Nima Rezaei, Asghar Aghamohammadi, Luigi D. Notarangelo (Eds.) Primary Immunodeficiency Diseases Nima Rezaei Asghar Aghamohammadi • Luigi D. Notarangelo (Eds.)

Primary Immunodeficiency Diseases

Definition, Diagnosis, and Management

With 55 Figures, mostly in Color Editor-in-Chief Nima Rezaei , Asthma and Allergy Research Institute Children’s Medical Center Hospital University of Medical Sciences Tehran 14194 and Section of Infection, Inflammation and Immunity School of and Biomedical Sciences The University of Sheffield S10 2RX, Sheffield UK

Editorial Consultants Asghar Aghamohammadi Division of Allergy and Clinical Immunology Children’s Medical Center Hospital Tehran University of Medical Sciences Tehran 14194 Iran

Luigi D. Notarangelo Division of Immunology Children’s Hospital Harvard Medical School Boston, MA 02115 USA

ISBN 978-3-540-78537-8 e-ISBN 978-3-540-78936-9

Library of Congress Control Number: 2008932110

© 2008 Springer-Verlag Berlin Heidelberg

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5 4 3 2 1 0 springer.com Dedication

This book would not have been possible without the continuous encouragement by our parents and our wives, Maryam, Soheila and Evelina. We wish to dedicate it to our children, Ariana, Hamid Reza, Fatemeh, Claudio, Marco and Giulia, with the hope that progress in diagnosis and management of these diseases may result in improved survival and quality of life for the next generations, and at the same time that international collaboration in research will happen without barriers. Whatever we have learnt, comes from our mentors. This book is therefore also dedicated to all of them, but most importantly to our patients and their families whose continuous support has guided us during the years. Foreword

This new text on Primary Immunodeficiency with a recognised authority in the subject. It is a Diseases covers all aspects of these fascinating disor- tribute to the rapid establishment of facilities in ders. So much basic immunology has been learned Tehran to both diagnose and treat such patients from studies of these patients and so much more has that this book could be written in record time thus still to be understood. In addition, we know little about ensuring that it is up-to-date as well as practical. the prevalence of these genetic disorders in any coun- The wide coverage of all aspects of primary immu- try. There is also a need to increase awareness of the nodeficiency diseases provides a comprehensive text conditions if we are to be able to define the resource and will serve as a tool for experts who care for these requirements for diagnosis, genetic counselling and patients in other geographical areas and who wish to treatment in the future. spread awareness and understanding of this rapidly The recent appreciation of these conditions in expanding field. Iran and the flood of papers describing patients with primary immunodeficiency diseases make it Helen Chapel timely that many chapters in this volume should be Raif Geha authored by an Iranian investigator in combination Hans Ochs Preface

Primary immunodeficiency diseases (PID) are a group disease are discussed separately. Syndromic immuno- of inborn disorders with defects in one or more com- deficiencies are briefly presented in chapter 10, whilst ponents of the immune system, characterized by some of them are explained in greater detail in other increased incidence of infections, autoimmunity and chapters. Although management of the various forms of malignancies. Although primary immunodeficiency PID is discussed in chapters 2-9, the global therapeutic diseases seem to be rare, the number of diagnosed approach to common PID represents the focus of dis- patients is growing up in the recent years and more cussion in chapter 11. than 150 different forms of PID are now known. Yet, The book is the result of valuable contributions from because of inadequate medical awareness, a significant more than 40 senior and junior scientists in this field number of patients with PID are not recognized or are from more than 30 universities worldwide. We would diagnosed late. This latency leads to an increased rate like to acknowledge the expertise of all contributors, of morbidity and mortality among the affected indi- for generously giving their time and considerable viduals. effort in preparing their respective chapters. We are Our understanding about PID is rapidly improv- also grateful to Springer for giving us the opportunity ing, and this may facilitate the accuracy of diagno- to publish this book. sis and efficiency of management. This book is an We hope that this book will be comprehensible, attempt to gather the most recent advances in this cogent, and manageable for physicians and nurses, field, and tries to provide a concise and structured who wish to learn more about primary immunodefi- review of hitherto known PID. Although the ulti- ciency diseases. Moreover, it is our hope that the book mate orientation of the book is toward practical will represent a useful resource for doctors in training as diagnosis and management, the pathophysiology of well as for specialists in clinical decision-making and diseases is also discussed. For this purpose, this book treatment planning. consists of 11 chapters. The first chapter gives an over- view on PID and presents a classification of these dis- Nima Rezaei orders. In chapters 2-9, definition, etiology, clinical Asghar Aghamohammadi manifestations, diagnosis, and management of each Luigi Notarangelo Contents

1 An Introduction to Primary 2.2 T-B+ Severe Combined Immunodeficiency Immunodeficiency Diseases ...... 1 (g c Deficiency, JAK3 Deficiency, IL7-Rg Deficiency, CD45 Deficiency, CD3g/ Nima Rezaei, Francisco A. Bonilla, CD3l/CD3e/CD3x Deficiencies) ...... 42 Kathleen E. Sullivan, Esther de Vries, 2.2.1 Definition ...... 42 and Jordan S. Orange 2.2.2 Etiology ...... 42 1.1 Definition ...... 1 2.2.3 Clinical Manifestations ...... 44 1.1.1 Background ...... 1 2.2.4 Diagnosis ...... 45 1.1.2 History...... 2 2.2.5 Management ...... 46 1.1.3 Registries ...... 2 2.3 T-B- Severe Combined Immunodeficiency 1.2 Etiology ...... 2 (RAG1/2 Deficiencies, Artemis 1.2.1 Classification...... 2 Deficiency, ADA Deficiency) ...... 48 1.2.2 Genetic Defects ...... 11 2.3.1 Definition ...... 48 1.2.3 Pathophysiology ...... 12 2.3.2 Etiology ...... 49 1.3 Clinical Manifestations...... 14 2.3.3 Clinical Manifestations ...... 52 1.3.1 Infections...... 14 2.3.4 Diagnosis ...... 52 1.3.2 Autoimmunity ...... 15 2.3.5 Management ...... 52 1.3.3 Malignancies ...... 19 2.4 Omenn Syndrome...... 53 1.3.4 Other Manifestations ...... 19 2.4.1 Definition ...... 53 1.4 Diagnosis ...... 20 2.4.2 Etiology ...... 53 1.4.1 Warning Signs and Symptoms. . . . 20 2.4.3 Clinical Manifestations ...... 53 1.4.2 Diagnostic Approach ...... 21 2.4.4 Diagnosis ...... 53 1.4.3 Laboratory Tests ...... 24 2.4.5 Management ...... 54 1.5 Management ...... 25 2.5 DNA Ligase IV Deficiency ...... 54 1.5.1 General Considerations ...... 25 2.5.1 Definition ...... 54 1.5.2 Vaccination ...... 26 2.5.2 Etiology ...... 54 1.5.3 Antibiotics ...... 27 2.5.3 Clinical Manifestations ...... 54 1.5.4 Immunoglobulin Replacement 2.5.4 Diagnosis ...... 55 Therapy ...... 28 2.5.5 Management ...... 55 1.5.5 Transplantation...... 28 2.6 Cernunnos Deficiency ...... 55 1.5.6 Gene Therapy ...... 29 2.6.1 Definition ...... 55 1.5.7 Adjunct Therapies ...... 29 2.6.2 Etiology ...... 55 2.6.3 Clinical Manifestations ...... 55 2 Combined T and B Cell 2.6.4 Diagnosis ...... 55 Immunodeficiencies ...... 39 2.6.5 Management ...... 56 2.7 Purine Nucleoside Phosphorylase Françoise Le Deist, Despina Moshous, Steven J. Howe, (PNP) Deficiency ...... 56 Amit Nahum, Fotini D. Kavadas, Elana Lavine, 2.7.1 Definition ...... 56 Chaim M. Roifman, and Alain Fischer 2.7.2 Etiology ...... 56 2.7.3 Clinical Manifestations ...... 57 2.1 Introduction ...... 39 XII Contents

2.7.4 Diagnosis ...... 58 2.14.4 Diagnosis ...... 73 2.7.5 Management...... 58 2.14.5 Management...... 74 2.8 Immunoglobulin Class Switch 2.15 CD25 Deficiency...... 74 Recombination Deficiencies (affecting 2.15.1 Definition ...... 74 CD40–CD40L) (CD40 ligand 2.15.2 Etiology...... 74 Deficiency, CD40 Deficiency) ...... 59 2.15.3 Clinical Manifestations ...... 75 2.8.1 Definition ...... 59 2.15.4 Diagnosis ...... 75 2.8.2 Etiology...... 59 2.15.5 Management...... 76 2.8.3 Clinical Manifestations ...... 60 2.16 STAT5B Deficiency...... 76 2.8.4 Diagnosis ...... 61 2.16.1 Definition ...... 76 2.8.5 Management...... 61 2.16.2 Etiology...... 76 2.9 MHC Class II Deficiency (CIITA 2.16.3 Clinical Manifestations ...... 77 Deficiency, RFX5 Deficiency, RFXAP 2.16.4 Diagnosis ...... 77 Deficiency, RFXANK Deficiency) ...... 62 2.16.5 Management...... 78 2.9.1 Definition ...... 62 2.9.2 Etiology...... 62 3 Predominantly Antibody 2.9.3 Clinical Manifestations ...... 63 Deficiencies ...... 97 2.9.4 Diagnosis ...... 64 2.9.5 Management...... 64 Asghar Aghamohammadi, Vassilios Lougaris, 2.10 MHC Class I Deficiency (TAP1/2 Alessandro Plebani, Toshio Miyawaki, Deficiencies, Tapasin Deficiency) ...... 65 Anne Durandy, and Lennart Hammarström 2.10.1 Definition ...... 65 3.1 Introduction ...... 97 2.10.2 Etiology...... 65 3.2 Agammaglobulinemia with Absent 2.10.3 Clinical Manifestations ...... 66 B Cells (Btk Deficiency, m Heavy Chain 2.10.4 Diagnosis ...... 67 Deficiency, l5/14.1 Deficiency, 2.10.5 Management...... 67 Iga Deficiency, Igb Deficiency, BLNK 2.11 CD8 Deficiency (CD8a Chain Defect, Deficiency, LRRC8 Deficiency, Other ZAP-70 Deficiency) ...... 68 Forms of Agammaglobulinemia) ...... 99 2.11.1 Definition ...... 68 3.2.1 Definition ...... 99 2.11.2 Etiology...... 68 3.2.2 Etiology...... 99 2.11.3 Clinical Manifestations ...... 69 3.2.3 Clinical Manifestations ...... 101 2.11.4 Diagnosis ...... 69 3.2.4 Diagnosis ...... 104 2.11.5 Management...... 70 3.2.5 Management...... 104 2.12 CD4 Deficiency (p56lck Deficiency, 3.3 Hypogammaglobulinemia with Idiopathic CD4 Lymphopenia)...... 70 Normal/Low Number of B Cells 2.12.1 Definition ...... 70 (Common Variable 2.12.2 Etiology...... 70 Immunodeficiency, ICOS Deficiency, 2.12.3 Clinical Manifestations ...... 71 TACI Deficiency, CD19 Deficiency, 2.12.4 Diagnosis ...... 71 Other Forms of 2.12.5 Management...... 71 Hypogammaglobulinemia) ...... 105 2.13 CRAC Deficiency ...... 72 3.3.1 Definition ...... 105 2.13.1 Definition ...... 72 3.3.2 Etiology...... 105 2.13.2 Etiology...... 72 3.3.3 Clinical Manifestations ...... 108 2.13.3 Clinical 3.3.4 Diagnosis ...... 110 Manifestations ...... 72 3.3.5 Management...... 110 2.13.4 Diagnosis ...... 72 3.4 Immunoglobulin Class Switch 2.13.5 Management...... 73 Recombination Deficiencies (Due 2.14 Winged-Helix-Nude (WHN) to Intrinsic B Cell Defects) Deficiency ...... 73 (AID Deficiency, UNG Deficiency, 2.14.1 Definition ...... 73 Other CSR Selective Deficiencies)...... 111 2.14.2 Etiology...... 73 3.4.1 Definition ...... 111 2.14.3 Clinical Manifestations ...... 73 3.4.2 Etiology...... 111 Contents XIII

3.4.3 Clinical Manifestations ...... 113 4.3 Cyclic Neutropenia...... 135 3.4.4 Diagnosis ...... 113 4.3.1 Definition ...... 135 3.4.5 Management ...... 113 4.3.2 Etiology...... 135 3.5 Selective IgA Deficiency ...... 113 4.3.3 Clinical 3.5.1 Definition ...... 113 Manifestations ...... 136 3.5.2 Etiology ...... 114 4.3.4 Diagnosis ...... 136 3.5.3 Clinical Manifestations ...... 114 4.3.5 Management...... 136 3.5.4 Diagnosis ...... 115 4.4 Leukocyte Adhesion Deficiency 3.5.5 Management ...... 115 (LAD Types 1–3) ...... 136 3.6 Other Immunoglobulin Isotypes 4.4.1 Definition ...... 136 or Light Chain Deficiencies (Isolated 4.4.2 Etiology...... 137 IgG Subclass Deficiency, IgA with 4.4.3 Clinical Manifestations ...... 137 IgG Subclass Deficiency, Ig Heavy 4.4.4 Diagnosis ...... 139 Chain Deletions, k Light Chain 4.4.5 Management...... 139 Deficiency) ...... 116 4.5 RAC-2 Deficiency...... 141 3.6.1 Definition ...... 116 4.5.1 Definition ...... 141 3.6.2 Etiology ...... 116 4.5.2 Etiology...... 141 3.6.3 Clinical 4.5.3 Clinical Manifestations ...... 141 Manifestations...... 116 4.5.4 Diagnosis ...... 141 3.6.4 Diagnosis ...... 117 4.5.5 Management...... 141 3.6.5 Management ...... 117 4.6 β-Actin Deficiency ...... 141 3.7 Specific Antibody Deficiency with 4.6.1 Definition ...... 141 Normal Immunoglobulin 4.6.2 Etiology...... 141 Concentrations ...... 117 4.6.3 Clinical Manifestations ...... 142 3.7.1 Definition ...... 117 4.6.4 Diagnosis ...... 143 3.7.2 Etiology ...... 117 4.6.5 Management...... 143 3.7.3 Clinical Manifestations ...... 118 4.7 Chronic Granulomatous Disease 3.7.4 Diagnosis ...... 118 (CGD) (gp91 phox Deficiency, p22 phox 3.7.5 Management ...... 118 Deficiency, p47 phox Deficiency, p67 phox 3.8 Transient Hypogammaglobulinemia Deficiency)...... 143 of Infancy...... 118 4.7.1 Definition ...... 143 3.8.1 Definition ...... 118 4.7.2 Etiology...... 143 3.8.2 Etiology ...... 118 4.7.3 Clinical Manifestations ...... 144 3.8.3 Clinical Manifestations ...... 118 4.7.4 Diagnosis ...... 148 3.8.4 Diagnosis ...... 119 4.7.5 Management...... 149 3.8.5 Management ...... 119 4.8 Neutrophil G-6PD Deficiency ...... 152 4 Phagocytes Defects ...... 131 4.8.1 Definition ...... 152 4.8.2 Etiology...... 153 Uwe Wintergerst, Sergio D. Rosenzweig, 4.8.3 Clinical Manifestations ...... 153 Mario Abinun, Harry L. Malech, 4.8.4 Diagnosis ...... 153 Steven M. Holland, and Nima Rezaei 4.8.5 Management...... 153 4.1 Introduction ...... 131 4.9 Myeloperoxidase 4.2 Severe Congenital Neutropenias Deficiency ...... 153 (ELA2 Deficiency, GFI1 Deficiency, 4.9.1 Definition ...... 153 HAX1 Deficiency, CSF3R Deficiency, 4.9.2 Etiology...... 153 Neutropenia with Myelodysplasia) ...... 131 4.9.3 Clinical Manifestations ...... 153 4.2.1 Definition ...... 131 4.9.4 Diagnosis ...... 154 4.2.2 Etiology ...... 132 4.9.5 Management...... 154 4.2.3 Clinical Manifestations ...... 134 4.10 Specific Granule Deficiency...... 154 4.2.4 Diagnosis ...... 134 4.10.1 Definition ...... 154 4.2.5 Management ...... 134 4.10.2 Etiology...... 154 XIV Contents

4.10.3 Clinical Manifestations ...... 154 5.4.4 Diagnosis ...... 177 4.10.4 Diagnosis ...... 154 5.4.5 Management ...... 178 4.10.5 Management...... 155 5.5 Autoimmune Lymphoproliferative 4.11 Shwachman–Diamond Syndrome . . . . 155 Syndrome (ALPS) (ALPS Ia, Ib, IIa, 4.11.1 Definition ...... 155 IIb, III) ...... 178 4.11.2 Etiology...... 155 5.5.1 Definition ...... 178 4.11.3 Clinical Manifestations ...... 156 5.5.2 Etiology ...... 178 4.11.4 Diagnosis ...... 156 5.5.3 Clinical Manifestations ...... 180 4.11.5 Management...... 157 5.5.4 Diagnosis ...... 180 4.12 Localised Juvenile Periodontitis ...... 158 5.5.5 Management ...... 181 4.12.1 Definition ...... 158 5.6 Autoimmune Polyendocrinopathy 4.12.2 Etiology...... 158 with Candidiasis and Ectodermal 4.12.3 Clinical Manifestations ...... 158 Dystrophy (APECED)...... 182 4.12.4 Diagnosis ...... 158 5.6.1 Definition ...... 182 4.12.5 Management...... 158 5.6.2 Etiology ...... 182 4.13 Papillon–Lefèvre Syndrome...... 158 5.6.3 Clinical Manifestations ...... 182 4.13.1 Definition ...... 158 5.6.4 Diagnosis ...... 183 4.13.2 Etiology...... 158 5.6.5 Management ...... 184 4.13.3 Clinical Manifestations ...... 159 5.7 Immunodysregulation, 4.13.4 Diagnosis ...... 159 Polyendocrinopathy, Enteropathy, 4.13.5 Management...... 159 X-Linked (IPEX) ...... 184 5.7.1 Definition ...... 184 5 Genetic Disorders of Immune 5.7.2 Etiology ...... 184 Regulation ...... 167 5.7.3 Clinical Manifestations ...... 185 5.7.4 Diagnosis ...... 186 Carsten Speckmann, Jan Rohr, 5.7.5 Management ...... 186 and Stephan Ehl 5.1 Introduction ...... 167 6 Defects in Innate Immunity: Receptors and Signaling Components ...... 195 5.2 Familial Hemophagocytic Lymphohistiocytosis (Perforin Deficiency, Nima Parvaneh, Joachim Roesler, MUNC13-4 Deficiency, Syntaxin 11 Steven M. Holland, and Tim Niehues Deficiency) ...... 168 5.2.1 Definition ...... 168 6.1 Introduction ...... 195 5.2.2 Etiology ...... 168 6.2 Defective Toll-Like Receptor 5.2.3 Clinical Manifestations ...... 169 (TLR) Signaling Without 5.2.4 Diagnosis ...... 169 Ectodermal Dysplasia (IRAK-4 5.2.5 Management ...... 171 Deficiency, TLR3 Deficiency, 5.3 Immunodeficiency with Hypopigmentation UNC-93B Deficiency) ...... 196 (Chediak-Higashi Syndrome, Griscelli 6.2.1 Definition ...... 196 Syndrome, Type II, Hermansky-Pudlak 6.2.2 Etiology ...... 198 Syndrome, Type II, p14 Deficiency)...... 172 6.2.3 Clinical Manifestations ...... 198 5.3.1 Definition ...... 172 6.2.4 Diagnosis ...... 198 5.3.2 Etiology ...... 172 6.2.5 Management ...... 199 5.3.3 Clinical Manifestations ...... 173 6.3 Defective Toll-Like Receptor (TLR) 5.3.4 Diagnosis ...... 173 Signaling with Ectodermal Dysplasia 5.3.5 Management ...... 174 (XL- and AD-Anhidrotic Ectodermal 5.4 X-Linked Lymphoproliferative Dysplasias with Immunodeficiency) . . . . . 199 Syndrome (XLP) (SAP Deficiency, 6.3.1 Definition ...... 199 XIAP Deficiency) ...... 175 6.3.2 Etiology ...... 199 5.4.1 Definition ...... 175 6.3.3 Clinical Manifestations ...... 200 5.4.2 Etiology ...... 175 6.3.4 Diagnosis ...... 201 5.4.3 Clinical Manifestations ...... 176 6.3.5 Management ...... 201 Contents XV

6.4 Mendelian Susceptibility to 7.4.4 Diagnosis ...... 222 Mycobacterial Diseases (IFN-g 7.4.5 Management ...... 223 Receptor 1/2 Deficiencies, IL-12/23 7.5 Cryopyrin-Associated Periodic Syndrome Receptor b1 Chain Deficiency, (CAPS) (Chronic Infantile Neurological IL-12p40 Deficiency, STAT1 Deficiency, Cutaneous Articular Syndrome, LZ-NEMO Deficiency) ...... 201 Muckle–Wells Syndrome, Familial Cold 6.4.1 Definition ...... 201 Autoinflammatory Syndrome) ...... 223 6.4.2 Etiology ...... 202 7.5.1 Definition ...... 223 6.4.3 Clinical Manifestations ...... 203 7.5.2 Etiology ...... 223 6.4.4 Diagnosis ...... 203 7.5.3 Clinical Manifestations ...... 223 6.4.5 Management ...... 204 7.5.4 Diagnosis ...... 224 6.5 Warts, Hypogammaglobulinemia, 7.5.5 Management ...... 224 Infections, Myelokathexis (WHIM) 7.6 Blau Syndrome ...... 224 Syndrome...... 205 7.6.1 Definition ...... 224 6.5.1 Definition ...... 205 7.6.2 Etiology ...... 224 6.5.2 Etiology ...... 205 7.6.3 Clinical Manifestations ...... 225 6.5.3 Clinical Manifestations ...... 205 7.6.4 Diagnosis ...... 225 6.5.4 Diagnosis ...... 206 7.6.5 Management ...... 225 6.5.5 Management ...... 206 7.7 Pyogenic Arthritis, Pyoderma 6.6 Epidermodysplasia Verruciformis Gangrenosum and Acne Syndrome (EV Types 1,2) ...... 207 (PAPA) ...... 225 6.6.1 Definition ...... 207 7.7.1 Definition ...... 225 6.6.2 Etiology ...... 207 7.7.2 Etiology ...... 225 6.6.3 Clinical Manifestations ...... 207 7.7.3 Clinical Manifestations ...... 225 6.6.4 Diagnosis ...... 208 7.7.4 Diagnosis ...... 226 6.6.5 Management ...... 208 7.7.5 Management ...... 226 7.8 Multifactorial/Polygenic 7 Autoinflammatory Disorders...... 215 Autoinflammatory Diseases ...... 226 7.8.1 Periodic Fever, Aphtous Stomatitis, Stefan Berg and Anders Fasth Pharyngitis and Cervical 7.1 Introduction ...... 215 Adenitis (PFAPA) ...... 226 7.2 Familial Mediterranean Fever (FMF) . . . 217 7.8.2 Systemic Onset Juvenile 7.2.1 Definition ...... 217 Idiopathic Arthritis 7.2.2 Etiology ...... 218 (SoJIA)...... 227 7.2.3 Clinical Manifestations ...... 218 7.8.3 Adult-Onset Still’s Disease 7.2.4 Diagnosis ...... 219 (AOSD) ...... 227 7.2.5 Management ...... 219 7.8.4 Chronic Recurrent Multifocal 7.3 Mevalonate Kinase Deficiency (MKD) Osteomyelitis (CRMO) ...... 227 (Hyperimmunoglobulinemia D 7.8.5 Crohn’s Disease (CD)...... 227 and Periodic Fever Syndrome, 7.8.6 Behçet’s Disease (BD)...... 227 Mevalonic aciduria)...... 220 7.8.7 “Undifferentiated” ...... 228 7.3.1 Definition ...... 220 8 Complement Deficiencies ...... 235 7.3.2 Etiology ...... 220 7.3.3 Clinical Manifestations ...... 220 Maryam Mahmoudi, Tom Eirik Mollnes, 7.3.4 Diagnosis ...... 221 Taco W. Kuijpers, and Dirk Roos 7.3.5 Management ...... 221 7.4 Tumor Necrosis Factor Receptor- 8.1 Introduction ...... 235 Associated Periodic Syndrome 8.2 Deficiencies of Classical Pathway (TRAPS)...... 221 Components (C1q/C1r/C1s 7.4.1 Definition ...... 221 Deficiencies, C4 Deficiency, C2 7.4.2 Etiology ...... 222 Deficiency) ...... 238 7.4.3 Clinical Manifestations ...... 222 8.2.1 Definition ...... 238 XVI Contents

8.2.2 Etiology ...... 238 9.2 Other Syndromes Associated 8.2.3 Clinical Manifestations ...... 239 with Defective DNA Repair (Ataxia- 8.2.4 Diagnosis ...... 239 Telangiectasia, Ataxia-Like Syndrome, 8.2.5 Management ...... 239 Nijmegen Breakage Syndrome, 8.3 Deficiencies of Lectin Pathway Bloom’s Syndrome, Components (MBL Deficiency, ICF Syndrome) ...... 252 MASP2 Deficiency) ...... 239 9.2.1 Definition ...... 252 8.3.1 Definition ...... 239 9.2.2 Etiology ...... 253 8.3.2 Etiology ...... 240 9.2.3 Clinical Manifestations ...... 254 8.3.3 Clinical Manifestations ...... 240 9.2.4 Diagnosis ...... 257 8.3.4 Diagnosis ...... 240 9.2.5 Management ...... 257 8.3.5 Management ...... 240 9.3 Di George Syndrome ...... 258 8.4 Deficiencies of Alternative Pathway 9.3.1 Definition ...... 258 Components (Factor D Deficiency, 9.3.2 Etiology ...... 258 Properdin Deficiency) ...... 240 9.3.3 Clinical Manifestations ...... 259 8.4.1 Definition ...... 240 9.3.4 Diagnosis ...... 261 8.4.2 Etiology ...... 241 9.3.5 Management ...... 261 8.4.3 Clinical Manifestations ...... 241 9.4 Wiskott-Aldrich Syndrome ...... 262 8.4.4 Diagnosis ...... 241 9.4.1 Definition ...... 262 8.4.5 Management ...... 241 9.4.2 Etiology ...... 262 8.5 Deficiency of Complement 9.4.3 Clinical Manifestations ...... 264 Component C3 ...... 241 9.4.4 Diagnosis ...... 265 8.5.1 Definition ...... 241 9.4.5 Management ...... 266 8.5.2 Etiology ...... 242 9.5 Hyper-IgE Syndrome (Stat3 8.5.3 Clinical Manifestations ...... 242 Deficiency, Tyk2 Deficiency, HIES 8.5.4 Diagnosis ...... 242 with Unknown Origin) ...... 267 8.5.5 Management ...... 242 9.5.1 Definition ...... 267 8.6 Deficiencies of Terminal Pathway 9.5.2 Etiology ...... 267 Components (C5-9 Deficiencies) ...... 242 9.5.3 Clinical Manifestations ...... 267 8.6.1 Definition ...... 242 9.5.4 Diagnosis ...... 268 8.6.2 Etiology ...... 242 9.5.5 Management ...... 269 8.6.3 Clinical 9.6 Immuno-Osseous Dysplasias Manifestations...... 242 (Schimke Syndrome, Cartilage 8.6.4 Diagnosis ...... 242 Hair Hypoplasia) ...... 269 8.6.5 Management ...... 243 9.6.1 Definition ...... 269 8.7 Deficiencies of Complement Regulatory 9.6.2 Etiology ...... 270 Proteins (C1 Inhibitor Deficiency, 9.6.3 Clinical Manifestations ...... 271 Factor I Deficiency, Factor H Deficiency, 9.6.4 Diagnosis ...... 272 CD46 Deficiency, CD55 Deficiency, 9.6.5 Management ...... 272 CD59 Deficiency)...... 243 9.7 Chronic Mucocutaneous Candidiasis . . . 272 8.7.1 Definition ...... 243 9.7.1 Definition ...... 272 8.7.2 Etiology ...... 243 9.7.2 Etiology ...... 273 8.7.3 Clinical Manifestations ...... 244 9.7.3 Clinical Manifestations ...... 273 8.7.4 Diagnosis ...... 245 9.7.4 Diagnosis ...... 274 8.7.5 Management ...... 246 9.7.5 Management ...... 274 9.8 Netherton Syndrome ...... 274 9 Other Well-Defined 9.8.1 Definition ...... 274 Immunodeficiencies ...... 251 9.8.2 Etiology ...... 275 9.8.3 Clinical Manifestations ...... 275 Mehdi Yeganeh, Eleonora Gambineri, 9.8.4 Diagnosis ...... 276 Kamran Abolmaali, Banafshe Tamizifar, 9.8.5 Management ...... 276 and Teresa Español 9.9 Dyskeratosis Congenita and Høyeraal- 9.1 Introduction ...... 251 Hreidarsson Syndrome...... 276 Contents XVII

9.9.1 Definition ...... 276 10.4.10 OLEDAID Syndrome ...... 299 9.9.2 Etiology ...... 276 10.4.11 Dyskeratosis Congenita . . . . . 300 9.9.3 Clinical Manifestations . . . . . 277 10.4.12 Hermansky–Pudlak 9.9.4 Diagnosis...... 278 Syndrome, Type II ...... 300 9.9.5 Management...... 278 10.4.13 Poikiloderma with Neutropenia ...... 300 10 Syndromic Immunodeficiencies ...... 291 10.4.14 Acrodermatitis Enteropathica ...... 300 Jeffrey E. Ming and E. Richard Stiehm 10.4.15 Netherton Syndrome ...... 300 10.1 Introduction ...... 291 10.4.16 p14 Deficiency ...... 300 10.2 Syndromes Associated with 10.5 Syndromes Associated with Growth Deficiency ...... 293 Neurologic Dysfunction ...... 300 10.2.1 Cartilage Hair 10.5.1 Myotonic Dystrophy ...... 300 Hypoplasia ...... 294 10.5.2 Høyeraal–Hreidarsson 10.2.2 Schimke Immuno-osseous Syndrome ...... 301 Dysplasia ...... 294 10.5.3 Cohen Syndrome ...... 301 10.2.3 Short-Limb Skeletal 10.6 Inborn Errors of Metabolism Dysplasia with Combined Associated with Immunodeficiency ...... 294 Immunodeficiency ...... 301 10.2.4 Roifman Syndrome 10.6.1 Adenosine Deaminase (Roifman Syndrome 1) . . . . . 294 Deficiency ...... 301 10.2.5 Roifman–Costa Syndrome 10.6.2 Purine Nucleoside (Roifman Syndrome 2) ...... 294 Phosphorylase Deficiency . . . 301 10.2.6 Spondyloenchondrodysplasia 295 10.6.3 Leukocyte Adhesion 10.2.7 Growth Hormone Pathway Deficiency, Type 2...... 301 Defects...... 295 10.6.4 Congenital Disorders of 10.2.8 Kabuki Syndrome...... 295 Glycosylation, Type I ...... 302 10.2.9 CHARGE Association ...... 295 10.6.5 Glycogen Storage Disease 10.2.10 Rubinstein–Taybi Ib/Ic ...... 303 Syndrome ...... 295 10.6.6 Barth Syndrome ...... 303 10.2.11 Mulvihill–Smith 10.6.7 Galactosemia...... 303 Syndrome ...... 296 10.6.8 Branched-Chain Amino 10.3 Syndromes Associated with Acidurias ...... 303 Gastrointestinal Dysfunction ...... 296 10.6.9 Lysinuric Protein 10.3.1 Shwachman–Diamond Intolerance ...... 303 Syndrome ...... 298 10.7 Syndromes with Chromosome 10.3.2 Familial Intestinal Instability and/or Defective Polyatresia ...... 298 DNA Repair Associated with 10.3.3 Trichohepatoenteric Immunodeficiency ...... 303 Syndrome ...... 298 10.7.1 Nijmegen Breakage 10.4 Syndromes Associated with Cutaneous Syndrome ...... 303 Abnormalities ...... 298 10.7.2 Bloom Syndrome ...... 304 10.4.1 Wiskott–Aldrich Syndrome. . 298 10.7.3 Ataxia-Telangiectasia ...... 304 10.4.2 Chediak–Higashi Syndrome . 298 10.7.4 DNA Ligase IV Deficiency. . . 305 10.4.3 Griscelli Syndrome, Type II. . 298 10.7.5 ICF Syndrome...... 305 10.4.4 Omenn Syndrome ...... 298 10.7.6 Fanconi Pancytopenia ...... 305 10.4.5 WHN Deficiency ...... 299 10.8 Syndromes Associated with 10.4.6 Papillon–Lefèvre Syndrome . 299 Chromosomal Abnormalities 10.4.7 WHIM Syndrome...... 299 of Number or Structure...... 305 10.4.8 Hypohidrotic/Anhidrotic 10.8.1 Deletions of 22q11 Ectodermal Dysplasia...... 299 and 10p13-p14 ...... 305 10.4.9 Incontinentia Pigmenti . . . . . 299 10.8.2 Trisomy 21...... 305 XVIII Contents

10.8.3 Partial Deletions of 11.4.3 Chronic Granulomatous Chromosome 4p...... 306 Disease...... 323 10.8.4 Turner Syndrome ...... 306 11.5 Therapy for Genetic Disorders of Immune Regulation...... 323 11 Treatment of Primary 11.5.1 Chediak-Higashi Immunodeficiency Diseases ...... 315 Syndrome ...... 323 11.5.2 Griscelli Syndrome, Hale Yarmohammadi Type II ...... 324 and Charlotte Cunningham-Rundles 11.5.3 X-Linked Lymphoproliferative 11.1 Introduction ...... 315 Syndrome ...... 324 11.2 Therapy for Combined T 11.6 Therapy for Defects in Innate and B Cell Immunodeficiencies . . . . . 315 Immunity: Receptors and Signaling 11.2.1 Severe Combined Components ...... 325 Immunodeficiency ...... 315 11.6.1 IRAK-4 Deficiency ...... 325 11.2.2 Immunoglobulin Class 11.6.2 Mendelian Susceptibility Switch Recombination to Mycobacterial Deficiencies (Affecting Diseases ...... 325 CD40-CD40L) ...... 317 11.6.3 Warts, Hypogammaglobulinemia, 11.2.3 MHC Class II Deficiency . . . . 318 Infections, Myelokathexis 11.3 Therapy for Predominantly (WHIM) Syndrome ...... 325 Antibody Deficiencies ...... 318 11.7 Therapy for Autoinflammatory 11.3.1 Agammaglobulinemia Disorders...... 325 with Absent B Cells ...... 318 11.7.1 Familial Mediterranean 11.3.2 Hypogammaglobulinemia Fever ...... 325 with Normal/Low Number 11.7.2 Other Autoinflammatory of B Cells ...... 319 Disorders...... 326 11.3.3 Immunoglobulin Class 11.8 Therapy for Complement Switch Recombination Deficiencies...... 326 Deficiencies (Due to 11.8.1 Deficiencies of Intrinsic B Cell Defects). . . . . 319 Classical, Lectin 11.3.4 Selective IgA and Alternative Pathways Deficiency ...... 320 Components ...... 326 11.3.5 Isolated IgG Subclass 11.8.2 Deficiencies of Terminal Deficiency ...... 321 Pathway Components ...... 326 11.3.6 Specific Antibody Deficiency 11.8.3 C1 Inhibitor Deficiency . . . . . 326 with Normal Immunoglobulin 11.9 Therapy for Other Well-Defined Concentrations ...... 321 Immunodeficiencies...... 326 11.3.7 Transient 11.9.1 Ataxia-Telangiectasia ...... 326 Hypogammaglobulinemia 11.9.2 Di George Syndrome ...... 327 of Infancy ...... 321 11.9.3 Wiskott-Aldrich 11.4 Therapy for Phagocytes Defects . . . . . 321 Syndrome ...... 328 11.4.1 Severe Congenital 11.9.4 Hyper-IgE Syndrome ...... 328 Neutropenias/Cyclic 11.9.5 Chronic Mucocutaneous Neutropenia ...... 321 Candidiasis ...... 328 11.4.2 Leukocyte Adhesion Index...... 335 Deficiency ...... 323 Contributors

Mario Abinun, MD Helen M. Chapel, MD Children’s BMT Unit Department of Immunology Newcastle General Hospital John Radcliffe Hospital NE4 6BE, Newcastle OX3 9DU, Oxford UK UK Chapter 4 Phagocytes Defects Foreword

Kamran Abolmaali, MD, MRCS Charlotte Cunningham-Rundles, MD, PhD Brigham and Women’s Hospital Department of Medicine Harvard Medical School Mount Sinai Medical Center Boston, MA 02115 New York, NY 10029 USA USA Section 9.6 Immuno-Osseous Dysplasias Chapter 11 Treatment of Primary Immunodeficiency Diseases Asghar Aghamohammadi, MD Division of Allergy and Clinical Immunology Esther de Vries, MD, PhD Children’s Medical Center Hospital Jeroen Bosch Hospital loc GZG Tehran University of Medical Sciences 5200ME `s-Hertogenbosch Tehran 14194 The Netherlands Iran Chapter 1 An Introduction to Primary Editorial Consultant Immunodeficiency Diseases Chapter 3 Predominantly Antibody Deficiencies Section 1.4 Diagnosis

Stefan Berg, MD, PhD Anne Durandy, MD, PhD Department of INSERM U768 Göteborg University Hôpital Necker-Enfants Malades The Queen Silvia Children’s Hospital 75015 Paris SE-416 85 Göteborg France Sweden Section 3.4 Immunoglobulin Class Switch Chapter 7 Autoinflammatory Disorders Recombination Deficiencies (due to Intrinsic B Cell Defects) Francisco A. Bonilla, MD, PhD Division of Immunology Stephan Ehl, MD Children’s Hospital Boston Center for Pediatrics and Adolescent Boston, MA 02115 Medicine USA 79106 Freiburg Chapter 1 An Introduction to Primary Germany Immunodeficiency Diseases Chapter 5 Genetic Disorders of Immune Section 1.2 Etiology Regulation XX Contributors

Teresa Español, MD, PhD Steven M. Holland, MD Immunology Unit Laboratory of Clinical Infectious Diseases Vall d’Hebron University Hospital National Institute of Allergy and 08035 Barcelona Infectious Diseases Spain National Institutes of Health Chapter 9 Other Well-Defined Immunodeficiencies Bethesda, MD 20892-1684 USA Anders Fasth, MD, PhD Section 4.7 Chronic Granulomatous Disease (CGD) Department of Pediatrics Chapter 6 Defects in Innate Immunity: Receptors and Göteborg University Signaling Components The Queen Silvia Children’s Hospital SE-416 85 Göteborg Steven J. Howe, PhD Sweden Molecular Immunology Unit Chapter 7 Autoinflammatory Disorders Institute of Child Health University College London Alain Fischer, MD, PhD WC1N 1EH, London Unité d’Immunologie et Hématologie UK Pédiatrique Section 2.3 T-B- Severe Combined Immunodeficiency Hôpital Necker-Enfants Malades Section 2.4 Omenn Syndrome 75015 Paris France Fotini D. Kavadas, MD, FRCPC Chapter 2 Combined T and B Cell Immunodeficiencies Division of Immunology and Allergy Department of Paediatrics Eleonora Gambineri, MD The Hospital for Sick Children Department of Pediatrics The University of Toronto University of Florence Toronto, Ontario M5G 1X8 “Anna Meyer” Children’s Hospital Canada 50132 Firenze Section 2.16 STAT5B Deficiency Italy Section 9.3 Di George Syndrome Taco W. Kuijpers, MD, PhD Section 9.4 Wiskott-Aldrich Syndrome Division of Pediatric Hematology, Immunology and Infectious diseases Raif S. Geha, MD Emma Children’s Hospital Division of Allergy/ Immunology/Rheumatology/ Academic Medical Center Dermatology University of Amsterdam Children’s Hospital 1105 AZ Amsterdam Harvard Medical School The Netherlands Boston, MA 02115 and Department of Blood Cell Research USA Sanquin Research and Landsteiner Foreword Laboratory University of Amsterdam Lennart Hammarström, MD, PhD 1066 CX Amsterdam Division of Clinical Immunology The Netherlands Department of Laboratory Medicine Chapter 8 Complement Deficiencies Karolinska Institute SE-141 86 Stockholm Elana Lavine, MD, FRCPC Sweden Division of Immunology and Allergy Section 3.3 Hypogammaglobulinemia with Normal/Low Department of Paediatrics Number of B Cells The Hospital for Sick Children The University of Toronto Toronto, Ontario M5G 1X8 Canada Section 2.7 Purine Nucleoside Phosphorylase (PNP) Deficiency Contributors XXI

Françoise Le Deist, MD, PhD Tom Eirik Mollnes, MD, PhD Department de Microbiologie et d’Immunologie Institute of Immunology Hospital Saint Justine Rikshospitalet University Hospital University of Montréal University of Oslo Montreal, Quebec H3T 1C5 N-0027 Oslo Canada Norway Section 2.8 Immunoglobulin Class Switch Chapter 8 Complement Deficiencies Recombination Deficiencies (affecting CD40-CD40L) Sections 2.9 and 2.10 MHC Class II and I Deficiency Despina Moshous, MD, PhD Sections 2.11 and 2.12 CD8 and CD4 Deficiency Unité d’Immunologie et Hématologie Section 2.13 CRAC Deficiency Pédiatrique Section 2.14 Winged-Helix-Nude (WHN) Deficiency AP-HP Hôpital Necker-Enfants Malades 75743 Paris Cedex 15 Vassilios Lougaris, MD France Department of Pediatrics Section 2.1 Introduction and Institute for Molecular Medicine “A. Nocivelli” Section 2.2 T-B+ Severe Combined University of Brescia 25123 Brescia Immunodeficiency Italy Section 2.5 DNA Ligase IV Deficiency Section 3.2 Agammaglobulinemia with Absent B Cells Section 2.6 Cernunnos Deficiency

Maryam Mahmoudi, MD Amit Nahum, MD, PhD Department of Nutrition and Biochemistry Division of Immunology and Allergy School of Public Health and Institute of Public Department of Paediatrics Health Research The Hospital for Sick Children Tehran University of Medical Sciences The University of Toronto Toronto, Tehran 14147 Ontario M5G 1X8 Iran Canada Chapter 8 Complement Deficiencies Section 2.15 CD25 Deficiency

Harry L. Malech, MD Tim Niehues, MD, PhD Laboratory of Host Defenses HELIOS Clinic Krefeld Genetic Immunotherapy Section Academic Hospital University of National Institute of Allergy and Infectious Diseases Düsseldorf National Institutes of Health Immunodeficiency and Pediatric Rheumatology Bethesda, MD 20892-1456 Center USA 47805 Krefeld Chapter 4 Phagocytes Defects Germany Chapter 6 Defects in Innate Immunity: Jeffrey E. Ming, MD, PhD Receptors and Signaling Components Department of Pediatrics Division of Human Genetics and Molecular Biology Luigi D. Notarangelo, MD The Children’s Hospital of Philadelphia Division of Immunology The University of Pennsylvania School of Medicine Children’s Hospital Philadelphia, PA 19104 Harvard Medical School USA Boston, MA 02115 Chapter 10 Syndromic Immunodeficiencies USA Editorial Consultant Toshio Miyawaki, MD, PhD Department of Pediatrics Hans D. Ochs, MD Faculty of Medicine Seattle Children’s Hospital Research Institute Toyama Medical and Pharmaceutical University Research Center for Immunity and Immunotherapy Toyama 930-0194 Seattle, WA 98101 Japan USA Chapter 3 Predominantly Antibody Deficiencies Foreword XXII Contributors

Jordan Orange, MD, PhD Jan Rohr, MD Division of Allergy and Immunology Center for Pediatrics and Adolescent The Children’s Hospital of Philadelphia Medicine University of Pennsylvania School of Medicine 79106 Freiburg Philadelphia, PA 19104 Germany USA Chapter 5 Genetic Disorders of Immune Regulation Chapter 1 An Introduction to Primary Immunodeficiency Diseases Chaim M. Roifman, MD, FRCPC Section 1.5 Management Division of Immunology and Allergy Department of Paediatrics Nima Parvaneh, MD The Hospital for Sick Children Department of Pediatrics The University of Toronto Children’s Medical Center Hospital Toronto, Ontario M5G 1X8 Tehran University of Medical Sciences Canada Tehran 14194 Section 2.7 Purine Nucleoside Phosphorylase (PNP) Iran Deficiency Chapter 6 Defects in Innate Immunity: Receptors Section 2.15 CD25 Deficiency and Signaling Components Section 2.16 STAT5B Deficiency

Alessandro Plebani, MD, PhD Dirk Roos, PhD Department of Pediatrics Department of Blood Cell Research and Institute for Molecular Medicine “A. Nocivelli” Sanquin Research and Landsteiner Laboratory University of Brescia Academic Medical Center 25123 Brescia University of Amsterdam Italy 1066 CX Amsterdam Section 3.2 Agammaglobulinemia with Absent The Netherlands B Cells Chapter 8 Complement Deficiencies

Nima Rezaei, MD Sergio D. Rosenzweig, MD, PhD Immunology, Asthma and Allergy Servicio de Inmunologia Research Institute Hospital Nacional de Pediatria J. P. Garrahan Children’s Medical Center Hospital Buenos Aires Tehran University of Medical Sciences Argentina Tehran 14194 Section 4.7 Chronic Granulomatous Disease (CGD) Iran and Carsten Speckmann, MD Section of Infection, Inflammation and Immunity Center for Pediatrics and Adolescent Medicine School of Medicine and Biomedical Sciences 79106 Freiburg The University of Sheffield Germany S10 2RX, Sheffield Chapter 5 Genetic Disorders of Immune Regulation UK Editor-in-Chief E. Richard Stiehm, MD Chapter 1 An Introduction to Primary Immunodeficiency UCLA School of Medicine Diseases Division of Immunology, Allergy Chapter 4 Phagocytes Defects and Rheumatology Department of Pediatrics Joachim Roesler, MD, PhD Mattel Children‘s Hospital at UCLA University Clinic Carl Gustav Carus Los Angeles, CA 90095 Department of Pediatrics USA 01307 Dresden Chapter 10 Syndromic Immunodeficiencies Germany Chapter 6 Defects in Innate Immunity: Receptors and Signaling Components Contributors XXIII

Kathleen E. Sullivan, MD, PhD Hale Yarmohammadi, MD, MPH Division of Allergy and Immunology Department of Medicine The Children’s Hospital of Philadelphia Mount Sinai Medical Center University of Pennsylvania School of Medicine New York, NY 10029 Philadelphia, PA 19104 USA USA Chapter 11 Treatment of Primary Immunodeficiency Chapter 1 An Introduction to Primary Diseases Immunodeficiency Diseases Section 1.3 Clinical Manifestations Mehdi Yeganeh, MD Immunology, Asthma and Allergy Banafshe Tamizifar, MD Research Institute Department of Dermatology Children’s Medical Center Hospital Razi Hospital Tehran University of Medical Sciences Tehran University of Medical Sciences Tehran 14194 Tehran 11996 Iran Iran Chapter 9 Other Well-Defined Immunodeficiencies Section 9.7 Chronic Mucocutaneous Candidiasis Section 9.2 Other Syndromes Associated with Defective Section 9.8 Netherton Syndrome DNA Repair Section 9.9 Dyskeratosis Congenita and Høyeraal- Section 9.5 Hyper-IgE Syndrome (HIES) Hreidarsson Syndrome

Uwe Wintergerst, MD University Children’s Hospital Department of Immunodeficiency Diseases 80337 Munich Germany Chapter 4 Phagocytes Defects Abbreviations

Ab Antibodies BCR B Cell Receptor AA Aplastic Anemia BD Behçet’s Disease AD Autosomal Dominant BLNK B Cell Linker ADA Adenosine Deaminase BMT Bone Marrow Transplantation ADHD Attention Deficit–Hyperactivity BS Bloom’s Syndrome Disorder BTK Bruton Tyrosine Kinase AFP Alpha-Fetoprotein C1INH C1 Inhibitor aHUS Atypical Familial Hemolytic Uremic C3NeF C3-Nephritic Factor Syndrome CAPS Cryopyrin-Associated Periodic AICDA Activation-Induced cytidine Syndrome Deaminase CARD15 Caspase Recruitment Domain Family 15 AID Activation-Induced Cytidine CBC Complete Blood Count Deaminase CBP CREB-Binding Protein AIR Autoinhibitory Region CD Crohn’s Disease AIRE Autoimmune Regulator CD40L CD40 Antigen Ligand ALPS Autoimmune Lymphoproliferative CDG Congenital Disorders of Glycosylation Syndrome CDGS Carbohydrate-Deficient Glycoprotein AMICAR Amino Caproic Acid Syndromes ANA Anti Nuclear Antibody CEBPE CCAAT/Enhancer-Binding Protein, AOSD Adult-Onset Still’s disease Epsilon AP Alternative Pathway CFD Complement Factor D APC Antigen-Presenting Cells CGD Chronic Granulomatous Disease APECED Autoimmune Polyendocrinopathy CHARGE Coloboma, Heart defects, Atresia of with Candidiasis and Ectodermal the choanae, Retardation of growth Dystrophy and development, Genital and urinary APRIL A Proliferation-Inducing Ligand abnormalities, Ear abnormalities and/ APS Autoimmune Polyendocrine or hearing loss Syndrome CHH Cartilage Hair Hypoplasia AR Autosomal Recessive CHS Chediak-Higashi Syndrome ASC Apoptosis-Associated Speck-Like CIITA Class II Transactivator Protein CINCA Chronic Infantile Neurological A-T Ataxia-Telangiectasia Cutaneous Articular Syndrome ATG Antithymocyte Globulin CLAD Canine LAD ATLD Ataxia-Telangiectasia-Like Disorder CLD Chronic Lung Disease ATM Ataxia-Telangiectasia Mutated CMC Chronic Mucocutaneous Candidiasis BAFF B Cell Activating Factor of the TNF CMO Chronic Multifocal Osteomyelitis Family CMV Cytomegalovirus BFFR BAFF Receptor CNS Central Nervous System BCG Bacille-Calmette-Guérin COMT Catechol-O-Methyltranferase BCMA B Cell Maturation Antigen CP Classical Pathway XXVI Abbreviations

CRAC Calcium++ Release-Activated Calcium GAF Gamma Activating Factor Channels GBD GTPase-Binding Domain CRACM1 Calcium Release-Activated Calcium G-CSF Granulocyte Colony-Stimulating Factor Modulator 1 GCSFR Granulocyte Colony-Stimulating Factor CRMO Chronic Recurrent Multifocal Receptor Osteomyelitis GM-CSF Granulocyte Macrophage Colony- CRP C-Reactive Protein Stimulating Factor CSA Colony Survival Assay GDP Guanosine Diphosphate CSF Colony Stimulating Factor GFI1 Growth Factor-Independent 1 CSR Class Switch Recombination GHBP Growth Hormone Binding Protein CTL CD8+ Cytotoxic T Cells GHD Growth Hormone Deficiency CTSC Cathepsin C GHI Growth Hormone Insensitivity CVID Common Variable Immunodeficiency GHR GH Receptor DAF Decay-Accelerating Factor GS Griscelli Syndrome DAG Diacylglycerol GSD Glycogen Storage Disease DC Dendritic Cells GTP Guanosine Triphosphate DCLRE1C DNA Cross-Link Repair Protein 1C GVHD Graft Versus Host Disease DGS Di George Syndrome HAE Hereditary Angioedema DHR Dihydrorhodamine-123 HAX1 HCLS1-Associated Protein X1 DISC Death Inducing Signaling Complex HH Høyeraal-Hreidarsson DMARD Disease Modifying Antirheumatic HIB Haemophilus influenzae Type B Vaccine Drugs HIDS Hyperimmunoglobulinemia D and DNT Double Negative T Cells Periodic Fever Syndrome DP Dominant Partial HIES Hyper-IgE Syndrome DPT Diphtheria, Pertussis, Tetanus Vaccine HIGM Hyper-IgM DSB Double Strand Breaks HIV Human Immunodeficiency Virus DTH Delayed-Type Hypersensitivity HLA Human Leukocyte Antigen EBNA Epstein-Barr Nuclear Antigen HLH Hemophagocytic Lymphohistiocytosis EBV Epstein-Barr Virus HPS Hermansky Pudlak Syndrome ECHO Enterocytopathic Human Orphan HPV Human Papiloma Virus EDA Ectodermal Dysplasia HR Homologous Recombination EGFR Epidermal Growth Factor Receptor HRCT High Resolution Computed ELA2 Elastase 2 Tomography ELISA Enzyme-Linked Immunosorbent Assay HSC Hematopoietic Stem Cell EM Environmental Mycobacteria HSCT Hematopoietic Stem Cell ER Endoplasmic Reticulum Transplantation ESR Erythrocyte Sedimentation Rate HSE Herpes Simplex-1 Encephalitis EV Epidermodysplasia Verruciformis HSV Herpes Simplex Virus FADD Fas-Associated Death Domain ICAM Intercellular Adhesion Molecule FCAS Familial Cold Autoinflammatory ICF Immunodeficiency, Centromeric Syndrome Region Instability, and Facial FCU Familial Cold Urticaria Anomalies FHL Familial Hemophagocytic ICL Idiopathic CD4+ T Lymphocytopenia Lymphohistiocytosis ICOS Inducible Costimulator FIM Fulminant Infectious Mononucleosis IFN-γ Interferon-Gamma FISH Fluorescence In Situ Hybridization IFNGR Interferon, Gamma, Receptor FMF Familial Mediterranean Fever Ig Immunoglobulin FNA Fine Needle Aspiration IGKC Immunoglobulin Kappa Constant FOXN1 Forkhead Box N1 ID Immunodeficiency FRP1 Formyl Peptide Receptor 1 IKK IkB Kinase FSGS Focal, Segmental Glomerulosclerosis IL Interleukin G6PD Glucose-6-Phosphate Dehydrogenase IL2RG IL-2 Receptor Gamma Abbreviations XXVII

IL7-R IL-7 Receptor MWS Muckle–Wells Syndrome ILC Ichthyosis Linearis Circumflexa MyD88 Myeloid Differentiation Factor-88 IPEX Immunodeficiency, NALP3 NACHT, Leucine-Rich Repeat- and Polyendocrinopathy, X-linked PYRIN Domain-Containing Protein 3 IR Ionizing Radiation NBS Nijmegen Breakage Syndrome IRAK Interleukin-1 Receptor-Associated NBT Nitroblue Tetrazolium Kinase NCF1 Neutrphil Cytosolic Factor 1 ITAMs Immunoreceptor Tyrosine-Based NEMO Nuclear Factor-kappa-B Essential Activation Motifs Modulator ITGB2 Integrin, Beta-2 NF Nuclear Factor ITP Idiopathic Thrombocytopenia NF-kB Nuclear Factor kappa B Purpura NFAT Nuclear Factor of Activated T-Cells IVIG Intravenous Immunoglobulin NHEJ Nonhomologous End Joining JAK3 Janus-Associated Kinase 3 NHL Non-Hodgkin Lymphoma JIA Juvenile Idiopathic Arthritis NK Natural Killer LAD Leukocyte Adhesion Deficiency NLR NOD-Like Receptor LCA Leukocyte-Common Antigen NOD Nucleotide-Binding and LCL Lymphoblastoid Cell Lines Oligomerization Domain LEF1 Lymphoid Enhancer-Binding Factor 1 NOMID Neonatal-Onset Multisystem LEKTI Lympho-Epithelial Kazal-Type Related Inflammatory Disease Inhibitor NSAID Nonsteroid Anti-Inflammatory Drugs LIG4 Ligase IV OLEDAID Osteopetrosis, Lymphedema, LIP Lymphoid Interstitial Pneumonitis Ectodermal Dysplasia, Anhidrotic LRR Leucine-Rich Repeat type, and Immune Deficiency LP Lectin Pathway OMIM Online Mendelian Inheritance in Man LPS Lipopolysaccharide OS Omenn Syndrome LYST Lysosomal Trafficking Regulator PAD Primary Antibody Deficiencies LZ Leucine Zipper PAMP Pathogen-Associated Molecular MAC Membrane Attack Complex Pattern MALT Mucosa-Associated Lymphoid Tissue PAPA Pyogenic Arthritis, Pyoderma MAPK Mitogen-Activated Protein Kinase Gangrenosum and Acne MASP MBL-Associated Serine Proteinases PBC Primary Billiary Chirosis MB Mycobacteria PBSC Peripheral Blood Stem Cells MBL Mannan-Binding Lectin PCAM Platelet Cell Adhesion Molecule MCP Membrane Cofactor Protein PCR Polymerase Chain Reactions MDS Myelodysplasia PDC Pyruvate Dehydrogenase Complex MEFV Mediterranean Fever PEG Polyethylene Glycol MHC Major Histocompatibility Complex PFAPA Periodic Fever, Aphtous Stomatitis, MKD Mevalonate Kinase Deficiency Pharyngitis and Cervical Adenitis MMF Mycophenolate Mofetil PGA Pediatric Granulomatous Arthritis MMR Mumps, Measles, Rubella PHA Phytohmagglutanin MPGN Membranoproliferative PID Primary Immunodeficiency Diseases Glomerulonephritis PIGA Phosphatidylinositol Glycan, Class A MPO Myeloperoxidase PK Protein Kinases MRI Magnetic Resonance Imaging PLAD Pre-Ligand-Associated Domain MSMD Mendelian Susceptibility to PMA Phorbol Myristate Acetate Mycobacterial Diseases PNH Paroxysmal Nocturnal MTOC Microtubule Organizing Center Hemoglobinuria MTX Methotrexate PNP Purine Nucleoside Phosphorylase MVA Mevalonic Aciduria PRR Pattern Recognition Receptor MVD Mevalonate Kinase Deficiency PTH Parathyroid Hormone MVK Mevalonate Kinase PWM Pokeweed Mitogen XXVIII Abbreviations

RA Rheumatoid Arthritis TBI Total Body Irradiation RAST Radioallergosorbent Test TCC Terminal C5b-9 Complement RAG Recombination Activating Genes Complex RC Recessive Complete TCR T Cell Receptor RDS Radioresistant DNA Synthesis TERC Telomerase RNA Component RFX Regulatory Factor X TERT Telomerase Reverse Transcriptase RIA Radio Immuno Assay TGF Transforming Growth Factor ROS Reactive Oxygen Species THI Transient Hypogammaglobulinemia RP Recessive Partial of Infancy RSS Recombination Signal Sequence TIR Toll-Interleukin-1 Receptor RSV Respiratory Syncytial Virus TIRAP Toll-Interleukin-1 Receptor Domain- SAA Serum Amyloid A Containing Adaptor Protein SAD Specific Antibody Deficiency TLR Toll-Like Receptor SAP SLAM-Associated Protein TMEM142A Transmembrane protein 142A SBDS Shwachman–Bodian–Diamond TMP-SMX Trimethoprim-Sulfametoxazole syndrome TNF Tumor Necrosis Factor SCE Sister-Chromatid Exchanges TNFRSF5 Tumor Necrosis Factor Receptor SCID Severe Combined Immunodeficiency Superfamily, Member 5 SCIG Subcutaneous Immunoglobulin TNFS5B Tumor Necrosis Factor Ligand SCN Severe Congenital Neutropenia Superfamily, Member 5 SDF-1 Stromal Cell-Derived Factor-1 TPN Total Parenteral Nutrition SDS Shwachman–Diamond Syndrome TRAM Toll Receptor-Associated Molecule SERCA Sarcoplasmic Endoplasmic Reticulum TRAPS TNF Receptor-Associated Periodic Calcium ATPase Syndrome SGD Specific Granule Deficiency TREC T Cell Receptor Excision Circles SH2D1A Src Homology 2-Domain Protein TRIF Toll Receptor-Associated Activator SHM Somatic Hypermutation of Interferon SIgAD Selective IgA Deficiency TYK2 Tyrosine Kinase 2 SIOD Schimke Immuno-Osseous UNG Uracyl-DNA Glycosylase Dysplasia VCA Viral Capsid Antigen SL Secretory Lysosomes VZV Varicella- Zoster Virus SLAM Signaling Lymphocytic Activation WAS Wiskott–Aldrich Syndrome Molecule WASP Wiskott–Aldrich Syndrome SLE Systemic Lupus Erythematosus Protein SOCE Store Operated Ca2+ Entry WHIM Warts, Hypogammaglobulinemia, SSB Single Strand Breaks Infections, Myelokathexis STAT Signal Transducer and Activator WHN Winged-Helix-Nude of Transcription WIP WASP-Interacting Protein STX11 Syntaxin 11 XIAP X-linked Inhibitor-of-Apotosis TACI Transmembrane Activator and XL X-Linked Calcium Modulator and Cyclophilin XLA X-linked agammaglobulinemia Ligand Interactor XLF XRCC4-Like Factor TAP Transporter Associated with Antigen XLP X-Linked Lymphoproliferative Processing XLT X-Linked Thrombocytopenia TAPBP TAP-Binding Protein ZAP Zeta Associated Protein