Lorenzo Norsa1,2,3, Roberto Berni Canani4,5,6, Remi Duclaux-Loras7,8, Emeline Bequet9, Jutta Köglmeier10, Richard K Russell11, Holm H Uhlig12, Simon Travis12, Jennifer Hollis12, Sibylle Koletzko13,14, Giusi Grimaldi4, Giuseppe Castaldo5, Astor Rodrigues12, Jaques Deflandre15, Lukasz Dembinski16, Neil Shah10, Peter Heinz-Erian17, Andreas Janecke17, Saara Leskinen18, Satu Wedenoja19, Ritva Koskela20, Alain Lachaux7, Kaija-Leena Kolho21, Frank M Ruemmele1. 1. Assistance Publique - Hôpitaux de Paris, Hôpital Necker Enfants Malades, Pediatric Gastroenterology Hepatology and Nutrition, Paris, France. 2. Pediatric Gastroenterology Hepatology and Transplantation, ASST Papa Giovanni XXIII, Bergamo, Italy. 3. Université de Paris, Faculté de Médecine, Paris, France. 4. Department of Translational Medical Science - Pediatric Section, University 'Federico II', Naples, Italy. 5. CEINGE Advanced Biotechnologies, University Federico II, Naples, Italy. 6. European Laboratory for the Investigation of Food Induced Diseases, University 'Federico II', Naples, Italy. 7. Department of Paediatric Gastroenterology Hepatology and Nutrition, Hospices Civils de Lyon, Hôpital Femme Mère Enfant, Bron, France. 8. CIRI unité Inserm U1111, ENS Lyon, France. 9. Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University Hospital Liège, Belgium. 10. Pediatric Gastroenterology Hepatology and Nutrition, Great Ormond Street Hospital for Sick Children, London, UK. 11. Pediatric Gastroenterology Hepatology and Nutrition, Royal Hospital for Children, Glasgow, UK. 12. Translational Gastroenterology Unit and Biomedical Research Centre, University of Oxford, Oxford, UK. 13. Division of Gastroenterology and Hepatology, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, Munich, Germany. 14. Department of Paediatrics, School of Medicine Collegium Medicum University of Warmia and Mazury, Olsztyn, Poland. 15. Department of Gastroenterology, CHR Citadelle, Liège, Belgium. 16. Department of Paediatrics, Gastroenterology and Nutrition, Medical University of Warsaw, Warsaw, Poland. 17. Department of Pediatrics I, Medical University of Innsbruck, Innsbruck, Austria. 18. Department of Paediatric Gastroenterology, Kuopio University Hospital, Kuopio, Finland. 19. Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. 20. Department of Internal Medicine, Oulu University Hospital, Oulu, Finland. 21. Department of Paediatric Gastroenterology, Children's Hospital and University of Helsinki, Helsinki, Finland and Tampere University, Tampere, Finland.
Abstract
BACKGROUND: 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 diarrhoea 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]. The prevalence of IBD in our cohort of CLD was higher than the highest prevalence of IBD in Europe [p < 0.0001]. The age of onset was variable [13.5 years, interquartile range: 8.5-23.5 years]. Patients with CLD and IBD had lower z-score for height than those without IBD. Four of 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 immunosuppressants [azathioprine or mercaptopurine], one on 5-ASA and one off-treatment. CONCLUSIONS: A substantial proportion of patients with CLD develop IBD. This suggests the potential involvement of SL26A3-mediated anion transport in IBD pathogenesis. Patients with CLD-associated IBD may require surgery for treatment failure or colon cancer.
BACKGROUND: 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 diarrhoea 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]. The prevalence of IBD in our cohort of CLD was higher than the highest prevalence of IBD in Europe [p < 0.0001]. The age of onset was variable [13.5 years, interquartile range: 8.5-23.5 years]. Patients with CLD and IBD had lower z-score for height than those without IBD. Four of 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 immunosuppressants [azathioprine or mercaptopurine], one on 5-ASA and one off-treatment. CONCLUSIONS: A substantial proportion of patients with CLD develop IBD. This suggests the potential involvement of SL26A3-mediated anion transport in IBD pathogenesis. Patients with CLD-associated IBD may require surgery for treatment failure or colon cancer.
Authors: Ema Bogdanic; Thomas Müller; Peter Heinz-Erian; Dorota Garczarczyk-Asim; Andreas R Janecke; Aline Rückel Journal: Mol Genet Genomic Med Date: 2022-06-30 Impact factor: 2.473