Pediatric Evans syndrome is associated with a high frequency of potentially damaging variants in immune genes

Author:

Hadjadj Jérôme12,Aladjidi Nathalie34,Fernandes Helder34,Leverger Guy5,Magérus-Chatinet Aude12,Mazerolles Fabienne12,Stolzenberg Marie-Claude12,Jacques Sidonie12,Picard Capucine26,Rosain Jérémie26,Fourrage Cécile78,Hanein Sylvain9,Zarhrate Mohammed810,Pasquet Marlène11,Abou Chahla Wadih12,Barlogis Vincent13ORCID,Bertrand Yves14,Pellier Isabelle15,Colomb Bottollier Elodie16,Fouyssac Fanny17,Blouin Pascale18,Thomas Caroline19,Cheikh Nathalie20,Dore Eric21,Pondarre Corinne2223,Plantaz Dominique24,Jeziorski Eric25,Millot Frédéric26,Garcelon Nicolas227,Ducassou Stéphane34,Perel Yves34,Leblanc Thierry28,Neven Bénédicte1229,Fischer Alain2293031,Rieux-Laucat Frédéric12

Affiliation:

1. Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, Institut Imagine, Unité Mixte de Recherche (UMR) 1163, INSERM, Paris, France;

2. Imagine Institute, Paris Descartes–Sorbonne Paris Cité University, Paris, France;

3. Centre de Référence National des Cytopénies Auto-immunes de l’Enfant (CEREVANCE) and

4. Pediatric Oncology Hematology Unit, University Hospital, Plurithématique CIC (CICP), Centre d’Investigation Clinique (CIC) 1401, INSERM Bordeaux, France;

5. Pediatric Oncology Immunology Hematology Unit, Hospital Armand-Trousseau, Paris, France;

6. Study Center for Primary Immunodeficiencies, Necker Hospital for Sick Children, Assistance Publique–Hôpitaux de Paris (AP-HP), Paris, France;

7. Bioinformatics Core Facility, Institut Imagine, Structure Fédérative de Recherche Necker, Unité 1163, INSERM, Paris, France;

8. Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Service (UMS) 3633, INSERM, Paris Descartes–Sorbonne Paris Cité University, Paris, France;

9. Translational Genetic, Institut Imagine, UMR 1163, INSERM, Paris, France;

10. Genomics Core Facility, Institut Imagine, Structure Fédérative de Recherche Necker, Paris Descartes–Sorbonne Paris Cité University, Paris, France;

11. Pediatric Oncology Immunology Hematology Unit, Hospital des Enfants, Toulouse, France;

12. Department of Pediatric Hematology, Jeanne de Flandre Hospital, Centre Hospitalier Régional Universitaire (CHU) Lille, Lille, France;

13. Department of Paediatric Haematology, Hopital La Timone, CHU de Marseille, Marseille, France;

14. Institute of Pediatric Haematology and Oncology, Hospices Civils de Lyon, Lyon, France;

15. Pediatric Unit, Universitary Hospital Angers, Angers, France;

16. Department of Pediatric Hematology-Oncology, Hôpital d’Enfants, CHU de Dijon, Dijon, France;

17. Department of Pediatric Hematology-Oncology, University Hospital Nancy, Nancy, France;

18. Department of Pediatric Hematology-Oncology, Hôpital Clocheville, Centre Hospitalier Régionaux et Universitaire (CHRU) de Tours, Tours, France;

19. Service d’Hématologie Pédiatrique, Hôpital Enfant-Adolescent, CHU Nantes, France;

20. Department of Pediatric Hematology-Oncology, University Hospital Besançon, Besançon, France;

21. Pediatric Unit, CHU Clermont-Ferrand, Clermont-Ferrand, France;

22. Department of Pediatrics, Paris-Est Creteil University, Creteil, France;

23. Unité 955, INSERM, Creteil, France;

24. Department of Pediatric Hematology-Oncology, University Hospital Grenoble, Grenoble, France;

25. Pediatric Oncology Hematology Unit, Hospital Arnaud de Villeneuve, Montpellier, France;

26. Department of Pediatric Onco-Hematology, Poitiers University Hospital, Poitiers, France;

27. Institut Imagine, Centre de Recherche des Cordeliers, Equipe 22, UMR 1138, INSERM, Paris France;

28. Pediatric Hematology Unit, Hospital Robert Debré, Paris, France;

29. Paediatric Immuno-Haematology and Rheumatology Department, Necker-Enfants Malades University Hospital, AP-HP, Paris, France;

30. UMR 1163, INSERM, Paris, France; and

31. Collège de France, Paris, France

Abstract

Abstract Evans syndrome (ES) is a rare severe autoimmune disorder characterized by the combination of autoimmune hemolytic anemia and immune thrombocytopenia. In most cases, the underlying cause is unknown. We sought to identify genetic defects in pediatric ES (pES), based on a hypothesis of strong genetic determinism. In a national, prospective cohort of 203 patients with early-onset ES (median [range] age at last follow-up: 16.3 years ([1.2-41.0 years]) initiated in 2004, 80 nonselected consecutive individuals underwent genetic testing. The clinical data were analyzed as a function of the genetic findings. Fifty-two patients (65%) received a genetic diagnosis (the M+ group): 49 carried germline mutations and 3 carried somatic variants. Thirty-two (40%) had pathogenic mutations in 1 of 9 genes known to be involved in primary immunodeficiencies (TNFRSF6, CTLA4, STAT3, PIK3CD, CBL, ADAR1, LRBA, RAG1, and KRAS), whereas 20 patients (25%) carried probable pathogenic variants in 16 genes that had not previously been reported in the context of autoimmune disease. Lastly, no genetic abnormalities were found in the remaining 28 patients (35%, the M− group). The M+ group displayed more severe disease than the M− group, with a greater frequency of additional immunopathologic manifestations and a greater median number of lines of treatment. Six patients (all from the M+ group) died during the study. In conclusion, pES was potentially genetically determined in at least 65% of cases. Systematic, wide-ranging genetic screening should be offered in pES; the genetic findings have prognostic significance and may guide the choice of a targeted treatment.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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