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

Jérôme Hadjadj; Nathalie Aladjidi; Helder Fernandes; Guy Leverger; Aude Magérus-Chatinet; Fabienne Mazerolles; Marie-Claude Stolzenberg; Sidonie Jacques; Capucine Picard; Jeremie Rosain; Cécile Fourrage; Sylvain Hanein; Mohammed Zarhrate; Marlene Pasquet; Wadih Chahla; Vincent Barlogis; Yves Bertrand; Isabelle Pellier; Elodie Colomb Bottollier; Fanny Fouyssac; Pascale Blouin; Caroline Thomas; Nathalie Cheikh; Eric Dore; Corinne Pondarre; Dominique Plantaz; Eric Jeziorski; Frédéric Millot; Nicolas Garcelon; Stéphane Ducassou; Yves Perel; Thierry Leblanc; Bénédicte Neven; Alain Fischer; Frédéric Rieux-Laucat

doi:10.1182/blood-2018-11-887141.

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

Jérôme Hadjadj ¹ Nathalie Aladjidi ^{2, 3} Helder Fernandes ^{2, 3} Guy Leverger ⁴ Aude Magérus-Chatinet ¹ Fabienne Mazerolles ¹ Marie-Claude Stolzenberg ¹ Sidonie Jacques ¹ Capucine Picard ^{5, 6} Jeremie Rosain ^{5, 6} Cécile Fourrage ^{7, 8} Sylvain Hanein ⁵ Mohammed Zarhrate ^{8, 5} Marlene Pasquet ⁹ Wadih Chahla ¹⁰ Vincent Barlogis ¹¹ Yves Bertrand ^{12, 13} Isabelle Pellier ¹⁴ Elodie Colomb Bottollier ¹⁵ Fanny Fouyssac ¹⁶ Pascale Blouin ¹⁷ Caroline Thomas ¹⁸ Nathalie Cheikh ¹⁹ Eric Dore ²⁰ Corinne Pondarre ²¹ Dominique Plantaz ²² Eric Jeziorski ²³ Frédéric Millot ²⁴ Nicolas Garcelon ^{5, 25} Stéphane Ducassou ^{2, 3} Yves Perel ^{2, 3} Thierry Leblanc ²⁶ Bénédicte Neven ^{1, 6} Alain Fischer ^{5, 27, 6} Frédéric Rieux-Laucat ⁵

1 Equipe Inserm U1163 - Immunogenetics of pediatric autoimmune diseases

IMAGINE - U1163 - Imagine - Institut des maladies génétiques

2 CIC Bordeaux

3 CEREVANCE - Centre de Référence National des Cytopénies Auto-immunes de l'Enfant

4 Service d'hématologie-immunologie-oncologie pédiatrique [CHU Trousseau]

5 IMAGINE - U1163 - Imagine - Institut des maladies génétiques

6 CHU Necker - Enfants Malades [AP-HP]

7 Equipe Inserm U1163 - The Clinical Bioinformatics laboratory

IMAGINE - U1163 - Imagine - Institut des maladies génétiques

8 SFR Necker - UMS 3633 / US24 - Structure Fédérative de Recherche Necker

9 Hôpital des Enfants

10 CHRU Lille - Centre Hospitalier Régional Universitaire [Lille]

11 Service d'hématologie pédiatrique

12 UMR AGAP - Amélioration génétique et adaptation des plantes méditerranéennes et tropicales

13 HCL - Hospices Civils de Lyon, Departement de Neurologie

14 Service d'Immuno-Hémato-Oncologie Pédiatrique

15 CHU Dijon

16 CHRU Nancy - Centre Hospitalier Régional Universitaire de Nancy

17 CHRU TOURS - Centre Hospitalier Régional Universitaire de Tours

18 CHU Nantes - Centre hospitalier universitaire de Nantes

19 CHRU Besançon - Centre Hospitalier Régional Universitaire [Besançon]

20 CHU Clermont-Ferrand

21 IMRB - Institut Mondor de Recherche Biomédicale

22 CHU - Centre Hospitalier Universitaire [Grenoble]

23 Hôpital Arnaud de Villeneuve

24 CHU Poitiers - Centre hospitalier universitaire de Poitiers

25 CRC (UMR_S_1138 / U1138) - Centre de Recherche des Cordeliers

26 Hôpital Robert Debré

27 CDF - Collège de 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 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.

Document type :

Journal articles

Domain :

Life Sciences [q-bio]

Life Sciences [q-bio] / Genetics / Human genetics

Life Sciences [q-bio] / Immunology

Life Sciences [q-bio] / Immunology / Adaptive immunology

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https://www.hal.inserm.fr/inserm-02439240
Contributor : Frédéric Rieux-Laucat <>
Submitted on : Tuesday, January 14, 2020 - 3:09:55 PM
Last modification on : Friday, March 27, 2020 - 2:30:18 AM

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

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

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