohort of CLD is higher than the highest prevalence of IBD in Europe (p < 0.0001). The age of onset was variable (13.5 years, IQR: 8.5 - 23.5 years). Patients with CLD and IBD had lower z-score for height than those without IBD. 4/12 patients had required surgery (ileostomy formation n=2, ileocaecal resection due to ileocaecal valve stenosis n=1, and colectomy due to stage II transverse colon cancer n=1). At last follow-up, 5/12 were on biologics (adalimumab, infliximab, or vedolizumab), 5/12 on immunosuppressant (azathioprine or mercaptopurine), one on 5-ASA and one off-treatment.

Conclusions: A substantial proportion of patients with CLD develop IBD. This suggests potential involvement of SL26A3-mediated anion transport in IBD pathogenesis. Patients with CLD-associated IBD may require surgery for treatment failure or colon cancer.

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