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

3. Nima Rezaei
Asghar Aghamohammadi • Luigi D. Notarangelo (Eds.)
Primary
Immunodeficiency
Diseases
Definition, Diagnosis, and Management
With 55 Figures, mostly in Color

4. Editor-in-Chief
Nima Rezaei
Immunology, Asthma and Allergy
Research Institute
Children’s Medical Center Hospital
Tehran University of Medical Sciences
Tehran 14194
Iran
and
Section of Infection, Inflammation and Immunity
School of Medicine 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
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5. 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.

6. 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

7. 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

8. 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

9. 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

10. 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

11. 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

12. 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

13. 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

14. 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

15. 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

16. 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 Pediatrics 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

17. 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

18. 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

19. 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

20. 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

21. 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

22. 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

23. 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

24. 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