Nima Rezaei Asghar Aghamohammadi Luigi D

Primary Immunodeficiency Diseases

Deﬁ nition, Diagnosis, and Management Second Edition

Nima Rezaei Asghar Aghamohammadi Luigi D. Notarangelo Editors 123 Primary Immunodeficiency Diseases Nima Rezaei Asghar Aghamohammadi Luigi D. Notarangelo Editors

Primary Immunodeficiency Diseases

Definition, Diagnosis, and Management

Second Edition Editors Nima Rezaei Asghar Aghamohammadi Research Center for Immunodeficiencies Research Center for Immunodeficiencies Children’s Medical Center Children’s Medical Center Tehran University of Medical Sciences Tehran University of Medical Sciences Tehran Tehran Iran Iran Department of Immunology and Primary Immunodeficiency Diseases Biology Network (PIDNet) School of Medicine Universal Scientific Education and Tehran University of Medical Sciences Research Network (USERN) Tehran Tehran Iran Iran

Network of Immunity in Infection Luigi D. Notarangelo Malignancy and Autoimmunity (NIIMA) Division of Immunology Universal Scientific Education and Boston Children’s Hospital Research Network (USERN) Harvard Medical School Tehran Boston, MA Iran USA

ISBN 978-3-662-52907-2 ISBN 978-3-662-52909-6 (eBook) DOI 10.1007/978-3-662-52909-6

Library of Congress Control Number: 2016959211

© Springer-Verlag Berlin Heidelberg 2017 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made.

Printed on acid-free paper

This Springer imprint is published by Springer Nature The registered company is Springer-Verlag GmbH Germany The registered company address is: Heidelberger Platz 3, 14197 Berlin, Germany 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, Arnika, 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 dedicated also to all of them, but most importantly to our patients and their families whose continuous support has guided us over the years. Foreword

With the advent of whole exome sequencing, the field of primary immunodeficiencies has exploded over the past 5 years. This updated edition ofPrimary Immunodeficiency Diseases by Nima Rezaei and a number of collaborators from around the world does a superb job of updating our knowledge of these fascinating disorders and covers all aspects for each of the diseases discussed, including current recommendations on treatment. A great deal of basic immunology has been learned from studies of these patients and much more has still to be discovered. This book addresses the need to increase awareness of the conditions worldwide and to define the resource requirements for diagnosis, genetic counseling, and treatment. The commitment of Iranian pediatric immunologists to patients with primary immunodeficiency diseases and their collaborative efforts to discover novel genetic defects and to apply state-of-the-art methods for their diagnosis and treatment are demonstrated in the many chapters in this volume authored jointly by Iranian investigators and recognized international authorities in the subject. It is a tribute to the establishment of modern facilities in Tehran to diagnose and treat such patients that this second edition includes the latest discoveries in the field, and thus is up to date as well as practical. The wide coverage of all aspects of primary immunodeficiency diseases provides a comprehensive text and will serve as a tool for experts who care for these patients in other geographical areas and who wish to spread awareness and understanding of this rapidly expanding field. It will be of great value to pediatric immunologists and will serve as a “Google-in-print” for primary immunodeficiency diseases.

Boston, MA, USA Raif Geha Seattle, WA, USA Hans Ochs Oxford, UK Helen Chapel

vii Preface

Primary immunodeficiency diseases (PIDs) are a heterogeneous group of inherited disorders with defects in one or more components of the immune system, characterized by increased incidence of infections, autoimmunity, and malignancies. PIDs are not considered as rare conditions anymore, while the number of diagnosed patients has significantly been growing up. Nevertheless, because of inadequate medical awareness, it is estimated that a significant number of patients with PIDs are not recognized or are diagnosed late. This latency leads to a substantial increased rate of morbidity and mortality among the affected individuals. It should also be added that more than 300 different forms of PIDs have already been identified. Considering the fact that only 150 different types of PIDs had been described in the first edition of the book, it can show that how much efforts have been made during last decade in the identification of novel PIDs, which led to a twice increase in the number of described PIDs. Our understanding on PID is rapidly improving, and this may facilitate the accuracy of diagnosis and efficiency of management. This book is an attempt to gather the most recent advances in this field and tries to provide a concise and structured review of hitherto known PIDs. Although the ulti- mate orientation of this book is toward practical diagnosis and management, the pathophysiology of diseases is also discussed. For this purpose, this book consists of 10 chapters. The first chapter gives an overview on PIDs and presents a classification of these disorders. In Chaps.2 , 3, 4, 5, 6, 7, 8, and 9, definition, etiology, clinical manifestations, diagnosis, and management of each disease are discussed separately. Syndromic immunodeficiencies are also briefly presented in Chap.10 , while some of them are explained in greater detail in other chapters. This book is the result of the valuable contribution of 55 PID experts from top centers of five continents. We would like to acknowledge the expertise of all contributors, for generously giving their time and considerable effort in preparing their respective chapters. We are also grateful to Springer for giving us the opportunity to publish this book. We hope that this book will be comprehensible, cogent, and manageable for physicians and nurses, who wish to learn more about PIDs. We were very pleased that the first edition of the book was very welcomed by the scientists from all over the world. It is our hope that second edition of

ix x Preface the book continues to represent a useful resource for doctors in training as well as for specialists and subspecialists in clinical decision-making and treatment planning.

Tehran, Iran Nima Rezaei Tehran, Iran Asghar Aghamohammadi Boston, MA, USA Luigi Notarangelo Contents

1 Introduction on Primary Immunodeficiency Diseases �� 1 Nima Rezaei, Francisco A. Bonilla, Mikko Seppänen, Esther de Vries, Ahmed Aziz Bousfiha, Jennifer Puck, and Jordan Orange 2 Combined T- and B-Cell Immunodeficiencies �� 83 Françoise Le Deist, Despina Moshous, Anna Villa, Waleed Al-Herz, Chaim M. Roifman, Alain Fischer, and Luigi D. Notarangelo 3 Predominantly Antibody Deficiencies �� 183 Asghar Aghamohammadi, Alessandro Plebani, Vassilios Lougaris, Anne Durandy, Antonio Condino-Neto, Hirokazu Kanegane, and Lennart Hammarström 4 Phagocytes Defects �� 245 Uwe Wintergerst, Taco W. Kuijpers, Sergio D. Rosenzweig, Steven M. Holland, Mario Abinun, Harry L. Malech, and Nima Rezaei 5 Genetic Disorders of Immune Regulation �� 295 Carsten Speckmann, Arndt Borkhardt, Bobby Gaspar, Eleonora Gambineri, and Stephan Ehl 6 Defects in Intrinsic and Innate Immunity: Receptors and Signaling Components �� 339 Nima Parvaneh, Desa Lilic, Joachim Roesler, Tim Niehues, Jean-Laurent Casanova, and Capucine Picard 7 Autoinflammatory Disorders �� 393 Stefan Berg, Per Wekell, Anders Fasth, Philip N. Hawkins, and Helen Lachmann 8 Complement Deficiencies �� 437 Maryam Mahmoudi, Per H. Nilsson, Tom Eirik Mollnes, Dirk Roos, and Kathleen E. Sullivan

xi xii Contents

9 Other Well-Defined Immunodeficiencies �� 461 Andrew R. Gennery, Laszlo Marodi, John B. Ziegler, Teresa Español, and Bodo Grimbacher 10 Syndromic Immunodeficiencies �� 519 Jeffrey E. Ming and E. Richard Stiehm Index �� 553 Contributors

Mario Abinun, MD Primary Immunodeficiency Group, Institute of Cellular Medicine (ICM), Newcastle upon Tyne Hospitals NHS FT, Newcastle University, Newcastle upon Tyne, UK Asghar Aghamohammadi, MD, PhD Research Center for Immuno deficiencies, Children’s Medical Center Hospital, Tehran University of Medical Sciences, Tehran, Iran Primary Immunodeficiency Diseases Network (PIDNet), Universal Scientific Education and Research Network (USERN), Tehran, Iran Waleed Al-Herz, MD Department of Pediatrics, Al-Sabah Hospital, Kuwait City, Kuwait Faculty of Medicine, Kuwait University, Kuwait City, Kuwait Stefan Berg, MD, PhD Department of Pediatrics, University of Gothenburg, The Queen Silvia Children’s Hospital, Gothenburg, Sweden Francisco A. Bonilla, MD, PhD Division of Immunology, Children’s Hospital Boston, Boston, MA, USA Arndt Borkhardt, MD Pediatric Oncology, Hematology and Clinical Immunology, Heinrich Heine University Medical Center, Düsseldorf, Germany Ahmed Aziz Bousfiha, MD Faculty of Medicine and Pharmacy, Clinical Immunology Unit, Casablanca Children Hospital Ibn Rushd, King Hassan II University, Casablanca, Morocco Jean-Laurent Casanova, MD, PhD St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University Hospital, New York, NY, USA Necker Hospital and School of Medicine, University Paris Descartes, Paris, France Antonio Condino-Neto, MD, PhD Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil Esther de Vries, MD, PhD Department of Pediatrics & Jeroen Bosch Academy, Jeroen Bosch Hospital, ‘s-Hertogenbosch, Netherlands Tranzo, Tilburg University, Tilburg, The Netherlands

xiii xiv Contributors

Anne Durandy, MD, PhD INSERM UMR 1163, The Human Lymphohematopoiesis Laboratory, Imagine Institute, and Hôpital Necker Enfants Malades, Paris, France Stephan Ehl, MD Center for Chronic Immunodeficiency, University Hospital Freiburg, Freiburg, Germany Teresa Español, MD, PhD Immunology Unit, Vall d’Hebron University Hospital, Barcelona, Spain Anders Fasth, MD, PhD Department of Pediatrics, Institute of Clinical Sciences, University of Gothenburg, Gothenburg, Sweden Alain Fischer, MD, PhD Unité d’Immunologie et Hématologie Pédiatrique, Hôpital Necker-Enfants Malades, Paris, France Eleonora Gambineri, MD “Nuerofarba” Department, Anna Meyer Chidlren’s Hospital, Florence, Italy Haematology Oncology Department, BMT Unit, University of Florence, Florence, Italy Bobby Gaspar, MD ICH Infect, Imm, Infla. & Physio Med UCL GOS, Institute of Child Health, Faculty of Pop Health Sciences, London NHS Trust, London, UK Andrew R. Gennery, MD Primary Immunodeficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK Bodo Grimbacher, MD Institute of Immunity & Transplantation, Royal Free Hospital, University College London, London, UK Center for Chronic Immunodeficiency, University Hospital Freiburg, Freiburg, Germany Lennart Hammarström, MD, PhD Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden Philip N. Hawkins, MBBS, PhD, FMedSci Royal Free Hospital London NHS Foundation Trust, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College London, London, UK Steven M. Holland, MD Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA Hirokazu Kanegane, MD, PhD Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan Taco W. Kuijpers, MD, PhD Pediatric Hematology, Immunology and Infectious Diseases, Academic Medical Center, Emma Children’s Hospital, University of Amsterdam, Amsterdam, The Netherlands Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, University of Amsterdam, Amsterdam, The Netherlands Contributors xv

Helen J. Lachmann, MA, MB, BChir, MD, FRCP, FRCPath Royal Free Hospital London NHS Foundation Trust, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College London, London, UK Françoise Le Deist, MD, PhD Department of Microbiology and Immunology, CHU Sainte Justine, University of Montréal, Montreal, QC, Canada Desa Lilic, MD, PhD Primary Immunodeficiency Group, Institute of Cellular Medicine, The Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK Vassilios Lougaris, MD Department of Clinical and Experimental Sciences, Pediatrics Clinic and Institute for Molecular Medicine A. Nocivelli, University of Brescia, Spedali Civili di Brescia, Brescia, Italy Maryam Mahmoudi, MD, PhD Department of Cellular and Molecular Nutrition, School of Nutrition and Dietetics, Tehran University of Medical Sciences, Tehran, Iran Dietitians and Nutrition Experts Team (DiNET), Universal Scientific Education and Research Network (USERN), Tehran, Iran Harry L. Malech, MD Laboratory of Host Defenses, Genetic Immunotherapy Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA Laszlo Marodi, MD Department of Infectious and Pediatric Immunology, University of Debrecen, Medical and Health Science Center, Debrecen, Hungary Jeffrey E. Ming, MD, PhD Division of Human Genetics, Department of Pediatrics, The Children’s Hospital of Philadelphia, The University of Pennsylvania School of Medicine, Philadelphia, PA, USA Tom Eirik Mollnes, MD, PhD Department of Immunology, Oslo University Hospital, Oslo, Norway K.G. Jebsen Inflammation Research Center, University of Oslo, Oslo, Norway Research Laboratory, Nordland Hospital, Bodø, Norway Faculty of Health Sciences, K.G. Jebsen TREC, University of Tromsø, Tromsø, Norway Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim, Norway Despina Moshous, MD, PhD Unité d’Immunologie et Hématologie Pédiatrique, AP-HP Hôpital Necker-Enfants Malades, Paris, France Tim Niehues, MD, PhD HELIOS Medical Center Krefeld, Academic Hospital of RWTH University Aachen, Immunodeficiency and Pediatric Rheumatology Division, Krefeld, NRW, Germany Per H. Nilsson, PhD Department of Immunology, Oslo University Hospital, Oslo, Norway K.G. Jebsen Inflammation Research Center, University of Oslo, Oslo, Norway xvi Contributors

Luigi D. Notarangelo, MD Division of Immunology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA Jordan Orange, MD, PhD Department of Immunology, Allergy and Rheumatology, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX, USA Nima Parvaneh, MD Division of Allergy and Clinical Immunology, Department of Pediatrics, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran Capucine Picard, MD, PhD Study Center of Primary Immunodeficiencies and Pediatric Hematology-Immunology Unit, Necker Hospital, Paris Descartes University, Paris, France Alessandro Plebani, MD, PhD Department of Clinical and Experimental Sciences, Pediatrics Clinic and Institute for Molecular Medicine A. Nocivelli, University of Brescia, Spedali Civili di Brescia, Brescia, Italy Jennifer M. Puck, MD Department of Pediatrics, University of California- San Francisco, San Francisco, CA, USA Nima Rezaei, MD, PhD Research Center for Immunodeficiencies, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran Department of Immunology and Biology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran Joachim Roesler, MD, PhD Department of Pediatrics, University Clinic Carl Gustav Carus, Dresden, Germany Chaim M. Roifman, MD, FRCPC Division of Immunology and Allergy, Department of Paediatrics, The Hospital for Sick Children, The University of Toronto, Toronto, ON, Canada Dirk Roos, PhD Sanquin Research and Landsteiner Laboratory, Department of Blood Cell Research, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands Sergio D. Rosenzweig, MD, PhD Immunology Service, Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, USA Mikko Seppänen, MD, PhD Rare Disease Center; and Adult Primary Immunodeficiency Unit, Infectious Diseases, Inflammation Center; Helsinki University Hospital (HUH), Helsinki, Finland Carsten Speckmann, MD Department of Pediatric Hematology and Oncology, Center of Pediatrics, Freiburg, Germany Contributors xvii

E. Richard Stiehm, MD Department of Pediatric Immunology/Allergy/ Rheumatology, Mattel Children’s Hospital at UCLA, UCLA Medical Center, Los Angeles, CA, USA Kathleen E. Sullivan, MD, PhD Division of Allergy and Immunology, The Children’s Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA Anna Villa, MD UOS/Istituto di Ricerca Genetica e Biomedica (IRGB), Milan Unit, Consiglio Nazionale delle Ricerche (CNR), Milan, Italy Division of Regenerative Medicine, Telethon Institute for Gene Therapy, Stem Cells and Gene Therapy, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, Milan, Italy Per Wekell, MD, PhD Department of Pediatrics, University of Gothenburg, NU-Hospital Group, Uddevalla, Sweden Uwe Wintergerst, MD Department of Pediatrics, Hospital St. Josef, Braunau, Austria John B. Ziegler, MD Department of Immunology and Infectious Diseases, Sydney Children’s Hospital, Randwick, NSW, Australia School of Women and Children’s Health, University of NSW, Sydney, NSW, Australia Introduction on Primary Immunodeficiency Diseases 1

Nima Rezaei, Francisco A. Bonilla, Mikko Seppänen, Esther de Vries, Ahmed Aziz Bousfiha, Jennifer Puck, and Jordan Orange

1.1 Definition tissues, and organs. B- and T- lymphocytes, phagocytic cells and soluble factors such as com- 1.1.1 Background plement are some of the major components of the immune system, and have specific critical func- The immune system is a complex network of tions in immune defense. cells and organs which cooperate to protect indi- When part of the immune system is missing or vidual against infectious microorganisms, as well does not work correctly, immunodeficiency as internally-derived threats such as cancers. The occurs; it may be either congenital (primary) or immune system specializes in identifying danger, acquired (secondary). Secondary immunodefi- containing and ultimately eradicating it. It is ciency diseases are caused by environmental fac- composed of highly specialized cells, proteins, tors such as infection with HIV, chemotherapy,

N. Rezaei, MD, PhD (*) E. de Vries, MD, PhD Research Center for Immunodeficiencies, Department of Pediatrics & Jeroen Bosch Academy, Children’s Medical Center, Tehran University of Jeroen Bosch Hospital, ‘s-Hertogenbosch, Medical Sciences, Tehran, Iran The Netherlands Department of Immunology and Biology, School of Tilburg University, Tilburg, The Netherlands Medicine, Tehran University of Medical Sciences, Tehran, Iran A.A. Bousfiha, MD Clinical Immunology Unit, Casablanca Children Network of Immunity in Infection, Malignancy and Hospital Ibn Rushd, Casablanca, Morocco Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran Faculty of Medicine and Pharmacy, King Hassan II University, Casablanca, Morocco F.A. Bonilla, MD, PhD Division of Immunology, Children’s Hospital Boston, J. Puck, MD Boston, MA, USA Department of Pediatrics, University of California- San Francisco, San Francisco, CA, USA M. Seppänen, MD, PhD Adult Primary Immunodeficiency Unit, Rare Disease J. Orange, MD, PhD Center, Infectious Diseases, Inflammation Center, Department of Immunology, Allergy and Helsinki University Hospital (HUH), Rheumatology, Texas Children’s Hospital, Baylor Helsinki, Finland College of Medicine, Houston, TX, USA

© Springer-Verlag Berlin Heidelberg 2017 1 N. Rezaei et al. (eds.), Primary Immunodeficiency Diseases, DOI 10.1007/978-3-662-52909-6_1 2 N. Rezaei et al. irradiation, malnutrition, and others; while pri- remain the keys to the successful management of mary immunodeficiency diseases (PIDs) are patients with PIDs [68, 136, 246]. hereditary disorders, caused by mutations of specific genes. Primary immunodeficiency diseases are a het- 1.1.2 History erogeneous group of inherited disorders with defects in one or more components of the The birth of the primary immunodeficiency field immune system. These diseases have a wide is attributed to Col. Ogden Bruton in 1952, who spectrum of clinical manifestations and labora- reported a male patient with early onset recur- tory findings; however, in the vast majority of rent infections and an absent gammaglobulin cases, they result in an unusually increased sus- peak on serum protein electrophoresis. This ceptibility to infections and a predisposition to child had an excellent response to immunoglob- autoimmune diseases and malignancies [44, 82, ulin replacement therapy [53]; later, the condi- 83, 120, 214, 218, 251, 278]. Primary immuno- tion ultimately became known as X-linked deficiencies constitute a large group of diseases, agammaglobulinemia (XLA) or Btk (Bruton’s including more than conservatively defined tyrosine kinase) deficiency. However, several hereditary disorders [14, 120, 218, 278], affect- patients with characteristic clinical manifesta- ing development of the immune system, its func- tions of immunodeficiency disorders had been tion, or both [24]. The number of known PIDs reported before 1950; e.g. Ataxia-telangiectasia has been increased considerably over the last (AT) in 1926 [283], chronic mucocutaneous two decades, through two lines of research: the candidiasis (CMCC) in 1929 [288], and Wiskott- genetic dissection of known clinical phenotypes Aldrich syndrome (WAS) in 1937 [315]. The and the investigation of new clinical phenotypes first patient with cellular deficiency was initially [41, 64, 89, 239, 284]. Some of these clinical reported in 1950 [124], the first case of a phago- phenotypes are more common than traditional cytic defect (severe congenital neutropenia: PID phenotypes. In particular, new PIDs confer- SCN) was reported in 1956 [155], and the first ring a specific predisposition to infections with case of complement deficiency (C2 deficiency) one or a few pathogens have been described was initially reported in 1966 [154]. [61], including genetic predisposition to EBV The discovery of PIDs and characterization of [294], Neisseria [142], papillomavirus [228], these diseases led to crucial contributions to Streptococcus pneumonia [236], weakly virulent understanding the functional organization of the mycobacteria [24, 146], herpes simplex virus immune system and molecular biology. Thus, the [64], and Candida albicans [118]. Mendelian study of PIDs has contributed to progress in predisposition to tuberculosis has even been immunological and molecular diagnostic tech- reported [114, 296]. In addition, various non- niques. These advances enabled increased recog- infectious phenotypes, as diverse as allergy, nition and characterization of new types of PIDs, angioedema, hemophagocytosis, autoinflamma- and identification of about 300 different types of tion, autoimmunity, thrombotic microangiopa- PIDs in the ensuing years (Tables 1.1, 1.2, 1.3, thy and cancer, have been shown to result from 1.4, 1.5, 1.6, 1.7, and 1.8) [235]. inborn errors of immunity, in at least some patients [61]. Although the number of patients diagnosed with PIDs is growing, many physi- 1.1.3 Epidemiology cians still know little about these disorders. Thus, many patients are diagnosed late; many Several PID registries have been established in cases suffer from complications by chronic different countries during the last three decades infections, irretrievable end-organ damage, or [2, 4, 9, 13, 18, 20, 35, 37, 49, 60, 106, 107, 110, even death before the definitive diagnosis is 111, 119, 128, 130, 143, 145, 152, 160, 161, 164, made. Timely diagnosis and appropriate treatment 166, 174, 180, 181, 190, 196, 207, 243, 246, 248, 1 Introduction on Primary Immunodeficiency Diseases 3 ) ) or (continued) ) ) ) ) TNFRSF5 RMRP TNFS5B CD247 ) , ) ) CHD7 ) or FoxN1 PRKDC AK2 , CD3G CD3E DCLRE1C CD3D CERNUNNOS CD3Z ADA , ) ) R ) or - ) CD45 ) IL7 , RAG1 RAG2 PNP ) or ) ) NHEJ1 binding protein 7 ( ) LCA ) DOCK2 ) TBX1 IL2RG JAK3 , ) or Forkhead box N1 ( ) or Forkhead ) ) ADA ) IL2RG CD40L ) LIG4 WHN AK2 ) alpha , R - SEMA3E LIG4 IL7 CORO1A DCLRE1C , 2 / Recombination-activating gene 2 ( Recombination-activating cross-link repair protein 1C ( Artemis or DNA ( catalytic subunit Protein kinase, DNA-activated IV ( ligase DNA Nonhomologous end-joining 1 ( Adenosine deaminase ( Purine nucleoside phosphorylase ( kinase 2 ( Adenylate IL-7 receptor ( antigen ( Leukocyte-common of T3 ( Gamma subunit antigen receptor, T-cell of T3 ( Delta subunit antigen receptor, T-cell of T3 ( Epsilon subunit antigen receptor, T-cell of T3 ( Zeta subunit antigen receptor, T-cell Coronin 1A ( gene 1 ( Recombination-activating Genetic defects ( IL-2 receptor gamma Janus-associated kinase 3 ( RAG1 Dedicator of Cytokinesis 2 ( member 5 ( superfamily, ligand necrosis factor Tumor ( CD40 antigen ligand member 5 ( receptor superfamily, necrosis factor Tumor 22q.11.2 deletion, T-box 1 ( 22q.11.2 deletion, T-box Chromodomain helicase DNA- Semaphorin 3E ( ( Winged-helix-nude ] 235 AR AR AR AR AR AR AR AR AR AR AR AR AR AR AR AR Inheritance XL AR AR AR XL AR De novo, AD De novo, AD AD AR

XLF deficiency / 1A deficiency - deficiency deficiency deficiency deficiency deficiency α deficiency ) ε ξ γ δ R - c deficiency PNP Artemis deficiency PKcs deficiency DNA ligase IV deficiency DNA Cernunnos deficiency ADA AK2 deficiency RAG 1 deficiency RAG 2 deficiency RAG Purine nucleoside phosphorylase ( CD3 CD3 CD3 CD3 Coronin JAK3 deficiency JAK3 IL7 CD45 deficiency γ CD40 ligand deficiency CD40 deficiency CHD7 deficiency SEMA3E deficiency WHN deficiency Modified IUIS classification of combined T- and B-cell immunodeficiencies [ Modified IUIS classification of combined

Diseases Omenn syndrome defects pathway Purine salvage Reticular dysgenesis DOCK2 deficiency T-B− combined immunodeficiency Severe T-B+ combined immunodeficiency Severe Complete DiGeorge syndrome Complete DiGeorge Immunoglobulin class switch Immunoglobulin recombination deficiencies affecting CD40-CD40L CHARGE syndrome with Combined immunodeficiency alopecia totalis Table 1.1 4 N. Rezaei et al. ) or ) ) ), B-cell CRACM1 ZAP70 TTC7A TNFRSF4 ) ) CARD11 ) ) TAP1 TAP2 ) ) ) LCK ) RFX5 TRAC ) ) RFXAP ) RHOH TMEM142A ) CD8A MALT1 SMARCAL1 tyrosine kinase ( ) containing protein 11 ( ) ), Mucosa-associated lymphoid tissue ) MST1 CIITA B2M TAPBP BCL10 ) ) ) RFXANK RMRP Ankyrin repeat containing regulatory factor X-associated protein factor repeat containing regulatory Ankyrin ( associated with antigen processing 1 ( Transporter associated with antigen processing 2 ( Transporter protein ( Tap-binding ( Beta-2 microglobulin Zeta-chain-associated protein of 70 kd signaling kinase ( CD8 antigen, alpha polypeptide ( SWI/SNF related, matrix associated, actin dependent regulator of SWI/SNF related, matrix associated, actin dependent regulator ( A-like chromatin, subfamily endoribonuclease component of mitochondrial RNA-processing RNA ( repeat domain.containing protein 7A ( Tetratricopeptide ( Class II transactivator 5 ( factor MHCII promoter X box regulatory X-associated protein ( factor Regulatory Lymphocyte-specific protein- Lymphocyte-specific Genetic defects Unknown Macrophage stimulating 1 ( T-cell receptor alpha chain constant region ( receptor alpha chain constant region T-cell calcium modulator 1 ( ORAI1 or Calcium release-activated protein 142A ( or Transmembrane Stromal interaction molecule 1 (STIM1) Caspase recruitment domain- CLL/lymphoma 10 ( lymphoma translocation gene 1 ( Ras homolog gene family, member H ( Ras homolog gene family, Tumor necrosis factor receptor superfamily, member 4 ( receptor superfamily, necrosis factor Tumor OX40 AR AR AR AR AR AR AR AR AR AR AR AR AR Inheritance Variable AR AR AR AR AR AR AR I deficiency 1 deficiency chain defect chain - - 70 deficiency α - microglobulin deficiency microglobulin - 2 β ZAP CD8 TAP1 deficiency TAP1 deficiency TAP2 deficiency TAPBP TTC7A deficiency deficiency CIITA RFX5 deficiency RFXAP deficiency RFXANK deficiency Schimke syndrome Schimke hair hypoplasia Cartilage ORAI STIM MST1 deficiency (continued)

deficiency α Lck deficiency CD8 deficiency MHC class I deficiency Diseases Combined immunodeficiency with Combined immunodeficiency intestinal atresias MHC class II deficiency Immuno-osseous dysplasias Idiopathic CD4 lymphocytopenia TCR CARD11/BCL10/MALT1 (CBM) CARD11/BCL10/MALT1 deficiencies complex STK4 deficiency CRAC channelopathy CRAC RHOH deficiency OX40 deficiency OX40 Table 1.1 1 Introduction on Primary Immunodeficiency Diseases 5 ) ) LRBA ) STAT5B ) ) MTHFD1 CTPS1 CD25 MAP3K14 ) or ) ) ) ) IL2RA ITK S) DOCK8 MAGT1 ) IL21R ICO ) IKZF IL21 ) IKBKB Interleukin 21 ( Interleukin 21 receptor ( Family zinc finger ( Family Inhibitor of kappa light chain gene enhancer in B cells, kinase of, beta ( Mitogen-activated protein 3 kinase 14 ( Mitogen-activated Lipopolysaccharide-responsive, beige-like anchor protein ( beige-like Lipopolysaccharide-responsive, Cytidine 5-prime triphosphate synthetase 1 ( 8 ( Dedicator of cytokinesis kinase ( IL2-inducible T-cell Magnesium transporter 1 ( alpha ( Interleukin 2 receptor, of transcription 5B ( Signal transducer and activator 1 ( dehydrogenase Methylenetetrahydrofolate Inducible costimulator ( AR AR AD de novo AR AR AR AR AR AR XL AR AR AR AR X-linked XL IL21 deficiency IL21R deficiency IKBKB deficiency STAT5b deficiency STAT5b MTHFD1 deficiency ICOS deficiency deficiency LRBA DOCK8 deficiency ITK deficiency deficiency MAGT1 CD25 deficiency autosomal dominant, AD autosomal recessive, autosomal recessive, IKAROS deficiency IKAROS IL21/IL21R deficiency IKK2 deficiency NIK deficiency CTPS1 deficiency Other combined immunodeficiencies Article published under the CC-BY license AR 6 N. Rezaei et al. ) ) BAFFR ) or ) CD20 TWEAK or or ) ) LRBA TNFRSF13B TNFRSF13C MS4A1 ), Phosphatidylinositol TTC37 TNFSF12 ) ) ) ) ) PIK3CD TRNT1 IGLL1 CD21 ) LRRC8 or MOGS ) CR2 NFKB2 PIK3R1 ) ) S) ) or SH2 domain containing leukocyte protein, 65-KD ) or SH2 domain containing leukocyte ) ) BTK ICO A) TCF3 ) ) responsive, beige-like anchor protein ( beige-like responsive, containing protein 8 ( BLNK IGHM CD79 CD79B CD19 CD81 ) SLP65 Membrane-spanning 4 domains, subfamily A, member 1 ( Membrane-spanning 4 domains, subfamily Inducible costimulator ( member 13B ( receptor superfamily, necrosis factor Tumor member 13C ( receptor superfamily, necrosis factor Tumor member 12 ( superfamily, ligand necrosis factor Tumor Lipopolysaccharide- CD19 antigen ( Complement component receptor 2 ( CD81 antigen ( 2 ( kappa-b, subunit Nuclear factor Mannosyl-oligosaccharide glycosidase ( nucleotidyltransferase CCA-adding, 1 ( tRNA repeat domain-containing protein 37 ( Tetratricopeptide Phosphatidylinositol 3-kinase, catalytic, delta ( 1 ( subunit 3-kinase, regulatory Unknown Genetic defects Bruton tyrosine kinase ( mu chain ( Ig heavy polypeptide 1 ( lambda-like Immunoglobulin CD79A antigen ( CD79B antigen ( protein ( B cell liker ( 3 ( factor Transcription Leucine-rich repeat- Unknown ] 235 AR AD or AR AR AR AR AR AR AR AD AD AR AR AR Variable XL AR AR AR AR AR AD AD Variable AR, AD gain-of- function Inheritance deficiency deficiency α β heavy chain deficiency heavy chain 5 deficiency ICOS deficiency deficiency TACI deficiency receptor BAFF TWEAK deficiency NFKB2 deficiency CD19 deficiency CD21 deficiency MOGS deficiency TRNT1 deficiency TTC37 deficiency CD81 deficiency μ λ Ig TCF3 deficiency LRRC8 deficiency Btk deficiency Ig BLNK deficiency Other forms of agammaglobulinemia Modified IUIS classification of predominantly antibody deficiencies [

Other monogenic defects associated with hypogammaglobulinemia CD19 complex deficiencies CD19 complex CD20 deficiency LRBA deficiency LRBA Common variable Common variable immunodeficiency Autosomal recessive Autosomal recessive agammaglobulinemia PI3K syndrome Other forms of with absent agammaglobulinemia B-cells X-linked agammaglobulinemia X-linked Diseases Table 1.2 1 Introduction on Primary Immunodeficiency Diseases 7 ) AICDA ) ) ) ) MSH6 UNG IGKC INO80 Unknown Unknown Activation-induced cytidine deaminase ( cytidine Activation-induced Unknown Unknown Unknown Chromosomal deletion at 14q32 ( Ig kappa constant region Uracil-DNA glycosylase ( Uracil-DNA MutS E. coli homolog of 6 ( ( subunit INO80 complex Variable Variable Variable Variable AR AR Variable AR AR AR AR X-linked XL deletions / Isolated IgG subclass deficiency IgA with IgG subclass deficiency AICDA deficiency AICDA UNG deficiency Ig heavy chain mutations deficiency k light chain MMR deficiency INO80 deficiency autosomal dominant, AD autosomal recessive, autosomal recessive, Transient Transient of hypogammaglobulinemia infancy Other immunoglobulin isotypes Other immunoglobulin or light chain deficiencies with Specific antibody deficiency normal immunoglobulin concentrations Immunoglobulin class switch Immunoglobulin recombination deficiencies B-cells affecting IgA deficiency Selective Article published under the CC-BY license AR 8 N. Rezaei et al. ) ) LAMTOR2 COH1 ) or ) ) ) ) ) VPS45A CSF3R VPS13B ) SLC37A4 ) ) or GDP-fucose transporter 1 or ) RAC2 CEBPE ) ) SBDS ) FERMT3 ) C16ORF57 ) ) SLC35C1 G6PT1 ) CYBA G6PC3 ) ) JAGN1 WASP CYBB ) ) ) ) ELANE ELANE HAX1 GFI1 NCF2 NCF4 NCF1 FRP1 CLPB ) ) ) MPO ) ITGB2 ) CTSC ACTB TAZ ) FUCT1 Genetic defects Cytochrome b(−245), beta subunit ( Cytochrome b(−245), beta subunit ( Cytochrome b(−245), alpha subunit 1 ( factor Neutrphil cytosolic 2 ( factor Neutrophil cytosolic 2 ( factor Neutrophil cytosolic Cathepsin c ( protein, epsilon ( CCAAT/enhancer-binding syndrome ( Shwachman-Bodian-Diamond Actin, beta ( peptide receptor 1 ( Formyl Integrin, beta-2 ( Integrin, 35, member C1 ( Solute carrier family ( (Drosophila) homolog 3 ( Fermitin family Ras-related C3 botulinum toxin substrate 2 ( Elastase, neutrophil-expressed ( Elastase, neutrophil-expressed Growth factor-independent 1 ( factor-independent Growth HCLS1-associated protein X1 ( Glucose-6-phosphatase, catalytic, 3 ( protein sorting 45, yeast, homolog of, A ( Vacuolar syndrome protein ( Wiskott-Aldrich 2 ( activator MAPK and MTOR Late endosomal/lysosomal adaptor, Jagunal, drosophila, homolog of, 1 ( ( Elastase, neutrophil-expressed Glucose-6-phosphatase transporter 1 ( Colony-stimulating factor 3 receptor, granulocyte ( granulocyte 3 receptor, factor Colony-stimulating Vacuolar protein sorting 13, yeast, homolog of, B ( Vacuolar Chromosome 16 open reading frame 57 ( Myeloperoxidase ( Tafazzin ( Tafazzin Caseinolytic peptidase B ( Inheritance XL AR AR AR AR AR AR AD AR AR AR AR AR AD AD AD AR AR AR AR XL AR AR AR AD AR AR XL AR AR ] 235 ) IIc - X-linked XL deficiency

Barth syndrome deficiency deficiency deficiency deficiency

( phox

phox phox phox phox

CSF receptor deficiency CSF receptor linked neutropenia linked - - p22 p47 p67 p40 gp91 ITGB2 or CD18 deficiency SCL35C1 or CDG deficiency FERMT3 or Kindlin3 deficiency ELANE deficiency GFI1 deficiency HAX1 deficiency G6PC3 deficiency VPS45 deficiency X p14 deficiency deficiency JAGN1 G Type II Type VII Type autosomal dominant, AD Modified IUIS classification of phagocytes defects [ Modified IUIS classification of phagocytes

autosomal recessive, autosomal recessive, -Actin deficiency Chronic granulomatous disease Diseases Leukocyte adhesion deficiency Leukocyte Severe congenital neutropenias Severe Shwachman-Diamond syndrome Shwachman-Diamond Specific granule deficiency Papillon-Lefèvre syndrome Papillon-Lefèvre Localized juvenile periodontitis Localized juvenile β RAC-2 deficiency RAC-2 3-Methylglutaconic Aciduria 3-Methylglutaconic Glycogen storage disease type 1b Cyclic neutropenia Myeloperoxidase deficiency Poikiloderma with neutropenia Cohen syndrome Table 1.3 Article published under the CC-BY license AR 1 Introduction on Primary Immunodeficiency Diseases 9

Table 1.4 Modified IUIS classification of genetic disorders of immune regulation235 [ ] Diseases Inheritance Genetic defects Familial hemophagocytic Perforin deficiency AR Perforin 1 (PRF1) lymphohistiocytosis UNC13D deficiency AR MUNC13-4 or UNC13D Syntaxin 11 deficiency AR Syntaxin 11 (STX11) STXBP2 deficiency AR Syntaxin-bnding protein 2 (STXBP2) Autoimmune FAS defect AD, AR Tumor necrosis factor receptor lymphoproliferative syndrome superfamily, member 6 (TNFRSF6) or CD95 or FAS FASLG defect AR Tumor necrosis factor ligand superfamily, member 6 (TNFSF6) or CD95L or FASL CASP10 deficiency AD Caspase 10, apoptosis-related cysteine protease (CASP10) CASP8 deficiency state AR Caspase 8, apoptosis-related cysteine protease (CASP8) RAS-associated AD Unknown, Neuroblastome RAS autoimmune viral oncogene homolog (NRAS) leukoproliferative disease FADD deficiency AR FAS-associated via death domain (FADD) CTLA4 deficiency AD Cytotoxic T lymphocyte-associated 4 (CTLA4) Chediak-Higashi syndrome AR Lysosomal trafficking regulator (LYST) Griscelli syndrome, type 2 AR Ras-associated protein rab27a (RAB27A) Hermansky-Pudlak syndrome HPS type 2 AR Adaptor-related protein complex 3, beta-1 subunit (AP3B1) HPS type 9 AR Biogenesis of lysosome-related organelles complex 1, subunit 6 (BLOC1S6) HPS10 AR Adaptor-related protein complex 3, delta-1 subunit (AP3D1) Other immunodeficiencies p14 deficiency AR MAPBP-interacting protein associated with (MAPBPIP) or P14 hypopigmentation Vici syndrome AR Ectopic P-granules autophagy protein 5, C. elegans, homolog of (EPG5) X-linked lymphoproliferative SAP deficiency XL src homology 2-domain protein syndromes (SH2D1A) XIAP deficiency XL Inhibitor-of-apotosis, X-linked (XIAP) or Baculoviral IAP repeat-containing protein 4 (BIRC4) MAGT1 deficiency XL Magnesium transporter 1 (MAGT1) Autosomal recessive ITK deficiency AR IL2-inducible T-cell kinase (ITK) lymphoproliferative syndromes CD27 deficiency AR Tumor necrosis factor receptor superfamily, member 7 (TNFRSF7 or CD27) Immunodysregulation, IPEX XL Forkhead box P3 (FOXP3) polyendocrinopathy, enteropathy, X-linked (continued) 10 N. Rezaei et al.

Table 1.4 (continued) Diseases Inheritance Genetic defects CD25 deficiency AR Interleukin 2 receptor, alpha (IL2RA) or CD25 STAT5B deficiency AR Signal transducer and activator of transcription 5B (STAT5B) ITCH deficiency AR Itchy E3 ubiquitin protein ligase, mouse, homolog of (ITCH) TPP2 deficiency AR Tripeptidyl peptidase II (TPP2) COPA deficiency AD Coatamer Protein Complex, Subunit Alpha (COPA) Article published under the CC-BY license AR autosomal recessive, AD autosomal dominant, XL X-linked

Table 1.5 Modified IUIS classification of defects in intrinsic and innate immunity: receptors and signaling components [235] Diseases Inheritance Genetic defects Anhidrotic ectodermal NEMO deficiency XL Inhibitor of kappa light polypeptide gene dysplasia with enhancer in B cells, kinase of, gamma immunodeficiency (IKBKG) or NF-kappa-B essential modulator (NEMO) IkBA gain-of-function AD Inhibitor of kappa light polypeptide gene mutations enhancer in B cells, kinase of, alpha (IKBA) HOIL1 and HOIP HOIL1 deficiency AR Heme-oxidized IRP2 ubiquitin ligase 1 deficiencies (HOIL1) HOIP deficiency AR HOIL1-interacting protein (HOIP) IRAK-4 and MyD88 IRAK-4 deficiency AR Interleukin 1 receptor-associated kinase 4 deficiencies (IRAK4) MyD88 deficiency AR Myeloid differentiation primary response gene 88 (MYD88) Herpes simplex encephalitis TLR3 deficiency AD Toll-like receptor 3 (TLR3) UNC93B deficiency AR UNC-93B TRAF3 deficiency AD TNF receptor-associated factor 3 (TRAF3) TRIF deficiency AR, AD Testis-specific ring finger proteinTRIF ( ) TBK1 deficiency AD Tank-binding kinase 1 (TBK1) IRF3 deficiency AD Interferon regulatory factor 3 (IRF3) Mendelian susceptibility to IFN-γ receptor 1 AR, AD Interferon, gamma, receptor 1 (IFNGR1) mycobacterial diseases deficiency IFN-γ receptor 2 AR, AD Interferon, gamma, receptor 2 (IFNGR2) deficiency IL-12/IL-23 receptor AR Interleukin 12 receptor, beta-1 (IL12RB1) β1 chain deficiency IL-12p40 deficiency AR Interleukin 12B (IL12B) DP-STAT1 deficiency AR, AD Signal transducer and activator of transcription 1 (STAT1) LZ-NEMO deficiency XL NF-kappa-B essential modulator (NEMO) Macrophage-specific XL Cytochrome b(−245), beta subunit (CYBB) CYBB deficiency AD-IRF8 deficiency AD Interferon regulatory factor 8 (IRF8) ISG15 deficiency AR Ubiquitin-like modifier ISG15 (ISG15) 1 Introduction on Primary Immunodeficiency Diseases 11

Table 1.5 (continued)

Diseases Inheritance Genetic defects Genetic defects of AR STAT1 deficiency AR Signal transducer and activator of interferon type I and III transcription 1 (STAT1) responses other than TLR3 STAT2 deficiency AR Signal transducer and activator of pathway transcription 2 (STAT2) TYK2 deficiency AR Protein-tyrosin kinase 2 (TYK2) IRF7 deficiency AR Interferon regulatory factor 7 (IRF7) Warts, AD Chemokine, CXC motif, receptor 4 hypogammaglobulinemia (CXCR4) infections, myelokathexis (WHIM) syndrome Epidermodysplasia EVER1 deficiency AR Epidermodysplasia verruciformis gene 1 verruciformis (EVER1) EVER2 deficiency AR Epidermodysplasia verruciformis gene 2 (EVER2) Chronic mucocutaneous IL17RA deficiency AR Interleukin 17 receptor A (IL17RA) candidiasis IL17F deficiency AD Interleukin 17 F (IL17F) IL17RC deficiency AR Interleukin 17 receptor C (IL17RC) STAT1 gain-of-function AD Signal transducer and activator of mutation transcription 1 (STAT1) ACT1 deficiency AR Nuclear factor kappa-B activator 1 (ACT1) CARD9 deficiency AR Caspase recruitment domain-containing protein 9 (CARD9) Autoimmune AR Autoimmune regulator (AIRE) polyendocrinopathy with candidiasis and ectodermal dystrophy RORC deficiency AR RAR-related orphan receptor C (RORC) Monocyte/dendritic cell AD GATA2 deficiency AD GATA-binding protein 2 (GATA2) deficiencies AR IRF8 deficiency AR Interferon regulatory factor 8 (IRF8) NK cell deficiencies MCM4 deficiency AR Minichromosome maintenance complex component 4 (MCM4) Pulmonary alveolar AR Colony-stimulating factor 2 receptor, alpha proteinosis (CSF2RA) AR Colony-stimulating factor 2 receptor, beta (CSF2RB) Isolated congenital asplenia AD NK2 homeobox 5 (NKX2-5) AD Ribosomal protein SA (RPS) Article published under the CC-BY license) AR autosomal recessive, AD autosomal dominant, XL X-linked 12 N. Rezaei et al.

Table 1.6 Modified IUIS classification of autoinflammatory disorders [235] Diseases Inheritance Genetic defects Familial mediterranean fever AR Mediterranean fever (MEFV) Mevalonate kinase deficiency Hyper-IgD and periodic AR Mevalonate kinase (MVK) fever syndrome Mevalonic aciduria AR Mevalonate kinase (MVK) TNF receptor-associated AD Tumor necrosis factor receptor periodic syndrome superfamily, member 1a (TNFRSF1A) Cryopyrin-associated Chronic infantile AD NLR family, pyrin domain periodic syndrome neurological cutaneous containing 3 (NLRP3) or articular syndrome Cias1 gene (CIAS1) or Muckle-Wells syndrome AD Nacht domain-, leucine-rich repeat-, and pyd-containing protein Familial cold AD 3 (NALP3) or Pyrin domain- autoinflammatory containing APAF1-like protein 1 syndrome (PYPAF1) Blau syndrome Pediatric granulomatous AD Caspase recruitment domain- arthritis containing protein 15 (CARD15) or Nucleotide-binding oligomerization domain protein 2 (NOD2) Pyogenic arthritis, pyoderma AD Proline/Serine/Threonine gangrenosum and acne phosphatase-interacting protein 1 syndrome (PSTPIP1) or CD2 antigen-binding protein 1 (CD2BP1) NLRP12 associated periodic AD Nacht domain-, leucine-rich fever syndrome repeat-, and pyd-containing protein 12 (NLRP12) Deficiency of ADA2 AR Cat eye syndrome chromosome region, candidate 1 (CECR1) STING-associated AD Transmembrane protein 173 vasculopathy with onset in (TMEM173) infancy Deficiency of the IL-1 AR Interleukin 1 receptor antagonist receptor antagonist (IL1RN) Majeed syndrome AR Lipin 2 (LPIN2) Deficiency of IL-36 receptor AR Interleukin 36 receptor antagonist antagonist (IL36RN) Chronic atypical neutrophilic AR Proteasome subunit beta type 8 dermatosis with (PSMB8) lipodystrophy and elevated temperature Early onset inflammatory IL-10 deficiency AR Interleukin 10 (IL10) bowel diseases IL-10Rα deficiency AR Interleukin 10 receptor alpha (IL10RA) IL-10Rβ deficiency AR Interleukin 10 receptor beta (IL10RB) NFAT5 haploinsufficiency AD Nuclear factor of activated T cells 5 (NFAT5) ADAM17 deficiency AR A disintegrin and metalloproteinase domain 17 (ADAM17) Autoinflammation and AD Phospholipase Cγ2 (PLCG2) PLCγ2-associated antibody deficiency and immune dysregulation 1 Introduction on Primary Immunodeficiency Diseases 13

Table 1.6 (continued) Diseases Inheritance Genetic defects Sideroblastic anemia, AR tRNA nucleotidyl transferase, immunodeficiency, fevers, CCA-adding, 1 (TRNT1) and developmental delay Aicardi-Goutieres syndromes AGS1 AR, AD Three prime repair exonuclease 1 (AGS) (TREX1) AGS2 AR Ribonuclease H2 subunit A (RNASEH2A) AGS3 AR Ribonuclease H2 subunit B (RNASEH2B) AGS4 AR Ribonuclease H2 subunit C (RNASEH2C) AGS5 AR SAM domain and HD domain 1 (SAMHD1) AGS6 AR Adenosine deaminase, RNA- specific (ADAR) AGS7 AD Interferon induced with helicase C domain 1 (IFIH1) CARD14 mediated psoriasis AD Caspase recruitment domain family member 14 (CARD14) Haploinsufficiency of A20 AR TNF alpha induced protein 3 (HA20) (TNFAIP3) Episodic fevers, enteropathy, AD NLR family, CARD domain and MAS due to NLRC4 containing 4 (NLRC4). hyperactivity TNFRSF11A-associated AD Tumor necrosis factor receptor disease superfamily member 11a (TNFRSF11A) Histiocytosis- AD Soluble carrier family 29, member lymphadenopathy plus 3 (SLC29A3) syndrome Cherubism AD SH3 domain-binding protein 2 (SH3BP2) Spondyloenchondro- AD Phosphatase, acid, type 5, dysplasia with immune tartrate-resistant (ACP5) dysregulation Article published under the CC-BY license AR autosomal recessive, AD autosomal dominant 14 N. Rezaei et al.

Table 1.7 Modified IUIS classification of complement deficiencies [235] Diseases Inheritance Genetic defects Deficiencies of classical C1q deficiency AR Complement component 1, q pathway components subcomponent, alpha, beta and gamma polypeptides (C1QA, C1QB, C1QG) C1r deficiency AR Complement component C1R C1s deficiency AR Complement component 1, s subcomponent (C1S) C4 deficiency AR Complement component 4A and 4B (C4A, C4B) C2 deficiency AR Complement component 2 Deficiencies of lectin MBL deficiency AR Lectin, mannose-binding, soluble, 2 pathway components (MBL2) or Mannose-binding protein, Serum (MBP1) MASP-2 deficiency AR Mannan-binding lectin serine protease 2 (MASP2) MASP-3 deficiency AR Mannan-binding lectin serine protease 1 (MASP1) Ficolin 3 deficiency AR Ficolin 3 (FCN3) Collectin 11 deficiency AR Collectin 11 (COLEC11) Deficiencies of alternative Factor D deficiency AR Complement factor D (CFD) pathway components Properdin deficiency XL Properdin P factor, complement (PFC) Deficiency of complement AR Complement component 3 (C3) component C3 Deficiencies of terminal C5 deficiency AR Complement component 5 pathway components C6 deficiency AR Complement component 6 C7 deficiency AR Complement component 7 C8a deficiency AR Complement component 8, alpha subunit (C8A) C8b deficiency AR Complement component 8, beta subunit (C8B) C9 deficiency AR Complement component 9 Deficiencies of soluble C1 inhibitor deficiency AD Complement component 1 inhibitor regulatory proteins (C1NH) Factor I deficiency AR Complement factor I (CFI) Factor H deficiency AR Complement factor H (CFH) Deficiencies of the MCP deficiency AD Membrane cofactor protein (MCP) regulatory proteins and or CD46 complement receptors DAF deficiency AR Decay-accelerating factor for complement (DAF) or CD55 antigen CD59 deficiency AR CD59 antigen p18-20 (CD59) PIGA deficiency XL Phosphatidylinositol glycan, class A (PIGA) CR3 deficiency AR Integrin, beta-2 (ITGB2) Article published under the CC-BY license AR autosomal recessive, AD autosomal dominant, XL X-linked 1 Introduction on Primary Immunodeficiency Diseases 15

Table 1.8 Modified IUIS classification of other well-defined immunodeficiencies235 [ ] Diseases Inheritance Genetic defects Ataxia-telangiectasia AR Ataxia-telangiectasia mutated gene (ATM) Ataxia telangiectasia-like AR Meiotic recombination 11, S. cerevisiae, disorder homolog of, A (MRE11A) Nijmegen breakage AR Nijmegen breakage syndrome gene syndrome (NBS1) RAD50 deficiency AR RAD50, cerevisiae, homolog of (RAD50) Radiosensitivity, AR Ring finger protein 168 RNF168( ) immunodeficiency, dysmorphic features and learning difficulties (RIDDLE) syndrome Bloom syndrome AR Bloom syndrome (BLM) Dyskeratosis congenita Dyskerin deficiency XL Dyskerin (DKC1) NHP2 deficiency AR Nucleolar protein family A, member 2 (NOLA2) or (NHP2) NHP3 deficiency AR Nucleolar protein family A, member 3 (NOLA3) or (NOP10, PCFT) RTEL1 deficiency AD, AR Regulator of telomere elongation helicase 1 (RTEL1) TERC deficiency AD Telomerase RNA component (TERC) TERT deficiency AD, AR Telomerase reverse transcriptase (TERT) TINF2 deficiency AD TRF1-interacting nuclear factor 2 (TINF2) TPP1 deficiency AD, AR ACD, mouse homolog of (ACD) DCLRE1B deficiency AR DNA cross-link repair protein 1B (DCLRE1B) or (SNM1/APOLLO) PARN deficiency AR Polyadenylate-specific ribonuclease (PARN) Rothmund-Thomson AD RECQ protein-like 4 (RECQL4) syndrome Other well defined DNA ligase IV deficiency AR DNA ligase IV (LIG4) immunodeficiencies with Cernunnos-XLF AR Nonhomologous end-joining 1 (NHEJ1) DNA repair defects deficiency or CERNUNNOS XRCC4 deficiency AR X-ray repair, complementing defective, in Chinese hamster, 4 (XRCC4) DNA PKcs deficiency AR Protein kinase, DNA-activated catalytic subunit (PRKDC) DNA ligase I deficiency AR DNA LIGASE I (LIG1) Fanconi anemia AR, XL FANCEF gene (FANCF) PMS2 deficiency AR Postmeiotic segregation increased S. cerevisiae, 2 (PMS2) MCM4 deficiency AR Minichromosome maintenance complex component 4 (MCM4) (continued)