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

Abstract

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.