The extended phenotype of LPS-responsive beige-like anchor protein (LRBA) deficiency

• Published in: Journal of allergy and clinical immunology Vol. 137; no. 1; pp. 223 - 230
• Main Authors: Gámez-Díaz, Laura, August, Dietrich, Stepensky, Polina, Revel-Vilk, Shoshana, Seidel, Markus G., Noriko, Mitsuiki, Morio, Tomohiro, Worth, Austen J.J., Blessing, Jacob, Van de Veerdonk, Frank, Feuchtinger, Tobias, Kanariou, Maria, Schmitt-Graeff, Annette, Jung, Sophie, Seneviratne, Suranjith, Burns, Siobhan, Belohradsky, Bernd H., Rezaei, Nima, Bakhtiar, Shahrzad, Speckmann, Carsten, Jordan, Michael, Grimbacher, Bodo
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2016; Elsevier Limited; Elsevier
• Subjects: Adaptor Proteins, Signal Transducing - deficiency; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Adolescent; Allergy and Immunology; Apoptosis; autoimmunity; B-Lymphocytes - immunology; Child; Child, Preschool; common variable Immunodeficiency; enteropathy; Female; Genotype & phenotype; Hematopoietic Stem Cell Transplantation; Humans; hypogammaglobulinemia; Immunologic Deficiency Syndromes - drug therapy; Immunologic Deficiency Syndromes - immunology; Immunologic Deficiency Syndromes - metabolism; Immunologic Deficiency Syndromes - therapy; Immunosuppressive Agents - therapeutic use; Infant; Infections; Inflammatory bowel disease; Kinases; Life Sciences; LPS-responsive beige-like anchor protein; lymphoproliferation; Male; Mutation; Patients; Pharmaceutical sciences; Phenotype; primary immunodeficiency; Protein expression; Proteins; Rodents; Siblings; T-Lymphocytes - immunology; ALPS-Ph; ITP; LRBA; LPS-responsive beige-like anchor protein; Treg; IBD; hypogammaglobulinemia; ALPS; CVID; autoimmunity; common variable Immunodeficiency; enteropathy; primary immunodeficiency; IPEX; lymphoproliferation; HSCT; Autoimmune lymphoproliferative syndrome of undetermined genetic cause; Idiopathic thrombocytopenic purpura; Inflammatory bowel disease; Autoimmune lymphoproliferative syndrome; Regulatory T; Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome; Hematopoietic stem cell transplantation
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2015.09.025

LPS-responsive beige-like anchor protein (LRBA) deficiency is a primary immunodeficiency caused by biallelic mutations in LRBA that abolish LRBA protein expression. We sought to report the extended phenotype of LRBA deficiency in a cohort of 22 LRBA-deficient patients. Clinical criteria, protein detection, and genetic sequencing were applied to diagnose LRBA deficiency. 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. This report describes the largest cohort of patients with LRBA deficiency and offers guidelines for physicians to identify LRBA deficiency, supporting appropriate clinical management.