Chronische oder schwere Darmerkrankung und Immundefekt: Manchmal ist es doch ein Kolibri

Zusammenfassung

Bei der Abklärung chronischer Darmerkrankungen sollte in bestimmten Fällen auch an einen primären (=angeborenen) Immundefekt (PID) gedacht werden. PIDs sind selten, aber mindestens 10 % der Betroffenen entwickeln eine Darmentzündung. Patienten mit einer chronisch-entzündlichen Darmentzündung (CED) aufgrund eines PID haben oft extraintestinale Manifestationen und sprechen auf die konventionelle Therapie oft nicht oder nur ungenügend an. Die frühkindliche Manifestation einer CED und bestimmte intestinale und extraintestinale Manifestationen können wegweisend für einen PID sein. Für einen kleinen Teil der monogenetisch verursachten Immundefekte wurde gezeigt, dass sie gezielt medikamentös behandelt oder durch eine allogene Stammzelltransplantation sogar geheilt werden können. Dafür ist eine frühzeitige und gezielte Diagnostik notwendig. Dieser Beitrag soll exemplarisch zeigen, wann klinische – sowohl gastrointestinale als auch extraintestinale – Zeichen und Befunde eine immunologische und gegebenenfalls genetische Diagnostik erfordern.

Abstract

In the work-up of chronic enteropathies an underlying inborn error of immunity (IEI) should be considered in certain cases. IEI are rare, but approximately 10% of patients may present with symptoms of inflammatory bowel disease (IBD), which is a much more common entity. Patients with IEI associated IBD may show extraintestinal symptoms or signs, and are often refractory to conventional anti-inflammatory treatment. In case of early-onset bowel inflammation and other intestinal or extraintestinal manifestations, an IEI should be excluded. A small fraction of monogenic IEI can be amenable to targeted therapies, or even corrected by allogeneic stem cell transplantation. Therefore, early diagnosis is crucial. This paper shows examples of clinical – gastrointestinal as well as extraintestinal – signs and findings which require immunological and possibly genetic workup.

Schlüsselwörter

chronisch entzündliche Darmerkrankung - primäre Immundefekte

Keywords

inflammatory bowel disease - primary immunodeficiencies

^* geteilte Letztautorenschaft

Publication History

Received: 21 June 2021

Accepted after revision: 23 November 2021

Article published online:
16 March 2022

• Literatur

• 1 Zhang S, Jouanguy E, Zhang Q. Human inborn errors of immunity to infection affecting cells other than leukocytes: from the immune system to the whole organism. Curr Opin Immunol 2019; 59: 88-100
• 2 Tangye SG, Al-Herz W, Bousfiha A. et al. Human Inborn Errors of Immunity: 2019 Update on the Classification from the International Union of Immunological Societies Expert Committee. J Clin Immunol 2020; 40: 24-64
• 3 Schwerd T, Uhlig HH. Chronisch-entzündliche Darmerkrankung und Immundefekte. Monatsschrift Kinderheilkunde 2017; 165: 1092-1101
• 4 Uhlig HH, Schwerd T, Koletzko S. et al. The diagnostic approach to monogenic very early onset inflammatory bowel disease. Gastroenterology 2014; 147: 990-1007.e3
• 5 Buderus S, Scholz D, Behrens R. et al. Inflammatory bowel disease in pediatric patients: Characteristics of newly diagnosed patients from the CEDATA-GPGE Registry. Dtsch Arztebl Int 2015; 112: 121-127
• 6 Turner D, Muise AM. Very Early Onset IBD: How Very Different „on Average“?. J Crohns Colitis 2017; 11: 517-518
• 7 Kammermeier J, Dziubak R, Pescarin M. et al. Phenotypic and Genotypic Characterisation of Inflammatory Bowel Disease Presenting Before the Age of 2 years. ECCOJC 2017; 11: 60-69
• 8 Ashton JJ, Andreoletti G, Coelho T. et al. Identification of Variants in Genes Associated with Single-gene Inflammatory Bowel Disease by Whole-exome Sequencing. Inflammatory Bowel Diseases 2016; 22: 2317-2327
• 9 Pazmandi J, Kalinichenko A, Ardy RC. et al. Early-onset inflammatory bowel disease as a model disease to identify key regulators of immune homeostasis mechanisms. Immunol Rev 2019; 287: 162-185
• 10 Nameirakpam J, Rikhi R, Rawat SS. et al. Genetics on early onset inflammatory bowel disease: An update. Genes Dis 2020; 7: 93-106
• 11 Turner D, Ruemmele FM, Orlanski-Meyer E. et al. Management of Paediatric Ulcerative Colitis, Part 1: Ambulatory Care-An Evidence-based Guideline From European Crohn’s and Colitis Organization and European Society of Paediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr 2018; 67: 257-291
• 12 http://www.dgvs.de/wissen/leitlinien/leitlinien-dgvs/morbus-crohn/
• 13 van Rheenen PF, Aloi M, Assa A. et al. The Medical Management of Paediatric Crohn’s Disease: an ECCO-ESPGHAN Guideline Update. J Crohns Colitis 2020;
• 14 Kucharzik T, Dignass AU, Atreya R. et al. Aktualisierte S3-Leitlinie Colitis ulcerosa – Living Guideline: August 2020 – AWMF-Registriernummer: 021–009. Z Gastroenterol 2020; 58: e241-e326
• 15 Levine A, Koletzko S, Turner D. et al. ESPGHAN Revised Porto Criteria for the Diagnosis of Inflammatory Bowel Disease in Children and Adolescents. Journal of Pediatric Gastroenterology & Nutrition 2014; 58: 795-806
• 16 Maaser C, Sturm A, Vavricka SR. et al. ECCO-ESGAR Guideline for Diagnostic Assessment in IBD Part 1: Initial diagnosis, monitoring of known IBD, detection of complications. Journal of Crohn’s and Colitis 2019; 13: 144-164K
• 17 Uhlig HH, Charbit-Henrion F, Kotlarz D. et al. Clinical Genomics for the Diagnosis of Monogenic Forms of Inflammatory Bowel Disease: A Position Paper From the Paediatric IBD Porto Group of European Society of Paediatric Gastroenterology, Hepatology and Nutrition. Journal of Pediatric Gastroenterology & Nutrition 2021; 72: 456-473
• 18 Posovszky C. Congenital intestinal diarrhoeal diseases: A diagnostic and therapeutic challenge. Best practice & research Clinical gastroenterology 2016; 30: 187-211
• 19 Posovszky C, Barth TFE. The gut: center of immunity : Rare inflammatory bowel diseases caused by immunodeficiencies. Der Pathologe 2020; 41: 211-223
• 20 Bienias M, Gabrielyan A, Geberzahn L. et al. More severe than CVID: Combined immunodeficiency due to a novel §#ITL#§NFKB2§#/ITL#§ mutation. Pediatr Allergy Immunol 2021; 32: 793-797
• 21 Hauck F, Magg T, Krolo A. et al. Variant PIK3R1 Hypermorphic Mutation and Clinical Phenotypes in a Family with Short Statures, Mild Immunodeficiency and Lymphoma. Klin Padiatr 2017; 229: 113-117
• 22 Zeissig Y, Petersen B-S, Milutinovic S. et al. XIAP variants in male Crohn’s disease. Gut 2015; 64: 66-76
• 23 Crowley E, Warner N, Fiedler K. et al. A13 Whole Exome sequencing of over 1000 pediatric IBD patients from a single centre identifies monogenic forms of IBD. Journal of the Canadian Association of Gastroenterology 2018; 1: 21-21
• 24 Crowley E, Warner N, Pan J. et al. Prevalence and Clinical Features of Inflammatory Bowel Diseases Associated With Monogenic Variants, Identified by Whole-Exome Sequencing in 1000 Children at a Single Center. Gastroenterology 2020; 158: 2208-2220
• 25 Ono S, Okano T, Hoshino A. et al. Hematopoietic Stem Cell Transplantation for XIAP Deficiency in Japan. J Clin Immunol 2017; 37: 85-91
• 26 Engelhardt KR, Shah N, Faizura-Yeop I. et al. Clinical outcome in IL-10- and IL-10 receptor-deficient patients with or without hematopoietic stem cell transplantation. J Allergy Clin Immunol 2013; 131: 825-830
• 27 Leung G, Muise AM. Monogenic Intestinal Epithelium Defects and the Development of Inflammatory Bowel Disease. Physiology 2018; 33: 360-369
• 28 Uhlig HH, Powrie F. Translating Immunology into Therapeutic Concepts for Inflammatory Bowel Disease. Annu Rev Immunol 2018; 36: 755-781
• 29 Zheng HB, de la Morena MT, Suskind DL. The Growing Need to Understand Very Early Onset Inflammatory Bowel Disease. Front Immunol 2021; 12: 675186
• 30 Braun CJ, Boztug K, Paruzynski A. et al. Gene Therapy for Wiskott-Aldrich Syndrome--Long-Term Efficacy and Genotoxicity. Science Translational Medicine 2014; 6: 227ra33-227ra33
• 31 Yska HAF, Elsink K, Kuijpers TW. et al. Diagnostic Yield of Next Generation Sequencing in Genetically Undiagnosed Patients with Primary Immunodeficiencies: a Systematic Review. J Clin Immunol 2019; 39: 577-591