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The extended phenotype of LRBA deficiency

Laura Gámez-Díaz1*, Dietrich August1, Polina Stepensky2, Shoshana Revel-Vilk2, Markus G. Seidel3, Mitsuiki Noriko4, Tomohiro Morio4, Austen Worth5, Jacob Bleesing6, Frank Van De Veerdonk7, Tobias Feuchtinger8, Maria G. Kanariou9, Annette Schmitt-Gräff1, Suranjith Seneviratne10, Siobhan Burns10, Bernd Belohradsky11, Nima Rezaei12, Shahrzad Bakhtiar13, Carsten Speckmann1, Michael Jordan7 and Bodo Grimbacher1, 10
  • 1 University Medical Center Freiburg, Center for Chronic Immunodeficiency, Germany
  • 2 Hadassah Hebrew University Hospital, Pediatric Hematology-Oncology and Bone Marrow Transplantation, Israel
  • 3 Medical University Graz, Deparment of Pediatrics and Adolescent Medicine, Divisioni of Pediatric Hematology-Oncology, Austria
  • 4 Medical and Dental University, Tokyo, Japan, Department of Pediatrics and Developmental Biology Graduate School of Medical and Dental Sciences, Japan
  • 5 Great Ormond Street Hospital for Children, Department of Immunology, United Kingdom
  • 6 Cincinnati Childrens Hospital Medical Center, University of Cincinnati Medical School, United States
  • 7 Radboud University of Cincinnati Medical School, Cincinnati Childrens Hospital Medical Center, Netherlands
  • 8 University Hospital Tübingen, laboratory of Immunotherapy, Germany
  • 9 Aghia Sophia Childrens Hospital, Department of Immunology, Greece
  • 10 Royal Free Hospital Foundation Trust, UCL Center for Immunodeficiency, United Kingdom
  • 11 University Childrens Hospital Munich, Division of Immunology and Infectious Disease, Germany
  • 12 Tehran University of Medical Sciences, Research Center for Immunodeficiencies, Iran
  • 13 Goethe University Frankfurt am Main, Division for Stem Cell Transplantation and Immunology, Germany

Background: LRBA (lipopolysaccharide-responsive-beige-like-anchor-protein) deficiency is a primary immunodeficiency caused by biallelic mutations in LRBA that abolish LRBA protein expression. Objective: We sought to report the extended phenotype of LRBA deficiency in a cohort of 22 LRBA-deficient patients. Methods: Clinical criteria, protein detection, and genetic sequencing were applied to diagnose LRBA deficiency. Results: Ninety-three patients met the inclusion criteria, and were considered “possible” LRBA deficiency. Twenty-four patients failed to express LRBA protein and were labeled “probable” LRBA deficiency whereas 22 were genetically confirmed as “definitive” LRBA deficiency, having biallelic mutations in LRBA. Seventeen of these were novel and included homozygous or compound heterozygous mutations. Immune dysregulation (95%), organomegaly (86%), recurrent infections (71%), and hypogammaglobulinemia (57%) were the main clinical complications observed in LRBA-deficient patients. Although 81% of LRBA-deficient patients had normal T cell counts, 73% had reduced regulatory T cell numbers. Most LRBA-deficient patients had low counts in the B cell subsets mainly in switched memory B cells (80%) and plasmablasts (92%) with a defective specific antibody response in 67%. Out of the 22 patients, three were deceased, two had successfully been treated by HSCT, seven patients are under immunoglobulin replacement, and 15 are on immunosuppressive treatment with systemic corticosteroids, alone or in combination with steroids sparing agents. Conclusion: This report describes the largest cohort of patients with LRBA deficiency and offers guidelines for physicians to identify LRBA deficiency, supporting an appropriate clinical management.

Acknowledgements

This study was supported by the Bundesministerium für Bildung und Forschung (BMBF) grant numbers: IFB/CCI: 01E01303, E-med SysINFLAME: 012X1306F, DZIF: 8000805-3, and BMBF PID-NET:01GM1111B.

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Keywords: LRBA, Primary immunodeficiency, CVID, Autoimmunity, hypogammaglobulinemia, enteropathy, LYMPHOPROLIFERATION

Conference: IMMUNOCOLOMBIA2015 - 11th Congress of the Latin American Association of Immunology - 10o. Congreso de la Asociación Colombiana de Alergia, Asma e Inmunología, Medellin, Colombia, 13 Oct - 16 Oct, 2015.

Presentation Type: Oral Presentation

Topic: Immunodeficiencies

Citation: Gámez-Díaz L, August D, Stepensky P, Revel-Vilk S, Seidel MG, Noriko M, Morio T, Worth A, Bleesing J, Van De Veerdonk F, Feuchtinger T, Kanariou MG, Schmitt-Gräff A, Seneviratne S, Burns S, Belohradsky B, Rezaei N, Bakhtiar S, Speckmann C, Jordan M and Grimbacher B (2015). The extended phenotype of LRBA deficiency. Front. Immunol. Conference Abstract: IMMUNOCOLOMBIA2015 - 11th Congress of the Latin American Association of Immunology - 10o. Congreso de la Asociación Colombiana de Alergia, Asma e Inmunología. doi: 10.3389/conf.fimmu.2015.05.00351

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Received: 28 May 2015; Published Online: 15 Sep 2015.

* Correspondence: Miss. Laura Gámez-Díaz, University Medical Center Freiburg, Center for Chronic Immunodeficiency, Freiburg, Select State, 79108, Germany, laura.gamez@uniklinik-freiburg.de