title: The extended phenotype of LPS-responsive beige-like anchor protein (LRBA) deficiency.
abstract: BACKGROUND
  LPS-responsive beige-like anchor protein (LRBA) 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 to have possible LRBA deficiency. Twenty-four patients did not express LRBA protein and were labeled as having probable LRBA deficiency, whereas 22 were genetically confirmed as having definitive LRBA deficiency, with 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 (Treg) cell numbers. Most LRBA-deficient patients had low B-cell subset counts, mainly in switched memory B cells (80%) and plasmablasts (92%), with a defective specific antibody response in 67%. Of the 22 patients, 3 are deceased, 2 were treated successfully with hematopoietic stem cell transplantation, 7 are receiving immunoglobulin replacement, and 15 are receiving immunosuppressive treatment with systemic corticosteroids alone or in combination with steroid-sparing agents.
  
  
  CONCLUSIONS
  This report describes the largest cohort of patients with LRBA deficiency and offers guidelines for physicians to identify LRBA deficiency, supporting appropriate clinical management.
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Laura
authors.initials: L
authors.lastname: Gámez-Díaz
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Dietrich
authors.initials: D
authors.lastname: August
authors.affiliation: Pediatric Hematology-Oncology and Bone Marrow Transplantation, Hadassah Hebrew University Hospital, Jerusalem, Israel.
authors.forename: Polina
authors.initials: P
authors.lastname: Stepensky
authors.affiliation: Pediatric Hematology-Oncology and Bone Marrow Transplantation, Hadassah Hebrew University Hospital, Jerusalem, Israel.
authors.forename: Shoshana
authors.initials: S
authors.lastname: Revel-Vilk
authors.affiliation: Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology-Oncology, Medical University Graz, Graz, Austria.
authors.forename: Markus G
authors.initials: MG
authors.lastname: Seidel
authors.affiliation: Department of Pediatrics and Developmental Biology Graduate School of Medical and Dental Sciences Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Mitsuiki
authors.initials: M
authors.lastname: Noriko
authors.affiliation: Department of Pediatrics and Developmental Biology Graduate School of Medical and Dental Sciences Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Morio
authors.affiliation: Department of Immunology, Great Ormond Street Hospital for Children, London, United Kingdom.
authors.forename: Austen J J
authors.initials: AJJ
authors.lastname: Worth
authors.affiliation: Cincinnati Children's Hospital Medical Center, University of Cincinnati Medical School, Cincinnati, Ohio.
authors.forename: Jacob
authors.initials: J
authors.lastname: Blessing
authors.affiliation: Department of Internal Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Frank
authors.initials: F
authors.lastname: Van de Veerdonk
authors.affiliation: Pediatric Hematology, Oncology and Stem Cell Transplantation, Dr. von Hauner University Children's Hospital, Ludwig-Maximilians-Universität, Munich, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Feuchtinger
authors.affiliation: Department of Immunology, "Aghia Sophia" Children's Hospital, Athens, Greece.
authors.forename: Maria
authors.initials: M
authors.lastname: Kanariou
authors.affiliation: Department of Pathology, University Hospital Freiburg, Freiburg, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Schmitt-Graeff
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Sophie
authors.initials: S
authors.lastname: Jung
authors.affiliation: UCL Centre for Immunodeficiency, Royal Free Hospital Foundation Trust, London, United Kingdom.
authors.forename: Suranjith
authors.initials: S
authors.lastname: Seneviratne
authors.affiliation: UCL Centre for Immunodeficiency, Royal Free Hospital Foundation Trust, London, United Kingdom.
authors.forename: Siobhan
authors.initials: S
authors.lastname: Burns
authors.affiliation: Division of Immunology and Infectious Disease, University Childrens Hospital Munich, Munich, Germany.
authors.forename: Bernd H
authors.initials: BH
authors.lastname: Belohradsky
authors.affiliation: Research Center for Immunodeficiencies, Children's Medical Center, and the Department of Immunology, School of Medicine Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Nima
authors.initials: N
authors.lastname: Rezaei
authors.affiliation: Division for Stem Cell Transplantation and Immunology, Department for Children and Adolescents Medicine, University Hospital Frankfurt, Goethe University Frankfurt am Main, Frankfurt, Germany.
authors.forename: Shahrzad
authors.initials: S
authors.lastname: Bakhtiar
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany; Center for Pediatrics and Adolescent Medicine, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Speckmann
authors.affiliation: Cincinnati Children's Hospital Medical Center, University of Cincinnati Medical School, Cincinnati, Ohio.
authors.forename: Michael
authors.initials: M
authors.lastname: Jordan
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany; UCL Centre for Immunodeficiency, Royal Free Hospital Foundation Trust, London, United Kingdom. Electronic address: bodo.grimbacher@uniklinik-freiburg.de.
authors.forename: Bodo
authors.initials: B
authors.lastname: Grimbacher
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D000293:Adolescent; D001402:B-Lymphocytes / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007223:Infant; D008297:Male; D009154:Mutation; D010641:Phenotype; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D007166:Immunosuppressive Agents; C428703:LRBA protein, human
keywords: LPS-responsive beige-like anchor protein; autoimmunity; common variable Immunodeficiency; enteropathy; hypogammaglobulinemia; lymphoproliferation; primary immunodeficiency