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Clin Immunol. 2018 Mar;188:52-57. doi: 10.1016/j.clim.2017.12.009. Epub 2018 Jan 10.

Pediatric-onset Evans syndrome: Heterogeneous presentation and high frequency of monogenic disorders including LRBA and CTLA4 mutations.

Author information

1
INSERM UMR 1163, Laboratory of Immunogenetics of pediatric autoimmune diseases, Paris, France; Pediatric immuno-hematology and rhumatology unit, RAISE reference centre for pediatric inflammatory rheumatic diseases and systemic autoimmune diseases, Necker-Enfants Malades University Hospital, Assistance publique - Hôpitaux de Paris, France; Sorbonne Universités, UPMC université Paris 06, Paris, France.
2
INSERM UMR 1163, Laboratory of Immunogenetics of pediatric autoimmune diseases, Paris, France; Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France.
3
Pediatric Hematology Oncology Immunology, Centre de Référence National des Cytopénies Auto-immunes de l'enfant, CEREVANCE, CIC 1401, CHU Bordeaux, France.
4
Genomic Platform, INSERM UMR 1163, Paris Descartes Sorbonne Paris Cité University, Imagine Institute, Paris, France.
5
Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France; INSERM UMR 1163, Bioinformatics Department, Imagine Institute, Paris, France.
6
Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France; Pediatric immuno-hematology and rhumatology unit, RAISE reference centre for pediatric inflammatory rheumatic diseases and systemic autoimmune diseases, Necker-Enfants Malades University Hospital, Assistance publique - Hôpitaux de Paris, France.
7
Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France; Hematology, Immunology, Infectiology, Hôpital Necker-Enfants Malades, Assistance publique - Hôpitaux de Paris, Paris, France.
8
Pediatrics, Infectiology, Rhumatology, Hôpital Arnaud de Villeneuve, CHRU de Montpellier, France.
9
Sorbonne Universités, UPMC université Paris 06, Paris, France; Pediatric hematology, Immunology, Oncology, Hôpital d'Enfants Armand Trousseau, Assistance publique - Hôpitaux de Paris, Paris, France.
10
Pediatric hematology, Immunology, Oncology, Hôpital d'Enfants Armand Trousseau, Assistance publique - Hôpitaux de Paris, Paris, France.
11
Pediatric immuno-hematology and rhumatology unit, RAISE reference centre for pediatric inflammatory rheumatic diseases and systemic autoimmune diseases, Necker-Enfants Malades University Hospital, Assistance publique - Hôpitaux de Paris, France.
12
Department of Pediatric Hematology and Oncology, Research Unit EA 3279, Aix-Marseille University, Timone Hospital, Marseille, France.
13
Pediatric Oncology, Hematology, Immunology, CHU d'Angers, Angers, France.
14
Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France; Adult hematology, Necker-Enfants Malades University Hospital, APHP, Paris, France; Inserm U1163, CNRS ERL 8254, Imagine Institute, Paris, France.
15
Pediatrics and Pediatric hematology, Hôpital de la Timone, Marseille, France.
16
Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France; INSERM UMR 1163, Laboratory of Normal and pathological homeostasis of the immune system, Paris, France; Study Center for Primary Immunodeficiencies, Necker-Enfants Malades Hospital, Assistance Publique Hôpitaux de Paris (APHP), Necker Medical School, Paris, France.
17
Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France; Pediatric immuno-hematology and rhumatology unit, RAISE reference centre for pediatric inflammatory rheumatic diseases and systemic autoimmune diseases, Necker-Enfants Malades University Hospital, Assistance publique - Hôpitaux de Paris, France; Study Center for Primary Immunodeficiencies, Necker-Enfants Malades Hospital, Assistance Publique Hôpitaux de Paris (APHP), Necker Medical School, Paris, France.
18
INSERM UMR 1163, Laboratory of Immunogenetics of pediatric autoimmune diseases, Paris, France; Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France; Pediatric immuno-hematology and rhumatology unit, RAISE reference centre for pediatric inflammatory rheumatic diseases and systemic autoimmune diseases, Necker-Enfants Malades University Hospital, Assistance publique - Hôpitaux de Paris, France; Collège de France, Paris, France.
19
INSERM UMR 1163, Laboratory of Immunogenetics of pediatric autoimmune diseases, Paris, France; Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France; Pediatric immuno-hematology and rhumatology unit, RAISE reference centre for pediatric inflammatory rheumatic diseases and systemic autoimmune diseases, Necker-Enfants Malades University Hospital, Assistance publique - Hôpitaux de Paris, France.
20
INSERM UMR 1163, Laboratory of Immunogenetics of pediatric autoimmune diseases, Paris, France; Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France. Electronic address: frederic.rieux-laucat@inserm.fr.

Abstract

Evans syndrome (ES) is defined by the combination of autoimmune hemolytic anemia and immune thrombocytopenia. Clinical presentation includes manifestations of immune dysregulation, found in primary immune deficiencies, autoimmune lymphoproliferative syndrome with FAS (ALPS-FAS), Cytotoxic T Lymphocyte Antigen-4 (CTLA-4) and Lipopolysaccharide-Responsive vesicle trafficking Beige-like and Anchor protein (LRBA) defects. We report the clinical history and genetic results of 18 children with ES after excluding ALPS-FAS. Thirteen had organomegaly, five lymphocytic infiltration of non-lymphoid organs, nine hypogammaglobulinemia and fifteen anomalies in lymphocyte phenotyping. Seven patients had genetic defects: three CTLA4 mutations (c.151C>T; c.109+1092_568-512del; c.110-2A>G) identified by Sanger sequencing and four revealed by Next Generation Sequencing: LRBA (c.2450+1C>T), STAT3 gain-of-function (c.2147C>T; c.2144C>T) and KRAS (c.37G>T). No feature emerged to distinguish patients with or without genetic diagnosis. Our data on pediatric-onset ES should prompt physicians to perform extensive screening for mutations in the growing pool of genes involved in primary immune deficiencies with autoimmunity.

KEYWORDS:

Autoimmune cytopenias; Extensive genetic screening; Immune checkpoint deficiencies; LRBA and CTLA-4 deficiencies

PMID:
29330115
DOI:
10.1016/j.clim.2017.12.009

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