Primary Immunodeficiency Diseases: Definition Diagnosis and Management

Primary immunodeficiency diseases (PID) are a group of disorders involving defects in one or more components of the
immune system, and are characterized by an increased incidence of infections, autoimmunity, and malignancies. Although
PID seem to be rare, the number of patients diagnosed has increased in recent years, and more than 150 different forms
of PID have been identified. Nevertheless, because of inadequate medical awareness, a significant number of patients
with PID are either not recognized as having a PID or are not diagnosed as early as they should be. Such delays lead to
a substantial increase in morbidity and mortality among affected individuals.
Our understanding of PID is improving rapidly, which will hopefully lead to more accurate diagnosis and efficient
disease management. This book contains the most recent advances in the field, as well as a concise and structured
review of previously identified PID. Although the book’s primary focus is on practical diagnosis and management, the
pathophysiology of PID is also discussed.
This book is a comprehensive yet manageable resource for physicians and nurses wishing to learn more about PID, as well
as a useful tool for both doctors-in-training and specialists in clinical decision-making and treatment planning.

Content Level » Research

Keywords » Diagnosis - Etiology - Infections - Management - Primary immunodeficiency diseases

Related subjects » Human Genetics - Immunology - Internal Medicine - Pediatrics


Contents
1 An Introduction to Primary
Immunodeficiency Diseases . . . . . . . . . . . . . . . . . . . 1
Nima Rezaei, Francisco A. Bonilla,
Kathleen E. Sullivan, Esther de Vries,
and Jordan S. Orange
1.1 Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.1.1 Background. . . . . . . . . . . . . . . . . . . . 1
1.1.2 History. . . . . . . . . . . . . . . . . . . . . . . . 2
1.1.3 Registries . . . . . . . . . . . . . . . . . . . . . . 2
1.2 Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
1.2.1 Classification . . . . . . . . . . . . . . . . . . . 2
1.2.2 Genetic Defects . . . . . . . . . . . . . . . . 11
1.2.3 Pathophysiology . . . . . . . . . . . . . . . 12
1.3 Clinical Manifestations. . . . . . . . . . . . . . . . 14
1.3.1 Infections. . . . . . . . . . . . . . . . . . . . . 14
1.3.2 Autoimmunity . . . . . . . . . . . . . . . . 15
1.3.3 Malignancies . . . . . . . . . . . . . . . . . . 19
1.3.4 Other Manifestations . . . . . . . . . . . 19
1.4 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
1.4.1 Warning Signs and Symptoms. . . . 20
1.4.2 Diagnostic Approach . . . . . . . . . . . 21
1.4.3 Laboratory Tests . . . . . . . . . . . . . . . 24
1.5 Management . . . . . . . . . . . . . . . . . . . . . . . . 25
1.5.1 General Considerations . . . . . . . . . 25
1.5.2 Vaccination . . . . . . . . . . . . . . . . . . . 26
1.5.3 Antibiotics . . . . . . . . . . . . . . . . . . . . 27
1.5.4 Immunoglobulin Replacement
Therapy . . . . . . . . . . . . . . . . . . . . . . 28
1.5.5 Transplantation. . . . . . . . . . . . . . . . 28
1.5.6 Gene Therapy . . . . . . . . . . . . . . . . . 29
1.5.7 Adjunct Therapies . . . . . . . . . . . . . 29
2 Combined T and B Cell
Immunodeficiencies . . . . . . . . . . . . . . . . . . . . . . . . . 39
Françoise Le Deist, Despina Moshous, Steven J. Howe,
Amit Nahum, Fotini D. Kavadas, Elana Lavine,
Chaim M. Roifman, and Alain Fischer
2.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . 39
2.2 T-B+ Severe Combined Immunodeficiency
(g c Deficiency, JAK3 Deficiency, IL7-Rg
Deficiency, CD45 Deficiency, CD3g/
CD3l/CD3e/CD3x Deficiencies) . . . . . . . . 42
2.2.1 Definition . . . . . . . . . . . . . . . . . . . . 42
2.2.2 Etiology . . . . . . . . . . . . . . . . . . . . . . 42
2.2.3 Clinical Manifestations . . . . . . . . . 44
2.2.4 Diagnosis . . . . . . . . . . . . . . . . . . . . . 45
2.2.5 Management . . . . . . . . . . . . . . . . . . 46
2.3 T-B- Severe Combined Immunodeficiency
(RAG1/2 Deficiencies, Artemis
Deficiency, ADA Deficiency) . . . . . . . . . . . . . 48
2.3.1 Definition . . . . . . . . . . . . . . . . . . . . 48
2.3.2 Etiology . . . . . . . . . . . . . . . . . . . . . . 49
2.3.3 Clinical Manifestations . . . . . . . . . 52
2.3.4 Diagnosis . . . . . . . . . . . . . . . . . . . . . 52
2.3.5 Management . . . . . . . . . . . . . . . . . . 52
2.4 Omenn Syndrome. . . . . . . . . . . . . . . . . . . . 53
2.4.1 Definition . . . . . . . . . . . . . . . . . . . . 53
2.4.2 Etiology . . . . . . . . . . . . . . . . . . . . . . 53
2.4.3 Clinical Manifestations . . . . . . . . . 53
2.4.4 Diagnosis . . . . . . . . . . . . . . . . . . . . . 53
2.4.5 Management . . . . . . . . . . . . . . . . . . 54
2.5 DNA Ligase IV Deficiency . . . . . . . . . . . . . 54
2.5.1 Definition . . . . . . . . . . . . . . . . . . . . 54
2.5.2 Etiology . . . . . . . . . . . . . . . . . . . . . . 54
2.5.3 Clinical Manifestations . . . . . . . . . 54
2.5.4 Diagnosis . . . . . . . . . . . . . . . . . . . . . 55
2.5.5 Management . . . . . . . . . . . . . . . . . . 55
2.6 Cernunnos Deficiency . . . . . . . . . . . . . . . . 55
2.6.1 Definition . . . . . . . . . . . . . . . . . . . . 55
2.6.2 Etiology . . . . . . . . . . . . . . . . . . . . . . 55
2.6.3 Clinical Manifestations . . . . . . . . . 55
2.6.4 Diagnosis . . . . . . . . . . . . . . . . . . . . . 55
2.6.5 Management . . . . . . . . . . . . . . . . . . 56
2.7 Purine Nucleoside Phosphorylase
(PNP) Deficiency . . . . . . . . . . . . . . . . . . . . 56
2.7.1 Definition . . . . . . . . . . . . . . . . . . . . 56
2.7.2 Etiology . . . . . . . . . . . . . . . . . . . . . . 56
2.7.3 Clinical Manifestations . . . . . . . . . 57
2.7.4 Diagnosis . . . . . . . . . . . . . . . . . . 58
2.7.5 Management. . . . . . . . . . . . . . . . 58
2.8 Immunoglobulin Class Switch
Recombination Deficiencies (affecting
CD40–CD40L) (CD40 ligand
Deficiency, CD40 Deficiency) . . . . . . . . . . 59
2.8.1 Definition . . . . . . . . . . . . . . . . . . 59
2.8.2 Etiology. . . . . . . . . . . . . . . . . . . . 59
2.8.3 Clinical Manifestations . . . . . . . 60
2.8.4 Diagnosis . . . . . . . . . . . . . . . . . . 61
2.8.5 Management. . . . . . . . . . . . . . . . 61
2.9 MHC Class II Deficiency (CIITA
Deficiency, RFX5 Deficiency, RFXAP
Deficiency, RFXANK Deficiency) . . . . . . . 62
2.9.1 Definition . . . . . . . . . . . . . . . . . . 62
2.9.2 Etiology. . . . . . . . . . . . . . . . . . . . 62
2.9.3 Clinical Manifestations . . . . . . . 63
2.9.4 Diagnosis . . . . . . . . . . . . . . . . . . 64
2.9.5 Management. . . . . . . . . . . . . . . . 64
2.10 MHC Class I Deficiency (TAP1/2
Deficiencies, Tapasin Deficiency) . . . . . . . 65
2.10.1 Definition . . . . . . . . . . . . . . . . . . 65
2.10.2 Etiology. . . . . . . . . . . . . . . . . . . . 65
2.10.3 Clinical Manifestations . . . . . . . 66
2.10.4 Diagnosis . . . . . . . . . . . . . . . . . . 67
2.10.5 Management. . . . . . . . . . . . . . . . 67
2.11 CD8 Deficiency (CD8a Chain Defect,
ZAP-70 Deficiency) . . . . . . . . . . . . . . . . . . 68
2.11.1 Definition . . . . . . . . . . . . . . . . . . 68
2.11.2 Etiology. . . . . . . . . . . . . . . . . . . . 68
2.11.3 Clinical Manifestations . . . . . . . 69
2.11.4 Diagnosis . . . . . . . . . . . . . . . . . . 69
2.11.5 Management. . . . . . . . . . . . . . . . 70
2.12 CD4 Deficiency (p56lck Deficiency,
Idiopathic CD4 Lymphopenia) . . . . . . . . . 70
2.12.1 Definition . . . . . . . . . . . . . . . . . . 70
2.12.2 Etiology. . . . . . . . . . . . . . . . . . . . 70
2.12.3 Clinical Manifestations . . . . . . . 71
2.12.4 Diagnosis . . . . . . . . . . . . . . . . . . 71
2.12.5 Management. . . . . . . . . . . . . . . . 71
2.13 CRAC Deficiency . . . . . . . . . . . . . . . . . . . 72
2.13.1 Definition . . . . . . . . . . . . . . . . . . 72
2.13.2 Etiology. . . . . . . . . . . . . . . . . . . . 72
2.13.3 Clinical
Manifestations . . . . . . . . . . . . . . 72
2.13.4 Diagnosis . . . . . . . . . . . . . . . . . . 72
2.13.5 Management. . . . . . . . . . . . . . . . 73
2.14 Winged-Helix-Nude (WHN)
Deficiency . . . . . . . . . . . . . . . . . . . . . . . . . 73
2.14.1 Definition . . . . . . . . . . . . . . . . . . 73
2.14.2 Etiology. . . . . . . . . . . . . . . . . . . . 73
2.14.3 Clinical Manifestations . . . . . . . 73
2.14.4 Diagnosis . . . . . . . . . . . . . . . . . . 73
2.14.5 Management. . . . . . . . . . . . . . . . 74
2.15 CD25 Deficiency. . . . . . . . . . . . . . . . . . . . 74
2.15.1 Definition . . . . . . . . . . . . . . . . . . 74
2.15.2 Etiology. . . . . . . . . . . . . . . . . . . . 74
2.15.3 Clinical Manifestations . . . . . . . 75
2.15.4 Diagnosis . . . . . . . . . . . . . . . . . . 75
2.15.5 Management. . . . . . . . . . . . . . . . 76
2.16 STAT5B Deficiency. . . . . . . . . . . . . . . . . . 76
2.16.1 Definition . . . . . . . . . . . . . . . . . . 76
2.16.2 Etiology. . . . . . . . . . . . . . . . . . . . 76
2.16.3 Clinical Manifestations . . . . . . . 77
2.16.4 Diagnosis . . . . . . . . . . . . . . . . . . 77
2.16.5 Management. . . . . . . . . . . . . . . . 78
3 Predominantly Antibody
Deficiencies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
Asghar Aghamohammadi, Vassilios Lougaris,
Alessandro Plebani, Toshio Miyawaki,
Anne Durandy, and Lennart Hammarström
3.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . 97
3.2 Agammaglobulinemia with Absent
B Cells (Btk Deficiency, m Heavy Chain
Deficiency, l5/14.1 Deficiency,
Iga Deficiency, Igb Deficiency, BLNK
Deficiency, LRRC8 Deficiency, Other
Forms of Agammaglobulinemia) . . . . . . . . 99
3.2.1 Definition . . . . . . . . . . . . . . . . . . 99
3.2.2 Etiology. . . . . . . . . . . . . . . . . . . . 99
3.2.3 Clinical Manifestations . . . . . . 101
3.2.4 Diagnosis . . . . . . . . . . . . . . . . . 104
3.2.5 Management. . . . . . . . . . . . . . . 104
3.3 Hypogammaglobulinemia with
Normal/Low Number of B Cells
(Common Variable
Immunodeficiency, ICOS Deficiency,
TACI Deficiency, CD19 Deficiency,
Other Forms of
Hypogammaglobulinemia) . . . . . . . . . . . 105
3.3.1 Definition . . . . . . . . . . . . . . . . . 105
3.3.2 Etiology. . . . . . . . . . . . . . . . . . . 105
3.3.3 Clinical Manifestations . . . . . . 108
3.3.4 Diagnosis . . . . . . . . . . . . . . . . . 110
3.3.5 Management. . . . . . . . . . . . . . . 110
3.4 Immunoglobulin Class Switch
Recombination Deficiencies (Due
to Intrinsic B Cell Defects)
(AID Deficiency, UNG Deficiency,
Other CSR Selective Deficiencies). . . . . . 111
3.4.1 Definition . . . . . . . . . . . . . . . . . 111
3.4.2 Etiology. . . . . . . . . . . . . . . . . . . 111
XII Contents
3.4.3 Clinical Manifestations . . . . . . . . 113
3.4.4 Diagnosis . . . . . . . . . . . . . . . . . . . . 113
3.4.5 Management . . . . . . . . . . . . . . . . . 113
3.5 Selective IgA Deficiency . . . . . . . . . . . . . . 113
3.5.1 Definition . . . . . . . . . . . . . . . . . . . 113
3.5.2 Etiology . . . . . . . . . . . . . . . . . . . . . 114
3.5.3 Clinical Manifestations . . . . . . . . 114
3.5.4 Diagnosis . . . . . . . . . . . . . . . . . . . . 115
3.5.5 Management . . . . . . . . . . . . . . . . . 115
3.6 Other Immunoglobulin Isotypes
or Light Chain Deficiencies (Isolated
IgG Subclass Deficiency, IgA with
IgG Subclass Deficiency, Ig Heavy
Chain Deletions, k Light Chain
Deficiency) . . . . . . . . . . . . . . . . . . . . . . . . . 116
3.6.1 Definition . . . . . . . . . . . . . . . . . . . 116
3.6.2 Etiology . . . . . . . . . . . . . . . . . . . . . 116
3.6.3 Clinical
Manifestations. . . . . . . . . . . . . . . . 116
3.6.4 Diagnosis . . . . . . . . . . . . . . . . . . . . 117
3.6.5 Management . . . . . . . . . . . . . . . . . 117
3.7 Specific Antibody Deficiency with
Normal Immunoglobulin
Concentrations . . . . . . . . . . . . . . . . . . . . . 117
3.7.1 Definition . . . . . . . . . . . . . . . . . . . 117
3.7.2 Etiology . . . . . . . . . . . . . . . . . . . . . 117
3.7.3 Clinical Manifestations . . . . . . . . 118
3.7.4 Diagnosis . . . . . . . . . . . . . . . . . . . . 118
3.7.5 Management . . . . . . . . . . . . . . . . . 118
3.8 Transient Hypogammaglobulinemia
of Infancy. . . . . . . . . . . . . . . . . . . . . . . . . . 118
3.8.1 Definition . . . . . . . . . . . . . . . . . . . 118
3.8.2 Etiology . . . . . . . . . . . . . . . . . . . . . 118
3.8.3 Clinical Manifestations . . . . . . . . 118
3.8.4 Diagnosis . . . . . . . . . . . . . . . . . . . . 119
3.8.5 Management . . . . . . . . . . . . . . . . . 119
4 Phagocytes Defects . . . . . . . . . . . . . . . . . . . . . . . . . 131
Uwe Wintergerst, Sergio D. Rosenzweig,
Mario Abinun, Harry L. Malech,
Steven M. Holland, and Nima Rezaei
4.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . 131
4.2 Severe Congenital Neutropenias
(ELA2 Deficiency, GFI1 Deficiency,
HAX1 Deficiency, CSF3R Deficiency,
Neutropenia with Myelodysplasia) . . . . . . 131
4.2.1 Definition . . . . . . . . . . . . . . . . . . . 131
4.2.2 Etiology . . . . . . . . . . . . . . . . . . . . . 132
4.2.3 Clinical Manifestations . . . . . . . . 134
4.2.4 Diagnosis . . . . . . . . . . . . . . . . . . . . 134
4.2.5 Management . . . . . . . . . . . . . . . . . 134
4.3 Cyclic Neutropenia. . . . . . . . . . . . . . . . . 135
4.3.1 Definition . . . . . . . . . . . . . . . . . 135
4.3.2 Etiology. . . . . . . . . . . . . . . . . . . 135
4.3.3 Clinical
Manifestations . . . . . . . . . . . . . 136
4.3.4 Diagnosis . . . . . . . . . . . . . . . . . 136
4.3.5 Management. . . . . . . . . . . . . . . 136
4.4 Leukocyte Adhesion Deficiency
(LAD Types 1–3) . . . . . . . . . . . . . . . . . . . 136
4.4.1 Definition . . . . . . . . . . . . . . . . . 136
4.4.2 Etiology. . . . . . . . . . . . . . . . . . . 137
4.4.3 Clinical Manifestations . . . . . . 137
4.4.4 Diagnosis . . . . . . . . . . . . . . . . . 139
4.4.5 Management. . . . . . . . . . . . . . . 139
4.5 RAC-2 Deficiency . . . . . . . . . . . . . . . . . . 141
4.5.1 Definition . . . . . . . . . . . . . . . . . 141
4.5.2 Etiology. . . . . . . . . . . . . . . . . . . 141
4.5.3 Clinical Manifestations . . . . . . 141
4.5.4 Diagnosis . . . . . . . . . . . . . . . . . 141
4.5.5 Management. . . . . . . . . . . . . . . 141
4.6 β-Actin Deficiency . . . . . . . . . . . . . . . . . 141
4.6.1 Definition . . . . . . . . . . . . . . . . . 141
4.6.2 Etiology. . . . . . . . . . . . . . . . . . . 141
4.6.3 Clinical Manifestations . . . . . . 142
4.6.4 Diagnosis . . . . . . . . . . . . . . . . . 143
4.6.5 Management. . . . . . . . . . . . . . . 143
4.7 Chronic Granulomatous Disease
(CGD) (gp91 phox Deficiency, p22 phox
Deficiency, p47 phox Deficiency, p67 phox
Deficiency) . . . . . . . . . . . . . . . . . . . . . . . . 143
4.7.1 Definition . . . . . . . . . . . . . . . . . 143
4.7.2 Etiology. . . . . . . . . . . . . . . . . . . 143
4.7.3 Clinical Manifestations . . . . . . 144
4.7.4 Diagnosis . . . . . . . . . . . . . . . . . 148
4.7.5 Management. . . . . . . . . . . . . . . 149
4.8 Neutrophil G-6PD
Deficiency . . . . . . . . . . . . . . . . . . . . . . . . 152
4.8.1 Definition . . . . . . . . . . . . . . . . . 152
4.8.2 Etiology. . . . . . . . . . . . . . . . . . . 153
4.8.3 Clinical Manifestations . . . . . . 153
4.8.4 Diagnosis . . . . . . . . . . . . . . . . . 153
4.8.5 Management. . . . . . . . . . . . . . . 153
4.9 Myeloperoxidase
Deficiency . . . . . . . . . . . . . . . . . . . . . . . . 153
4.9.1 Definition . . . . . . . . . . . . . . . . . 153
4.9.2 Etiology. . . . . . . . . . . . . . . . . . . 153
4.9.3 Clinical Manifestations . . . . . . 153
4.9.4 Diagnosis . . . . . . . . . . . . . . . . . 154
4.9.5 Management. . . . . . . . . . . . . . . 154
4.10 Specific Granule Deficiency. . . . . . . . . . 154
4.10.1 Definition . . . . . . . . . . . . . . . . . 154
4.10.2 Etiology. . . . . . . . . . . . . . . . . . . 154
Contents XIII
4.10.3 Clinical Manifestations . . . . . . 154
4.10.4 Diagnosis . . . . . . . . . . . . . . . . . 154
4.10.5 Management. . . . . . . . . . . . . . . 155
4.11 Shwachman–Diamond Syndrome . . . . 155
4.11.1 Definition . . . . . . . . . . . . . . . . . 155
4.11.2 Etiology. . . . . . . . . . . . . . . . . . . 155
4.11.3 Clinical Manifestations . . . . . . 156
4.11.4 Diagnosis . . . . . . . . . . . . . . . . . 156
4.11.5 Management. . . . . . . . . . . . . . . 157
4.12 Localised Juvenile Periodontitis . . . . . . 158
4.12.1 Definition . . . . . . . . . . . . . . . . . 158
4.12.2 Etiology. . . . . . . . . . . . . . . . . . . 158
4.12.3 Clinical Manifestations . . . . . . 158
4.12.4 Diagnosis . . . . . . . . . . . . . . . . . 158
4.12.5 Management. . . . . . . . . . . . . . . 158
4.13 Papillon–Lefèvre Syndrome. . . . . . . . . . 158
4.13.1 Definition . . . . . . . . . . . . . . . . . 158
4.13.2 Etiology. . . . . . . . . . . . . . . . . . . 158
4.13.3 Clinical Manifestations . . . . . . 159
4.13.4 Diagnosis . . . . . . . . . . . . . . . . . 159
4.13.5 Management. . . . . . . . . . . . . . . 159
5 Genetic Disorders of Immune
Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167
Carsten Speckmann, Jan Rohr,
and Stephan Ehl
5.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . 167
5.2 Familial Hemophagocytic
Lymphohistiocytosis (Perforin Deficiency,
MUNC13-4 Deficiency, Syntaxin 11
Deficiency) . . . . . . . . . . . . . . . . . . . . . . . . . 168
5.2.1 Definition . . . . . . . . . . . . . . . . . . . 168
5.2.2 Etiology . . . . . . . . . . . . . . . . . . . . . 168
5.2.3 Clinical Manifestations . . . . . . . . 169
5.2.4 Diagnosis . . . . . . . . . . . . . . . . . . . . 169
5.2.5 Management . . . . . . . . . . . . . . . . . 171
5.3 Immunodeficiency with Hypopigmentation
(Chediak-Higashi Syndrome, Griscelli
Syndrome, Type II, Hermansky-Pudlak
Syndrome, Type II, p14 Deficiency). . . . . . 172
5.3.1 Definition . . . . . . . . . . . . . . . . . . . 172
5.3.2 Etiology . . . . . . . . . . . . . . . . . . . . . 172
5.3.3 Clinical Manifestations . . . . . . . . 173
5.3.4 Diagnosis . . . . . . . . . . . . . . . . . . . . 173
5.3.5 Management . . . . . . . . . . . . . . . . . 174
5.4 X-Linked Lymphoproliferative
Syndrome (XLP) (SAP Deficiency,
XIAP Deficiency) . . . . . . . . . . . . . . . . . . . . 175
5.4.1 Definition . . . . . . . . . . . . . . . . . . . 175
5.4.2 Etiology . . . . . . . . . . . . . . . . . . . . . 175
5.4.3 Clinical Manifestations . . . . . . . . 176
5.4.4 Diagnosis . . . . . . . . . . . . . . . . . . . . 177
5.4.5 Management . . . . . . . . . . . . . . . . . 178
5.5 Autoimmune Lymphoproliferative
Syndrome (ALPS) (ALPS Ia, Ib, IIa,
IIb, III) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178
5.5.1 Definition . . . . . . . . . . . . . . . . . . . 178
5.5.2 Etiology . . . . . . . . . . . . . . . . . . . . . 178
5.5.3 Clinical Manifestations . . . . . . . . 180
5.5.4 Diagnosis . . . . . . . . . . . . . . . . . . . . 180
5.5.5 Management . . . . . . . . . . . . . . . . . 181
5.6 Autoimmune Polyendocrinopathy
with Candidiasis and Ectodermal
Dystrophy (APECED). . . . . . . . . . . . . . . . 182
5.6.1 Definition . . . . . . . . . . . . . . . . . . . 182
5.6.2 Etiology . . . . . . . . . . . . . . . . . . . . . 182
5.6.3 Clinical Manifestations . . . . . . . . 182
5.6.4 Diagnosis . . . . . . . . . . . . . . . . . . . . 183
5.6.5 Management . . . . . . . . . . . . . . . . . 184
5.7 Immunodysregulation,
Polyendocrinopathy, Enteropathy,
X-Linked (IPEX) . . . . . . . . . . . . . . . . . . . . 184
5.7.1 Definition . . . . . . . . . . . . . . . . . . . 184
5.7.2 Etiology . . . . . . . . . . . . . . . . . . . . . 184
5.7.3 Clinical Manifestations . . . . . . . . 185
5.7.4 Diagnosis . . . . . . . . . . . . . . . . . . . . 186
5.7.5 Management . . . . . . . . . . . . . . . . . 186
6 Defects in Innate Immunity: Receptors
and Signaling Components . . . . . . . . . . . . . . . . . . 195
Nima Parvaneh, Joachim Roesler,
Steven M. Holland, and Tim Niehues
6.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . 195
6.2 Defective Toll-Like Receptor
(TLR) Signaling Without
Ectodermal Dysplasia (IRAK-4
Deficiency, TLR3 Deficiency,
UNC-93B Deficiency) . . . . . . . . . . . . . . . . 196
6.2.1 Definition . . . . . . . . . . . . . . . . . . . 196
6.2.2 Etiology . . . . . . . . . . . . . . . . . . . . . 198
6.2.3 Clinical Manifestations . . . . . . . . 198
6.2.4 Diagnosis . . . . . . . . . . . . . . . . . . . . 198
6.2.5 Management . . . . . . . . . . . . . . . . . 199
6.3 Defective Toll-Like Receptor (TLR)
Signaling with Ectodermal Dysplasia
(XL- and AD-Anhidrotic Ectodermal
Dysplasias with Immunodeficiency) . . . . . 199
6.3.1 Definition . . . . . . . . . . . . . . . . . . . 199
6.3.2 Etiology . . . . . . . . . . . . . . . . . . . . . 199
6.3.3 Clinical Manifestations . . . . . . . . 200
6.3.4 Diagnosis . . . . . . . . . . . . . . . . . . . . 201
6.3.5 Management . . . . . . . . . . . . . . . . . 201
XIV Contents
6.4 Mendelian Susceptibility to
Mycobacterial Diseases (IFN-g
Receptor 1/2 Deficiencies, IL-12/23
Receptor b1 Chain Deficiency,
IL-12p40 Deficiency, STAT1 Deficiency,
LZ-NEMO Deficiency) . . . . . . . . . . . . . . . 201
6.4.1 Definition . . . . . . . . . . . . . . . . . . . 201
6.4.2 Etiology . . . . . . . . . . . . . . . . . . . . . 202
6.4.3 Clinical Manifestations . . . . . . . . 203
6.4.4 Diagnosis . . . . . . . . . . . . . . . . . . . . 203
6.4.5 Management . . . . . . . . . . . . . . . . . 204
6.5 Warts, Hypogammaglobulinemia,
Infections, Myelokathexis (WHIM)
Syndrome. . . . . . . . . . . . . . . . . . . . . . . . . . 205
6.5.1 Definition . . . . . . . . . . . . . . . . . . . 205
6.5.2 Etiology . . . . . . . . . . . . . . . . . . . . . 205
6.5.3 Clinical Manifestations . . . . . . . . 205
6.5.4 Diagnosis . . . . . . . . . . . . . . . . . . . . 206
6.5.5 Management . . . . . . . . . . . . . . . . . 206
6.6 Epidermodysplasia Verruciformis
(EV Types 1,2) . . . . . . . . . . . . . . . . . . . . . . 207
6.6.1 Definition . . . . . . . . . . . . . . . . . . . 207
6.6.2 Etiology . . . . . . . . . . . . . . . . . . . . . 207
6.6.3 Clinical Manifestations . . . . . . . . 207
6.6.4 Diagnosis . . . . . . . . . . . . . . . . . . . . 208
6.6.5 Management . . . . . . . . . . . . . . . . . 208
7 Autoinflammatory Disorders. . . . . . . . . . . . . . . . . 215
Stefan Berg and Anders Fasth
7.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . 215
7.2 Familial Mediterranean Fever (FMF) . . . 217
7.2.1 Definition . . . . . . . . . . . . . . . . . . . 217
7.2.2 Etiology . . . . . . . . . . . . . . . . . . . . . 218
7.2.3 Clinical Manifestations . . . . . . . . 218
7.2.4 Diagnosis . . . . . . . . . . . . . . . . . . . . 219
7.2.5 Management . . . . . . . . . . . . . . . . . 219
7.3 Mevalonate Kinase Deficiency (MKD)
(Hyperimmunoglobulinemia D
and Periodic Fever Syndrome,
Mevalonic aciduria). . . . . . . . . . . . . . . . . . 220
7.3.1 Definition . . . . . . . . . . . . . . . . . . . 220
7.3.2 Etiology . . . . . . . . . . . . . . . . . . . . . 220
7.3.3 Clinical Manifestations . . . . . . . . 220
7.3.4 Diagnosis . . . . . . . . . . . . . . . . . . . . 221
7.3.5 Management . . . . . . . . . . . . . . . . . 221
7.4 Tumor Necrosis Factor Receptor-
Associated Periodic Syndrome
(TRAPS). . . . . . . . . . . . . . . . . . . . . . . . . . . 221
7.4.1 Definition . . . . . . . . . . . . . . . . . . . 221
7.4.2 Etiology . . . . . . . . . . . . . . . . . . . . . 222
7.4.3 Clinical Manifestations . . . . . . . . 222
7.4.4 Diagnosis . . . . . . . . . . . . . . . . . . . . 222
7.4.5 Management . . . . . . . . . . . . . . . . . 223
7.5 Cryopyrin-Associated Periodic Syndrome
(CAPS) (Chronic Infantile Neurological
Cutaneous Articular Syndrome,
Muckle–Wells Syndrome, Familial Cold
Autoinflammatory Syndrome) . . . . . . . . . 223
7.5.1 Definition . . . . . . . . . . . . . . . . . . . 223
7.5.2 Etiology . . . . . . . . . . . . . . . . . . . . . 223
7.5.3 Clinical Manifestations . . . . . . . . 223
7.5.4 Diagnosis . . . . . . . . . . . . . . . . . . . . 224
7.5.5 Management . . . . . . . . . . . . . . . . . 224
7.6 Blau Syndrome . . . . . . . . . . . . . . . . . . . . . 224
7.6.1 Definition . . . . . . . . . . . . . . . . . . . 224
7.6.2 Etiology . . . . . . . . . . . . . . . . . . . . . 224
7.6.3 Clinical Manifestations . . . . . . . . 225
7.6.4 Diagnosis . . . . . . . . . . . . . . . . . . . . 225
7.6.5 Management . . . . . . . . . . . . . . . . . 225
7.7 Pyogenic Arthritis, Pyoderma
Gangrenosum and Acne Syndrome
(PAPA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225
7.7.1 Definition . . . . . . . . . . . . . . . . . . . 225
7.7.2 Etiology . . . . . . . . . . . . . . . . . . . . . 225
7.7.3 Clinical Manifestations . . . . . . . . 225
7.7.4 Diagnosis . . . . . . . . . . . . . . . . . . . . 226
7.7.5 Management . . . . . . . . . . . . . . . . . 226
7.8 Multifactorial/Polygenic
Autoinflammatory Diseases . . . . . . . . . . . . . .226
7.8.1 Periodic Fever, Aphtous Stomatitis,
Pharyngitis and Cervical
Adenitis (PFAPA) . . . . . . . . . . . . . 226
7.8.2 Systemic Onset Juvenile
Idiopathic Arthritis
(SoJIA). . . . . . . . . . . . . . . . . . . . . . 227
7.8.3 Adult-Onset Still’s Disease
(AOSD) . . . . . . . . . . . . . . . . . . . . . 227
7.8.4 Chronic Recurrent Multifocal
Osteomyelitis (CRMO) . . . . . . . . 227
7.8.5 Crohn’s Disease (CD). . . . . . . . . . 227
7.8.6 Behçet’s Disease (BD). . . . . . . . . . 227
7.8.7 “Undifferentiated” . . . . . . . . . . . . 228
8 Complement Deficiencies . . . . . . . . . . . . . . . . . . . . 235
Maryam Mahmoudi, Tom Eirik Mollnes,
Taco W. Kuijpers, and Dirk Roos
8.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . 235
8.2 Deficiencies of Classical Pathway
Components (C1q/C1r/C1s
Deficiencies, C4 Deficiency, C2
Deficiency) . . . . . . . . . . . . . . . . . . . . . . . . . 238
8.2.1 Definition . . . . . . . . . . . . . . . . . . . 238
Contents XV
8.2.2 Etiology . . . . . . . . . . . . . . . . . . . . . 238
8.2.3 Clinical Manifestations . . . . . . . . 239
8.2.4 Diagnosis . . . . . . . . . . . . . . . . . . . . 239
8.2.5 Management . . . . . . . . . . . . . . . . . 239
8.3 Deficiencies of Lectin Pathway
Components (MBL Deficiency,
MASP2 Deficiency) . . . . . . . . . . . . . . . . . . 239
8.3.1 Definition . . . . . . . . . . . . . . . . . . . 239
8.3.2 Etiology . . . . . . . . . . . . . . . . . . . . . 240
8.3.3 Clinical Manifestations . . . . . . . . 240
8.3.4 Diagnosis . . . . . . . . . . . . . . . . . . . . 240
8.3.5 Management . . . . . . . . . . . . . . . . . 240
8.4 Deficiencies of Alternative Pathway
Components (Factor D Deficiency,
Properdin Deficiency) . . . . . . . . . . . . . . . . 240
8.4.1 Definition . . . . . . . . . . . . . . . . . . . 240
8.4.2 Etiology . . . . . . . . . . . . . . . . . . . . . 241
8.4.3 Clinical Manifestations . . . . . . . . 241
8.4.4 Diagnosis . . . . . . . . . . . . . . . . . . . . 241
8.4.5 Management . . . . . . . . . . . . . . . . . 241
8.5 Deficiency of Complement
Component C3 . . . . . . . . . . . . . . . . . . . . . 241
8.5.1 Definition . . . . . . . . . . . . . . . . . . . 241
8.5.2 Etiology . . . . . . . . . . . . . . . . . . . . . 242
8.5.3 Clinical Manifestations . . . . . . . . 242
8.5.4 Diagnosis . . . . . . . . . . . . . . . . . . . . 242
8.5.5 Management . . . . . . . . . . . . . . . . . 242
8.6 Deficiencies of Terminal Pathway
Components (C5-9 Deficiencies) . . . . . . . 242
8.6.1 Definition . . . . . . . . . . . . . . . . . . . 242
8.6.2 Etiology . . . . . . . . . . . . . . . . . . . . . 242
8.6.3 Clinical
Manifestations. . . . . . . . . . . . . . . . 242
8.6.4 Diagnosis . . . . . . . . . . . . . . . . . . . . 242
8.6.5 Management . . . . . . . . . . . . . . . . . 243
8.7 Deficiencies of Complement Regulatory
Proteins (C1 Inhibitor Deficiency,
Factor I Deficiency, Factor H Deficiency,
CD46 Deficiency, CD55 Deficiency,
CD59 Deficiency). . . . . . . . . . . . . . . . . . . . 243
8.7.1 Definition . . . . . . . . . . . . . . . . . . . 243
8.7.2 Etiology . . . . . . . . . . . . . . . . . . . . . 243
8.7.3 Clinical Manifestations . . . . . . . . 244
8.7.4 Diagnosis . . . . . . . . . . . . . . . . . . . . 245
8.7.5 Management . . . . . . . . . . . . . . . . . 246
9 Other Well-Defined
Immunodeficiencies . . . . . . . . . . . . . . . . . . . . . . . . . 251
Mehdi Yeganeh, Eleonora Gambineri,
Kamran Abolmaali, Banafshe Tamizifar,
and Teresa Español
9.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . 251
9.2 Other Syndromes Associated
with Defective DNA Repair (Ataxia-
Telangiectasia, Ataxia-Like Syndrome,
Nijmegen Breakage Syndrome,
Bloom’s Syndrome,
ICF Syndrome) . . . . . . . . . . . . . . . . . . . . .252
9.2.1 Definition . . . . . . . . . . . . . . . . . . . 252
9.2.2 Etiology . . . . . . . . . . . . . . . . . . . . . 253
9.2.3 Clinical Manifestations . . . . . . . . 254
9.2.4 Diagnosis . . . . . . . . . . . . . . . . . . . . 257
9.2.5 Management . . . . . . . . . . . . . . . . . 257
9.3 Di George Syndrome . . . . . . . . . . . . . . . . 258
9.3.1 Definition . . . . . . . . . . . . . . . . . . . 258
9.3.2 Etiology . . . . . . . . . . . . . . . . . . . . . 258
9.3.3 Clinical Manifestations . . . . . . . . 259
9.3.4 Diagnosis . . . . . . . . . . . . . . . . . . . . 261
9.3.5 Management . . . . . . . . . . . . . . . . . 261
9.4 Wiskott-Aldrich Syndrome . . . . . . . . . . . 262
9.4.1 Definition . . . . . . . . . . . . . . . . . . . 262
9.4.2 Etiology . . . . . . . . . . . . . . . . . . . . . 262
9.4.3 Clinical Manifestations . . . . . . . . 264
9.4.4 Diagnosis . . . . . . . . . . . . . . . . . . . . 265
9.4.5 Management . . . . . . . . . . . . . . . . . 266
9.5 Hyper-IgE Syndrome (Stat3
Deficiency, Tyk2 Deficiency, HIES
with Unknown Origin) . . . . . . . . . . . . . . . 267
9.5.1 Definition . . . . . . . . . . . . . . . . . . . 267
9.5.2 Etiology . . . . . . . . . . . . . . . . . . . . . 267
9.5.3 Clinical Manifestations . . . . . . . . 267
9.5.4 Diagnosis . . . . . . . . . . . . . . . . . . . . 268
9.5.5 Management . . . . . . . . . . . . . . . . . 269
9.6 Immuno-Osseous Dysplasias
(Schimke Syndrome, Cartilage
Hair Hypoplasia) . . . . . . . . . . . . . . . . . . . . 269
9.6.1 Definition . . . . . . . . . . . . . . . . . . . 269
9.6.2 Etiology . . . . . . . . . . . . . . . . . . . . . 270
9.6.3 Clinical Manifestations . . . . . . . . 271
9.6.4 Diagnosis . . . . . . . . . . . . . . . . . . . . 272
9.6.5 Management . . . . . . . . . . . . . . . . . 272
9.7 Chronic Mucocutaneous Candidiasis . . . 272
9.7.1 Definition . . . . . . . . . . . . . . . . . . . 272
9.7.2 Etiology . . . . . . . . . . . . . . . . . . . . . 273
9.7.3 Clinical Manifestations . . . . . . . . 273
9.7.4 Diagnosis . . . . . . . . . . . . . . . . . . . . 274
9.7.5 Management . . . . . . . . . . . . . . . . . 274
9.8 Netherton Syndrome . . . . . . . . . . . . . . . . 274
9.8.1 Definition . . . . . . . . . . . . . . . . . . . 274
9.8.2 Etiology . . . . . . . . . . . . . . . . . . . . . 275
9.8.3 Clinical Manifestations . . . . . . . . 275
9.8.4 Diagnosis . . . . . . . . . . . . . . . . . . . . 276
9.8.5 Management . . . . . . . . . . . . . . . . . 276
9.9 Dyskeratosis Congenita and Høyeraal-
Hreidarsson Syndrome. . . . . . . . . . . . . . . 276
XVI Contents
9.9.1 Definition . . . . . . . . . . . . . . . . 276
9.9.2 Etiology . . . . . . . . . . . . . . . . . . 276
9.9.3 Clinical Manifestations . . . . . 277
9.9.4 Diagnosis. . . . . . . . . . . . . . . . . 278
9.9.5 Management . . . . . . . . . . . . . . 278
10 Syndromic Immunodeficiencies . . . . . . . . . . . . . 291
Jeffrey E. Ming and E. Richard Stiehm
10.1 Introduction . . . . . . . . . . . . . . . . . . . . . 291
10.2 Syndromes Associated with
Growth Deficiency . . . . . . . . . . . . . . . . 293
10.2.1 Cartilage Hair
Hypoplasia . . . . . . . . . . . . . . . 294
10.2.2 Schimke Immuno-osseous
Dysplasia . . . . . . . . . . . . . . . . . 294
10.2.3 Short-Limb Skeletal
Dysplasia with Combined
Immunodeficiency . . . . . . . . . 294
10.2.4 Roifman Syndrome
(Roifman Syndrome 1) . . . . . 294
10.2.5 Roifman–Costa Syndrome
(Roifman Syndrome 2) . . . . . .294
10.2.6 Spondyloenchondrodysplasia 295
10.2.7 Growth Hormone Pathway
Defects. . . . . . . . . . . . . . . . . . . 295
10.2.8 Kabuki Syndrome. . . . . . . . . . 295
10.2.9 CHARGE Association . . . . . . 295
10.2.10 Rubinstein–Taybi
Syndrome . . . . . . . . . . . . . . . . 295
10.2.11 Mulvihill–Smith
Syndrome . . . . . . . . . . . . . . . . 296
10.3 Syndromes Associated with
Gastrointestinal Dysfunction . . . . . . . 296
10.3.1 Shwachman–Diamond
Syndrome . . . . . . . . . . . . . . . . 298
10.3.2 Familial Intestinal
Polyatresia . . . . . . . . . . . . . . . . 298
10.3.3 Trichohepatoenteric
Syndrome . . . . . . . . . . . . . . . . 298
10.4 Syndromes Associated with Cutaneous
Abnormalities . . . . . . . . . . . . . . . . . . . . 298
10.4.1 Wiskott–Aldrich Syndrome. . 298
10.4.2 Chediak–Higashi Syndrome . 298
10.4.3 Griscelli Syndrome, Type II . . 298
10.4.4 Omenn Syndrome . . . . . . . . . 298
10.4.5 WHN Deficiency . . . . . . . . . . 299
10.4.6 Papillon–Lefèvre Syndrome . 299
10.4.7 WHIM Syndrome. . . . . . . . . . 299
10.4.8 Hypohidrotic/Anhidrotic
Ectodermal Dysplasia. . . . . . . 299
10.4.9 Incontinentia Pigmenti . . . . . 299
10.4.10 OLEDAID Syndrome. . . . . . . 299
10.4.11 Dyskeratosis Congenita . . . . . 300
10.4.12 Hermansky–Pudlak
Syndrome, Type II . . . . . . . . . 300
10.4.13 Poikiloderma with
Neutropenia . . . . . . . . . . . . . . 300
10.4.14 Acrodermatitis
Enteropathica . . . . . . . . . . . . . 300
10.4.15 Netherton Syndrome . . . . . . . 300
10.4.16 p14 Deficiency . . . . . . . . . . . . 300
10.5 Syndromes Associated with
Neurologic Dysfunction . . . . . . . . . . . 300
10.5.1 Myotonic Dystrophy . . . . . . . 300
10.5.2 Høyeraal–Hreidarsson
Syndrome . . . . . . . . . . . . . . . . 301
10.5.3 Cohen Syndrome . . . . . . . . . . 301
10.6 Inborn Errors of Metabolism
Associated with
Immunodeficiency . . . . . . . . . . . . . . . . 301
10.6.1 Adenosine Deaminase
Deficiency . . . . . . . . . . . . . . . . 301
10.6.2 Purine Nucleoside
Phosphorylase Deficiency . . . 301
10.6.3 Leukocyte Adhesion
Deficiency, Type 2. . . . . . . . . . 301
10.6.4 Congenital Disorders of
Glycosylation, Type I . . . . . . . 302
10.6.5 Glycogen Storage Disease
Ib/Ic . . . . . . . . . . . . . . . . . . . . . 303
10.6.6 Barth Syndrome . . . . . . . . . . . 303
10.6.7 Galactosemia. . . . . . . . . . . . . . 303
10.6.8 Branched-Chain Amino
Acidurias . . . . . . . . . . . . . . . . . 303
10.6.9 Lysinuric Protein
Intolerance . . . . . . . . . . . . . . . 303
10.7 Syndromes with Chromosome
Instability and/or Defective
DNA Repair Associated with
Immunodeficiency . . . . . . . . . . . . . . . . 303
10.7.1 Nijmegen Breakage
Syndrome . . . . . . . . . . . . . . . . 303
10.7.2 Bloom Syndrome . . . . . . . . . . 304
10.7.3 Ataxia-Telangiectasia . . . . . . . 304
10.7.4 DNA Ligase IV Deficiency. . . 305
10.7.5 ICF Syndrome. . . . . . . . . . . . . 305
10.7.6 Fanconi Pancytopenia . . . . . . 305
10.8 Syndromes Associated with
Chromosomal Abnormalities
of Number or Structure. . . . . . . . . . . . 305
10.8.1 Deletions of 22q11
and 10p13-p14 . . . . . . . . . . . . 305
10.8.2 Trisomy 21. . . . . . . . . . . . . . . . 305
Contents XVII
10.8.3 Partial Deletions of
Chromosome 4p. . . . . . . . . . . 306
10.8.4 Turner Syndrome . . . . . . . . . . 306
11 Treatment of Primary
Immunodeficiency Diseases . . . . . . . . . . . . . . . . 315
Hale Yarmohammadi
and Charlotte Cunningham-Rundles
11.1 Introduction . . . . . . . . . . . . . . . . . . . . . 315
11.2 Therapy for Combined T
and B Cell Immunodeficiencies . . . . . 315
11.2.1 Severe Combined
Immunodeficiency . . . . . . . . . 315
11.2.2 Immunoglobulin Class
Switch Recombination
Deficiencies (Affecting
CD40-CD40L) . . . . . . . . . . . . . 317
11.2.3 MHC Class II Deficiency . . . . 318
11.3 Therapy for Predominantly
Antibody Deficiencies . . . . . . . . . . . . . 318
11.3.1 Agammaglobulinemia
with Absent B Cells . . . . . . . . 318
11.3.2 Hypogammaglobulinemia
with Normal/Low Number
of B Cells . . . . . . . . . . . . . . . . . 319
11.3.3 Immunoglobulin Class
Switch Recombination
Deficiencies (Due to
Intrinsic B Cell Defects). . . . . 319
11.3.4 Selective IgA
Deficiency . . . . . . . . . . . . . . . . 320
11.3.5 Isolated IgG Subclass
Deficiency . . . . . . . . . . . . . . . . 321
11.3.6 Specific Antibody Deficiency
with Normal Immunoglobulin
Concentrations . . . . . . . . . . . . 321
11.3.7 Transient
Hypogammaglobulinemia
of Infancy . . . . . . . . . . . . . . . . 321
11.4 Therapy for Phagocytes Defects . . . . . 321
11.4.1 Severe Congenital
Neutropenias/Cyclic
Neutropenia . . . . . . . . . . . . . . 321
11.4.2 Leukocyte Adhesion
Deficiency . . . . . . . . . . . . . . . . 323
11.4.3 Chronic Granulomatous
Disease. . . . . . . . . . . . . . . . . . . 323
11.5 Therapy for Genetic Disorders
of Immune Regulation. . . . . . . . . . . . . 323
11.5.1 Chediak-Higashi
Syndrome . . . . . . . . . . . . . . . . 323
11.5.2 Griscelli Syndrome,
Type II . . . . . . . . . . . . . . . . . . . 324
11.5.3 X-Linked Lymphoproliferative
Syndrome . . . . . . . . . . . . . . . . 324
11.6 Therapy for Defects in Innate
Immunity: Receptors and Signaling
Components . . . . . . . . . . . . . . . . . . . . . 325
11.6.1 IRAK-4 Deficiency . . . . . . . . . 325
11.6.2 Mendelian Susceptibility
to Mycobacterial
Diseases . . . . . . . . . . . . . . . . . . 325
11.6.3 Warts, Hypogammaglobulinemia,
Infections, Myelokathexis
(WHIM) Syndrome . . . . . . . . . .325
11.7 Therapy for Autoinflammatory
Disorders . . . . . . . . . . . . . . . . . . . . . . . . 325
11.7.1 Familial Mediterranean
Fever . . . . . . . . . . . . . . . . . . . . 325
11.7.2 Other Autoinflammatory
Disorders. . . . . . . . . . . . . . . . . 326
11.8 Therapy for Complement
Deficiencies . . . . . . . . . . . . . . . . . . . . . . 326
11.8.1 Deficiencies of
Classical, Lectin
and Alternative Pathways
Components . . . . . . . . . . . . . . 326
11.8.2 Deficiencies of Terminal
Pathway Components . . . . . . 326
11.8.3 C1 Inhibitor Deficiency . . . . . 326
11.9 Therapy for Other Well-Defined
Immunodeficiencies. . . . . . . . . . . . . . . 326
11.9.1 Ataxia-Telangiectasia . . . . . . . 326
11.9.2 Di George Syndrome . . . . . . . 327
11.9.3 Wiskott-Aldrich
Syndrome . . . . . . . . . . . . . . . . 328
11.9.4 Hyper-IgE Syndrome . . . . . . . 328
11.9.5 Chronic Mucocutaneous
Candidiasis . . . . . . . . . . . . . . . 328
Index. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335
XVIII Contents
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