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Blood. 2019 Apr 2. pii: blood-2018-11-887141. doi: 10.1182/blood-2018-11-887141. [Epub ahead of print]

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

Author information

1
Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, INSERM UMR 1163-Institut Imagine, Paris, France; hadjadj_jerome@yahoo.fr.
2
Centre de Reference National des Cytopenies Auto-immunes de l'Enfant (CEREVANCE), CIC 1401, Inserm CICP, Bordeaux, France.
3
Pediatric Oncology Immunology Hematology Unit, Hospital Armand-Trousseau, Paris, France.
4
Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, INSERM UMR 1163-Institut Imagine, Paris, France.
5
Imagine Institute, Paris Descartes-Sorbonne Paris Cite University, Paris, France.
6
Study Center for Primary Immunodeficiencies, AP-HP, Necker Hospital for Sick Children, Paris, France.
7
Bioinformatics Core Facility, Institut Imagine-Structure Federative de Recherche Necker, INSERM U1163 and INSERM US24/CNRS UMS3633, Paris Descartes Sorbonne Paris Cite University, Paris, France.
8
Translational Genetic, INSERM UMR1163 and Institut Imagine, Paris, France.
9
Genomics Core Facility, Institut Imagine-Structure Federative de Recherche Necker, INSERM U1163 et INSERM US24/CNRS UMS3633, Paris Descartes Sorbonne Paris Cite University, Paris, France.
10
Pediatric Oncology Immunology Hematology Unit, Hospital des enfants, Toulouse, France.
11
Department of Pediatric Hematology, Jeanne de Flandre Hospital, CHU Lille, Lille, France.
12
Department of Paediatric Haematology, CHU de Marseille, Hopital La Timone, Marseille, France.
13
Institute of Pediatric Haematology and Oncology, Hospices Civils de Lyon, Lyon, France.
14
Pediatric Unit, University Hospital, Angers, France.
15
Department of Pediatric hematology-oncology, Hopital d'enfants, CHU de Dijon, Dijon, France.
16
Department of Pediatric Hematology-Oncology, University Hospital of Nancy, Nancy, France.
17
Department of pediatric hematology-oncology, Hopital Clocheville, CHRU de Tours, Tours, France.
18
Service d'Hematologie Pediatrique, Hopital Enfant-Adolescent, CHU Nantes, Nantes, France.
19
Department of Pediatric Hematology-Oncology, University Hospital of Besancon, Besancon, France.
20
Pediatric Unit, Centre Hospitalier Universitaire, Clermont-Ferrand, France.
21
Department of Pediatrics, INSERM Unit 955, Paris-Est Creteil University, Creteil, France.
22
Department of Pediatric Hematology-Oncology, University Hospital, Grenoble, France.
23
Pediatric Oncology Hematology Unit, Hospital Arnaud de Villeneuve, Montpellier, France.
24
Department of Pediatric Onco-Hematology, Poitiers University Hospital, Poitiers, France.
25
INSERM, Centre de Recherche des Cordeliers, UMR 1138 Equipe 22, Institut Imagine, Paris, France.
26
Pediatric Hematology and Oncology Unit, University Hospital, place Amelie Raba Leon, CIC 1401, Inserm, CICP, Bordeaux, France.
27
Pediatric Hematology Unit, Hospital Robert Debre, Paris, France.
28
Department of Immunology, INSERM UMR1163, PARIS, France.

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)) initiated in 2004, 80 non-selected 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 one 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.

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