International Union of Immunological Societies: 2017 Primary Immunodeficiency Diseases Committee Report on Inborn Errors of Immunity (original) (raw)

Abstract

Beginning in 1970, a committee was constituted under the auspices of the World Health Organization (WHO) to catalog primary immunodeficiencies. Twenty years later, the International Union of Immunological Societies (IUIS) took the remit of this committee. The current report details the categorization and listing of 354 (as of February 2017) inborn errors of immunity. The growth and increasing complexity of the field have been impressive, encompassing an increasing variety of conditions, and the classification described here will serve as a critical reference for immunologists and researchers worldwide.

Keywords: IUIS, primary immune deficiency, immune dysregulation, autoinflammatory disorders

Introduction

In 1970, Drs. Fudenberg, Good, Hitzig, Kunkel, Roitt, Rosen, Rowe, Seligmann, and Soothill met under the auspices of the World Health Organization to classify the emerging “primary immune deficiencies.” This august group focused on understanding whether immunodeficiencies could be categorized as B cell disorders or T cell disorders [1, 2]. Their initial report identified 16 distinct immunodeficiencies and included the prophetic comment that “the variable immunodeficiency group probably lumps together a series of syndromes…. Included in this group are cases previously classified as ‘congenital’, non-sex linked or sporadic hypogammaglobulinemia, primary ‘dysgammglobulinemia’ of both childhood and adult life, and ‘acquired’ primary hypogammaglobulinemia. It is hoped that careful analysis of such patients…. will result in delineation of several homogeneous syndromes…”. Indeed, the emergence of monogenic causes of hypogammaglobulinemia (Table 3) and disorders with variable immunoglobulin abnormalities associated with immune dysregulation (Table 4) have been the groups of immunodeficiencies most transformed by the advent of new technologies. Another group dramatically impacted by resetting of the clinical radar and new techniques has been the set of disorders associated with a limited spectrum of infectious susceptibility. The graphs in Fig. 1 define the transformation of the field over the interval during which next-generation sequencing came to prominence. The tremendous progress, energy, and enthusiasm in the field currently have led to a greater need than ever for a current cataloging of the disorders.

Table 3.

Predominantly antibody deficiencies

Disease Genetic defect Inheritance OMIM Ig Associated features
1. Severe reduction in all serum immunoglobulin isotypes with profoundly decreased or absent B cells, agammaglobulinemia
BTK deficiency, X-linked agammaglobulinemia (XLA) BTK XL 300300 All isotypes decreased in majority of patients, some patients have detectable immunoglobulins Severe bacterial infections, normal numbers of pro-B cells
μ heavy chain deficiency IGHM AR 147020 All isotypes decreased Severe bacterial infections, normal numbers of pro-B cells
λ5 deficiency IGLL1 AR 146770 All isotypes decreased Severe bacterial infections, normal numbers of pro-B cells
Igα deficiency CD79A AR 112205 All isotypes decreased Severe bacterial infections, normal numbers of pro-B cells
Igβ deficiency CD79B AR 147245 All isotypes decreased Severe bacterial infections, normal numbers of pro-B cells
BLNK deficiency BLNK AR 604515 All isotypes decreased Severe bacterial infections, normal numbers of pro-B cells
PIK3R1 deficiency PIK3R1 AR 171833 All isotypes decreased Severe bacterial infections, decreased or absent pro-B cells
E47 transcription factor deficiency TCF3 AD 147141 All isotypes decreased Recurrent bacterial infections
2. Severe reduction in at least 2 serum immunoglobulin isotypes with normal or low number of B cells, CVID phenotype
Common variable immune deficiency with no gene defect specified (CVID) Unknown Variable Low IgG and IgA and/or IgM Clinical phenotypes vary: most have recurrent infections, some have polyclonal lymphoproliferation, autoimmune cytopenias and/or granulomatous disease
PIK3CD mutation (GOF) PIK3CD GOF AD 602839 All isotypes decreased Severe bacterial infections; decreased or absent pro-B cells, EBV
PIK3R1 deficiency (LOF) PIK3R1 AD 616005 All isotypes decreased Severe bacterial infections, pro-B cells present and low numbers of memory B cells, EBV
PTEN Deficiency (LOF) PTEN AD 601728 Decreased Lymphoproliferation, autoimmunity
CD19 deficiency CD19 AR 107265 Low IgG and IgA and/or IgM Recurrent infections, may have glomerulonephritis
CD81 deficiency CD81 AR 186845 Low IgG, low or normal IgA and IgM Recurrent infections, may have glomerulonephritis
CD20 deficiency MS4A1 AR 112210 Low IgG, normal or elevated IgM and IgA Recurrent infections
CD21 deficiency CR2 AR 120650 Low IgG, impaired anti-pneumococcal response Recurrent infections
TACI deficiency TNFRSF13B (TACI) AD or AR 604907 Low IgG and IgA and/or IgM Variable clinical expression
BAFF receptor deficiency TNFRSF13C (BAFF-R) AR 606269 Low IgG and IgM, Variable clinical expression
TWEAK deficiency TNFSF12 AD 602695 Low IgM and A, lack of anti-pneumococcal antibody Pneumonia, bacterial infections, warts, thrombocytopenia. Neutropenia
Mannosyl-oligosaccharide glucosidase deficiency (MOGS) MOGS (GCS1) AR 601336 Severe hypogammaglobulinemia, Bacterial and viral infections, severe neurologic disease, also known as congenital disorder of glycosylation type IIb (CDG-IIb)
TRNT1 deficiency TRNT1 AR 612907 B cell deficiency and hypogammaglobulinemia Congenital sideroblastic anemia, deafness, developmental delay
TTC37 deficiency TTC37 AR 614649 Poor antibody response to pneumococcal vaccine Recurrent bacterial and viral infections, abnormal hair findings: trichorrhexis nodosa
NFKB1 deficiency NFKB1 AD 164011 Normal or low IgG, IgA, IgM, low or normal B cells, low memory B cells Recurrent sinopulmonary infections, COPD, EBV proliferation, autoimmune cytopenias, alopecia and autoimmune thyroiditis
NFKB2 deficiency NFKB2 AD 615577 Low serum IgG, A and M; low B cell numbers Recurrent sinopulmonary infections, alopecia, and endorinopathies
IKAROS deficiency IKZF1 AD 603023 Low IgG, IgA, IgM, low or normal B cells, potentially reducing levels with age Recurrent sinopulmonary infections
IRF2BP2 deficiency IRF2BP2 AD 615332 Hypogammaglobulenia, absent IgA Recurrent infections, possible autoimmunity and inflammatory disease
ATP6AP1 deficiency ATP6AP1 XL 300197 Variable immunoglobulin findings Hepatopathy, leukopenia, low copper
3. Severe reduction in serum IgG and IgA with normal/elevated IgM and normal numbers of B cells, hyper IgM
AID deficiency AICDA AR 605257 IgG and IgA decreased, IgM increased Bacterial infections, enlarged lymph nodes and germinal centers
UNG deficiency UNG AR 191525 IgG and IgA decreased, IgM increased Enlarged lymph nodes and germinal centers
INO80 INO80 AR 610169 IgG and IgA decreased, IgM increased Severe bacterial infections
MSH6 MSH6 AR 600678 Variable IgG, defects, increased IgM in some, normal B cells, low switched memory B cells, Ig-class switch recombination and somatic hypermutation defects Family or personal history of cancer
4. Isotype, light chain, or functional deficiencies with generally normal numbers of B cells
Ig heavy chain mutations and deletions Mutation or chromosomal deletion at 14q32 AR One or more IgG and/or IgA subclasses as well as IgE may be absent May be asymptomatic
Kappa chain deficiency IGKC AR 147200 All immunoglobulins have lambda light chain Asymptomatic
Isolated IgG subclass deficiency Unknown ? Reduction in one or more IgG subclass Usually asymptomatic, a minority may have poor antibody response to specific antigens and recurrent viral/bacterial infections
IgG subclass deficiency with IgA deficiency Unknown ? Reduced IgA with decrease in one or more IgG subclass Recurrent bacterial infections
Selective IgA deficiency Unknown ? Very low to absent IgA with other isotypes normal, normal subclasses and specific antibodies Bacterial infections, autoimmunity mildly increased
Specific antibody deficiency with normal Ig levels and normal B cells Unknown ? Normal Reduced ability to produce antibodies to specific antigens
Transient hypogammaglobulinemia of infancy Unknown ? IgG and IgA decreased Normal ability to produce antibodies to vaccine antigens, usually not associated with significant infections
CARD11 GOF CARD11 AD GOF 607210 High B cell numbers due to constitutive NF-κB activation Splenomegaly, lymphadenopathy, poor vaccine response
Selective IgM deficiency Unknown ? Absent serum IgM Pneumococcal / bacterial infections

Table 4.

Diseases of immune dysregulation

Disease Genetic defect Inheritance OMIM Circulating T cells Circulating B cells Functional defect Associated features
1. Familial hemophagocytic lymphohistiocytosis (FHL syndromes)
Perforin deficiency (FHL2) PRF1 AR 170280 Increased activated T cells Normal Decreased to absent NK and CTL activities cytotoxicity Fever, (H)SM, hemophagocytic lymphohistiocytosis (HLH), cytopenias
UNC13D/Munc13-4 deficiency (FHL3) UNC13D AR 608897 Increased activated T cells Normal Decreased to absent NK and CTL activities (cytotoxicity and/or degranulation) Fever, (H)SM, HLH, cytopenias,
Syntaxin 11 deficiency (FHL4) STX11 AR 605014 Increased activated T cells Normal Decreased NK activity (cytotoxicity and/or degranulation) Fever, (H)SM, cHLH, cytopenias,
STXBP2/Munc18-2 deficiency (FHL5) STXBP2 AR or AD 601717 Increased activated T cells Normal Decreased NK and CTL activities (cytotoxicity and/or degranulation) Fever, (H)SM, cHLH, cytopenias, enteropathy
FAAP24 deficiency FAAP24 AR 610884 Increased activated T cells Normal Failure to kill autologous EBV transformed B cells. Normal NK cell function EBV infection-driven lymphoproliferative disease
2. FHL syndromes with hypopigmentation
Chediak-Higashi syndrome LYST AR 606897 Increased activated T cells Normal Decreased NK and CTL activities (cytotoxicity and/or degranulation) Partial albinism, recurrent infections, fever, HSM, HLH, giant lysosomes, neutropenia, cytopenias, bleeding tendency, progressive neurological dysfunction
Griscelli syndrome, type 2 RAB27A AR 603868 Normal Normal Decreased NK and CTL activities (cytotoxicity and/or degranulation) Partial albinism, fever, HSM, HLH, cytopenias
Hermansky-Pudlak syndrome, type 2 AP3B1 AR 603401 Normal Normal Decreased NK and CTL activities (cytotoxicity and/or degranulation) Partial albinism, recurrent infections, pulmonary fibrosis, increased bleeding, neutropenia, HLH
Hermansky-Pudlak syndrome, type 10 AP3D1 AR 617050 Normal Normal Decreased NK and CTL activities (cytotoxicity and/or degranulation) Oculocutaneous albinism, severe neutropenia, recurrent infections, seizures, hearing loss, and neurodevelopmental delay
3. Regulatory T cell defects
IPEX, immune dysregulation, polyendocrinopathy, enteropathy X-linked FOXP3 XL 300292 Normal Normal Lack of (and/or impaired function of) CD4+ CD25+ FOXP3+ regulatory T cells (Tregs) Autoimmune enteropathy, early-onset diabetes, thyroiditis hemolytic anemia, thrombocytopenia, eczema, elevated IgE, IgA
CD25 deficiency IL2RA AR 147730 Normal to decreased Normal No CD4 + C25+ cells with impaired function of Tregs cells Lymphoproliferation, autoimmunity, impaired T cell proliferation
CTLA4 deficiency (ALPSV) CTLA4 AD 123890 Decreased Decreased Impaired function of Tregs. Autoimmune cytopenias, enteropathy, interstitial lung disease, extra-lymphoid lymphocytic infiltration recurrent infections
LRBA deficiency LRBA AR 606453 Normal or decreased CD4 numbers, T cell dysregulation Low or normal numbers of B cells Reduced I IgG and IgA in most Recurrent infections, inflammatory bowel disease, autoimmunity, EBV infections
STAT3 GOF mutation STAT3 AD (GOF) 102582 Decreased Decreased Enhanced STAT3 signaling, leading to increased Th17 cell differentiation, lymphoproliferation and autoimmunity. Decreased Tregs and impaired function Lymphoproliferation, solid organ autoimmunity, recurrent infections
BACH2 deficiency BACH2 AD 605394 Progressive T cell lymphopenia Impaired memory B cell development Haplosufficiency for a critical lineage specification transcription factor Lymphocytic colitis, sinopulmonary infections
4. Autoimmunity with or without Lymphoproliferation
APECED (APS-1), autoimmune polyendocrinopathy with candidiasis and ectodermal dystrophy AIRE AR or AD 607358 Normal Normal AIRE serves as check-point in the thymus for negative selection of autoreactive T cells and for generation of Tregs Autoimmunity: hypoparathyroidism hypothyroidism, adrenal insufficiency, diabetes, gonadal dysfunction and other endocrine abnormalities, chronic mucocutaneous candidiasis, dental enamel hypoplasia, alopecia areata enteropathy, pernicious anemia
ITCH deficiency ITCH AR 606409 Not assessed Not assessed Itch deficiency may cause immune dysregulation by affecting both anergy induction in autoreactive effector T cells and generation of Tregs Early-onset chronic lung disease (interstitial pneumonitis), autoimmunity (thyroiditis, type I diabetes, chronic diarrhea/enteropathy, and hepatitis), failure to thrive, developmental delay, dysmorphic facial features
ZAP-70 combined hypomorphic and activation mutations ZAP70 AR (LOF/GOF) 176947 Decreased CD8, normal or decreased CD4 cells Normal or decreased Hyperactive Zap70 kinase Severe autoimmunity
Tripeptidyl-peptidase II deficiency TPP2 AR 190470 Decreased Decreased TPP2 deficiency results in premature immunosenescence and immune dysregulation Variable lymphoproliferation, severe autoimmune cytopenias, hypergammaglobulinemia, recurrent infections
JAK1 GOF JAK1 AD GOF 147795 Not assessed Not assessed Hyperactive JAK1 HSM, eosinophilia, eosinophilic enteritis, thyroid disease, poor growth, viral infections
Prolidase deficiency PEPD AR 613230 Normal Normal Peptidase D Autoantibodies common, chronic skin ulcers, eczema, infections
5. Autoimmune lymphoproliferative syndrome (ALPS, Canale-Smith syndrome)
ALPS-FAS TNFRSF6 AD or AR 134637 Increased CD4−CD8−TCR α/β-double negative (DN) T cells Normal, low memory B cells Apoptosis defect FAS mediated Splenomegaly, adenopathies, autoimmune cytopenias, increased lymphoma risk, IgG and A normal or increased, elevated serum FasL and IL-10, vitamin B12
ALPS-FASLG FASLG AR 134638 Increased DN T cells Normal Apoptosis defect FAS mediated Splenomegaly, adenopathies, autoimmune cytopenias, SLE, soluble FasL is not elevated
ALPS-caspase 10 CASP10 AD 601762 Increased DN T cells Normal Defective lymphocyte apoptosis Adenopathies, splenomegaly, autoimmunity
ALPS-caspase 8 CASP8 AR 601763 Slightly increased DN T cells Normal Defective lymphocyte apoptosis and activation Adenopathies, splenomegaly, bacterial and viral infections, hypogammaglobulinemia
FADD deficiency FADD AR 602457 Increased DN T cells Normal Defective lymphocyte apoptosis Functional hyposplenism, bacterial and viral infections, recurrent episodes of encephalopathy and liver dysfunction
6. Immune dysregulation with colitis
IL-10 deficiency IL10 AR 124092 Normal Normal No functional IL-10 secretion Inflammatory bowel disease (IBD), Folliculitis, recurrent respiratory diseases, arthritis,
IL-10Ra deficiency IL10RA AR 146933 Normal Normal Leukocytes unresponsive to IL-10 IBD, Folliculitis, recurrent respiratory diseases, arthritis, lymphoma
IL-10Rb deficiency IL10RB AR 123889 Normal Normal Leukocytes unresponsive to IL-10, IL-22, IL-26, IL-28A, IL-28B, and IL-29 IBD, folliculitis, recurrent respiratory diseases, arthritis, lymphoma
NFAT5 haploinsufficiency NFAT5 AD 604708 Normal Normal Decreased memory B cells and plasmablasts IBD, recurrent sinopulmonary infections
7. Susceptibility to EBV and lymphoproliferative conditions
SH2D1A deficiency (XLP1) SH2D1A XL 300490 Normal or increased activated T cells Reduced memory B cells normal NK cell and CTL cytotoxic activity Clinical and immunologic features triggered by EBV infection: HLH, lymphoproliferation, aplastic anemia, lymphoma. hypogammaglobulinemia, absent iNKT cells
XIAP deficiency (XLP2) XIAP XL 300079 Normal or Increased activated T cells; low/normal iNKT cells Normal or reduced memory B cells Increased T cells susceptibility to apoptosis to CD95 and enhanced activation-induced cell death (AICD) EBV infection, splenomegaly, lymphoproliferation HLH, colitis, IBD, hepatitis low iNKT cells, hypogammaglobulinemia
CD27 deficiency CD27 AR 615122 Normal No memory B cells Low immunoglobulin after EBV infection Features triggered by EBV infection, HLH, aplastic anemia, low iNKT cells, lymphoma
CTPS1 deficiency CTPS1 AR 615897 Nl to low, poor proliferation to antigen Nl/low Nl/high IgG Recurrent/chronic bacterial and viral infections (EBV, VZV), lymphoproliferation, B cell non-Hodgkin lymphoma
RASGRP1 deficiency RASGRP1 AR 603962 Poor activation, proliferation, motility Poor activation, proliferation, motility Normal IgM, IgG, increased IgA Recurrent pneumonia, herpesvirus infections, EBV associated lymphoma
CD70 deficiency CD70 (TNFSF7) AR 602840 Nl number, low Treg, poor activation and function Nl number, poor antibody and memory responses Reduced IgM, IgG, IgA (75%) and reduced Ag-specific Ab responses (50%) EBV susceptibility, Hodgkin lymphoma
RLTPR (CARMIL2) deficiency RLTPR AR 610859 Nl number, low Treg, high CD4, poor function Nl number Nl to low, poor T dependent antibody response Recurrent bacterial, fungal and mycobacterial infections, viral warts, molluscum and EBV lymphoproliferative and other malignancy, atopy
ITK deficiency ITK AR 186973 Progressive decrease Normal Nl to low EBV associated B cell lymphoproliferation, lymphoma, Nl or low IgG
MAGT1 deficiency (XMEN) MAGT1 XL 300853 Low CD4Low recent thymic emigrant cells, poor proliferation to CD3 Normal Normal EBV infection, lymphoma, viral infections, respiratory and GI infections
PRKCD deficiency PRKCD AR 176977 Normal Low memory B cells, high CD5 B cells Apoptotic defect in B cells Recurrent infections, EBV chronic infection, lymphoproliferation, SLE-like autoimmunity (nephrotic and antiphospholipid syndromes), low IgG

Fig. 1.

Fig. 1

Each publication of the World Health Organization and IUIS Primary Immunodeficiencies Committee was reviewed for the number of conditions listed and displayed graphically [1–19]. The rapid increase in the twenty-first century relates to improved awareness and increasing use of sequencing. Assuming 20,000 coding genes in the human genome, inborn errors of immunity are implicated through mutations in 1.7% of these genes. There are now 330 specific disorders, 320 monogenic defects, 312 distinct genes (nine genes with both LOF and GOF and C4 deficiency requiring defects in both C4A and C4B). a The categorization of the inborn errors of immunity according the schema in the current manuscript. b The categorization of the inborn errors of immunity according to their inheritance

The new disorders (since 2015 [3]) represent an impressive spectrum of phenotypes. There are 354 distinct disorders with 344 different gene defects listed. The emerging dominance of next-generation sequencing has driven the rapid increase in the number of recognized disorders which has led to two major consequences. Often new inborn errors of immunity are initially described in a single kindred or a small number of kindreds. This may lead to incorrect assumptions about prevalence and phenotype. In fact, for most disorders, we have little idea of the prevalence within even the recognized population with the described phenotype. The second consequence of the rapid rise of next-generation sequencing is a striking expansion of the phenotypic spectrum associated with many diseases. Where once the phenotype of a given disorder was clear, the spectrum of manifestations often extends impressively once the ascertainment is not linked to a preconceived idea [20]. As a community, we recognize the importance of publishing cases and small series and to report specific mutations with clinical findings because publications are used to define likelihood of causality during bioinformatic analysis of next-generation sequencing results.

In 1999, the Committee on Primary Immunodeficiencies came under the auspices of the International Union of Immunological Societies (IUIS). The current committee met on February 23–24, 2017, in London to update the classification of human primary immunodeficiencies. Inclusion in this “master list” requires a body of literature supporting causality of a gene defect and a penetrance indicating clinical relevance [21]. Committee members vote on inclusion of each new disorder and this publications lists those included as of the February 2017 meeting. The landscape is changing so rapidly, and the number of primary immunodeficiencies growing so fast, that two major changes have been implemented. The published list will continue to serve as a reference; however, this list will now be available as a csv file on the IUIS website to enable sorting according to gene, disease name, or clinical/laboratory feature. This file will also include the associated ICD10 codes in order to promote harmonization of utilization. The second major change is to the nomenclature. The term primary immunodeficiency has an important legacy—the abbreviations PID or PIDD are often used by patient organizations and are recognized around the world. However, this terminology does limit the conceptualization of disorders to those in which susceptibility to infection is the main manifestation. The improving recognition of immune dysregulation diseases, including the growing field of autoinflammatory disorders and interferonopathies, has mandated that a more encompassing terminology be used. This manuscript, therefore, utilizes “inborn errors of immunity” as the descriptor for the work and the categorization. In addition to embracing technology to remain updated, the companion publication “Update of the Phenotypical IUIS Classification for Primary Immunodeficiencies” will provide a phenotype-oriented approach to the IUIS categorization of disorders. Moreover, a new free application can be found as “PID phenotypical diagnosis” or “PID classification” from iTunes and Android app stores [22, 23]. Information that is readily accessible is the new standard, and the IUIS Expert Committee on Primary Immunodeficiencies believes that improved access to information will positively impact patient care around the world.

The tables divide disease categories according to common phenotypes for ease of review and searching. Table 1 lists combined immunodeficiencies, Table 2 lists combined immunodeficiencies with syndromic features, Table 3 lists predominantly antibody deficiencies, Table 4 lists diseases of immune dysregulation, Table 5 lists defects of phagocyte number or function, Table 6 lists defects in intrinsic and innate immunity, Table 7 lists autoinflammatory diseases, Table 8 lists complement deficiencies, and Table 9 lists phenocopies of inborn errors of immunity. The division into phenotypes for the purpose of this list does not imply that the presentation is homogeneous. Each disorder is listed only once for the sake of simplicity although distinct modes of inheritance can be listed separately. There are nine genes for which both loss-of-function and gain-of-function variants have been identified: CFB, C3, CARD11, STAT1, STAT3, WAS, JAK1, IFIH1, and ZAP70. For these, the loss-of-function and gain-of-function aspects are listed. Within each table, there are additional sub-tables that segregate into coherent phenotypic sets. At the end of each table, the new disorders, added for this publication, are listed for easy reference. Other features important for navigation of the list include the use of OMIM links [24]. For additional information on a gene, the links can be accessed from within the online publication. For the second time, we also include non-inborn errors of immunity in Table 9, representing phenocopies of inborn errors which might be important to consider diagnostically.

Table 1.

Immunodeficiencies affecting cellular and humoral immunity

Disease Genetic defect Inheritance OMIM T cells B cells Ig Associated features
1. T-B+ severe combined immune deficiency (SCID)
γc deficiency (common gamma chain SCID, CD132 deficiency) IL2RG XL 308380 Very low Normal to high Low Low NK
JAK3 deficiency JAK3 AR 600173 Very low Normal to high Low Low NK
IL7Rα deficiency IL7R AR 146661 Very low Normal to high Low Nl NK
CD45 deficiency PTPRC AR 151460 Very low Normal Low Nl γ/δ Τ cells
CD3δ deficiency CD3D AR 186790 Very low Normal Low Nl NK, no γ/δ T cells
CD3ε deficiency CD3E AR 186830 Very low Normal Low Nl NK, no γ/δ T cells
CD3ζ deficiency CD247 AR 186780 Very low Normal Low Nl NK, no γ/δ T cells
Coronin-1A deficiency CORO1A AR 605000 Very low Normal Low Detectable thymus, EBV
LAT deficiency LAT AR 602354 Nl to low number Nl to low High Adenopathy, splenomegaly, recurrent infections, autoimmunity
2. T-B- SCID
RAG1 deficiency RAG1 AR 179615 Very low Very low Decreased Nl NK
RAG2 deficiency RAG2 AR 179616 Very low Very low Decreased Nl NK
DCLRE1C (Artemis) deficiency DCLRE1C AR 605988 Very low Very low Decreased Nl NK, radiation sensitive
DNA PKcs deficiency PRKDC AR 176977 Very low Very low Variable Nl NK, radiation sensitive, microcephaly
Cernunnos/XLF deficiency NHEJ1 AR 611290 Very low Very low Decreased Nl NK, radiation sensitive, microcephaly
DNA ligase IV deficiency LIG4 AR 601837 Very low Very low Decreased Nl NK, radiation sensitive, microcephaly
Reticular dysgenesis AK2 AR 103020 Very low Nl to low Decreased Granulocytopenia and deafness
Adenosine deaminase (ADA) deficiency ADA AR 608958 Very low Low, decreasing Low, decreasing Low NK, bone defects, may have pulmonary alveolar proteinosis, cognitive defects
3. Combined immunodeficiencies generally less profound than severe combined immunodeficiency
DOCK2 deficiency DOCK2 AR 603122 Low Normal IgG Nl or low, poor antibody responses Nl NK cells, but defective function. Poor interferon responses in hematopoietic and non-hematopoietic cells
CD40 ligand deficiency (CD154) CD40LG (TNFSF5) XL 300386 Nl to low sIgM+, IgD+ cells present, absent sIgG+, IgA+, and IgE+ cells IgM normal or high, other Ig isotypes low Neutropenia, thrombocytopenia, hemolytic anemia, opportunistic infections, biliary tract and liver disease, Cryptosporidium infections
CD40 deficiency CD40 (TNFRSF5) AR 109535 Normal sIgM+, IgD+ cells present, absent sIgG+, IgA+ and IgE+ cells IgM normal or high, other Ig isotypes low Neutropenia, opportunistic infections, gastrointestinal and biliary tract and liver disease, Cryptosporidium infections
ICOS deficiency ICOS AR 604558 Normal Normal Low Recurrent infections, autoimmunity, gastroenteritis, granulomas
CD3γ deficiency CD3G AR 186740 Nl number, but low TCR expression Normal Normal
CD8 deficiency CD8A AR 186910 Absent CD8, nl CD4 Normal Normal Recurrent infections, may be asymptomatic
ZAP-70 deficiency (ZAP70 LOF) ZAP70 AR 176947 Low CD8, Nl CD4 number but poor function Normal Normal May have immune dysregulation, autoimmunity
MHC class I deficiency TAP1 AR 170260 Low CD8, Nl CD4, absent MHC I on lymphocytes Normal Normal Vasculitis, pyoderma gangrenosum
MHC class I deficiency TAP2 AR 170261 Low CD8, Nl CD4, absent MHC I on lymphocytes Normal Normal Vasculitis, pyoderma gangrenosum
MHC class I deficiency TAPBP AR 601962 Low CD8, Nl CD4, absent MHC I on lymphocytes Normal Normal Vasculitis, pyoderma gangrenosum
MHC class I deficiency B2M AR 109700 Low CD8, Nl CD4, absent MHC I on lymphocytes Normal Normal Sinopulmonary infections, cutaneous granulomas. Absent β2m associated proteins MHC I, CD1a, CD1b, CD1c
MHC class II deficiency group A CIITA AR 600005 Low CD4 cellsAbsent MHC II expression on lymphocytes Normal Nl to low Respiratory and gastrointestinal infections, liver/biliary tract disease
MHC class II deficiency group B RFXANK AR 603200 Low CD4 cellsAbsent MHC II expression on lymphocytes Normal Nl to low Respiratory and gastrointestinal infections, liver/biliary tract disease
MHC class II deficiency group C RFX5 AR 601863 Low CD4 cellsAbsent MHC II expression on lymphocytes Normal Nl to low Respiratory and gastrointestinal infections, liver/biliary tract disease
MHC class II deficiency group D RFXAP AR 601861 Low CD4 cellsAbsent MHC II expression on lymphocytes Normal Nl to low Respiratory and gastrointestinal infections, liver/biliary tract disease
DOCK8 deficiency DOCK8 AR 243700 Low, poor proliferation, few, poorly functioning Treg Low, low CD27+ memory B cells Poor peripheral B cell tolerance Low IgM, Nl to high IgG and IgA, high IgE Low NK cells with poor function, eosinophilia, recurrent infections, cutaneous viral, fungal and staphylococcal infections, severe atopy, cancer diathesis
Rhoh deficiency RHOH AR 602037 Nl number, low naïve T cells, restricted repertoire, poor proliferation to CD3 Normal Normal HPV infection, lung granulomas, molluscum contagiosum, lymphoma
MST1 deficiency STK4 AR 614868 Low, low terminal differentiated effector memory (TEMRA) cells, low naïve T cells, poor proliferation Low High Intermittent neutropenia, bacterial, viral (HPV), candidal infections, EBV lymphoproliferation, autoimmune cytopenias, lymphoma, congenital heart disease
TCRα deficiency TRAC AR 615387 Absent TCRαβ, all T cells are γδ, poor proliferation Normal Normal Recurrent viral, bacterial, fungal infections, immune dysregulation and autoimmunity, diarrhea
LCK deficiency LCK AR 615758 Low CD4+, low Treg, restricted T cell repertoire, poor TCR signaling Normal Nl IgG and IgA, high IgM Recurrent infections, immune dysregulation, autoimmunity
MALT1 deficiency MALT1 AR 615468 Nl number, poor proliferation Normal Nl levels, poor specific antibody response Bacterial, fungal and viral infections
CARD11 deficiency (LOF) CARD11 AR 615206 Nl number, predominant naïve T cells, poor proliferation Normal, transitional B cell predominance Absent/low Pneumocystis jirovecii pneumonia, bacterial and viral infections
BCL10 deficiency BCL10 AR 616098 Nl number, low memory T and Treg cells, poor antigen and anti-CD3 proliferation Nl number, decreased memory and switched B cells Low Recurrent bacterial and viral infections, candidiasis, gastroenteritis
BCL11B deficiency BCL11B AD 617237 Low, poor proliferation Normal Normal Congenital abnormalities, neonatal teeth, dysmorphic facies, absent corpus callosum, neurocognitive deficits
IL-21 deficiency IL21 AR 615767 Nl number, nl/low function Low Low IgG Severe early-onset colitis, recurrent sinopulmonary infections
IL-21R deficiency IL21R AR 615207 Nl number, low cytokine production, poor antigen proliferation Normal Nl number, poor specific antibody responses Recurrent infections, Pneumocystis jiroveci, Cryptosporidium infections and liver disease
OX40 deficiency TNFRSF4 AR 615593 Nl numbers, low antigen specific memory CD4+ Nl numbers, low memory B cells Normal Impaired immunity to HHV8, Kaposi’s sarcoma
IKBKB deficiency IKBKB AR 615592 Nl number, absent Treg and γ/δ T cells, impaired TCR activation Nl number, poor function Low Recurrent bacterial, viral, fungal infections, opportunistic infections
NIK deficiency MAP3K14 AR 604655 Nl number, poor proliferation to antigen Low, low switched memory B cells Low Ig’s Low NK number and function, recurrent bacterial, viral and Cryptosporidium infections
RelB deficiency RELB AR 604758 Nl number, poor diversity, poor function Recurrent infections
Moesin deficiency MSN XL 300988 Nl number, defective migration, proliferation Low number Low Ig’s over time Recurrent infections with bacteria, varicella, neutropenia
TFRC deficiency TFRC AR 616740 Nl number, poor proliferation Nl number, low memory B cells Low Recurrent infections, neutropenia, thrombocytopenia

Table 2.

Combined immunodeficiencies with associated or syndromic features

Disease Genetic defect Inheritance OMIM T cells B cells Ig Associated features
1. Immunodeficiency with congenital thrombocytopenia
Wiskott-Aldrich syndrome (WAS LOF) WAS XL 300392 Progressive decrease in numbers, abnormal lymphocyte responses to anti-CD3 Normal numbers Low IgM and antibody responses to polysaccharides, often high IgA and IgE Thrombocytopenia with small platelets, recurrent bacterial and viral infections, bloody diarrhea, eczema, lymphoma, autoimmune disease, IgA nephropathy, vasculitis. XL thrombocytopenia is a mild form of WAS, and XL neutropenia is caused by missense mutations in the GTPase binding domain of WASp
WIP deficiency WIPF1 AR 602357 Reduced, defective lymphocyte responses to anti-CD3 Normal or low Normal, except for high IgE Thrombocytopenia with or without small platelets, recurrent bacterial and viral infections, eczema, bloody diarrhea, WAS protein absent
ARPC1B deficiency ARPC1B AR 604223 Normal Normal numbers Normal except for high IgA and IgE Mild thrombocytopenia with normal sized platelets, recurrent invasive infections, colitis, vasculitis, autoantibodies (ANA, ANCA), eosinophilia, defective Arp2/3, filament branching
2. DNA repair defects other than those listed in Table 1
Ataxia-telangiectasia ATM AR 607585 Progressive decrease, abnormal proliferation to mitogens Normal Often low IgA, IgE and IgG subclasses, increased IgM monomers, antibodies variably decreased Ataxia, telangiectasia, pulmonary infections, lymphoreticular and other malignancies, increased alpha fetoprotein, increased radiosensitivity, chromosomal instability and chromosomal translocations
Nijmegen breakage syndrome NBS1 AR 602667 Progressive decrease Variably reduced Often low IgA, IgE, and IgG subclasses, increased IgM, antibodies variably decreased Microcephaly, dysmorphic facies, lymphomas, solid tumors, increased radiosensitivity, chromosomal instability
Bloom Syndrome BLM (RECQL3) AR 604610 Normal Normal Low Short stature, dysmorphic facies, sun-sensitive erythema, marrow failure, leukemia, lymphoma, chromosomal instability
Immunodeficiency with centromeric instability and facial anomalies, ICF1 DNMT3B AR 602900 Decreased or normal, responses to PHA may be decreased Decreased or normal Hypogammaglobulinemia or agammaglobulinemia, variable antibody deficiency
Immunodeficiency with centromeric instability and facial anomalies, ICF2 ZBTB24 AR 614064 Decreased or normal, Decreased or normal Hypogammaglobulinemia or agammaglobulinemia, variable antibody deficiency
Immunodeficiency with centromeric instability and facial anomalies, ICF3 CDCA7 AR 609937 responses to PHA may be decreased Decreased or normal Hypogammaglobulinemia or agammaglobulinemia, variable antibody deficiency
Immunodeficiency with centromeric instability and facial anomalies, ICF4 HELLS AR 603946 Decreased or normal Decreased or normal Hypogammaglobulinemia or agammaglobulinemia, variable antibody deficiency
PMS2 deficiency PMS2 AR 600259 Normal Low B cells, switched and non-switched Low IgG and IgA, high IgM, abnormal antibody responses Recurrent infections, café-au-lait spots, lymphoma, colorectal carcinoma, brain tumors
RNF168 deficiency (radiosensitivity, immune deficiency, dysmorphic features, learning difficulties [RIDDLE] syndrome) RNF168 AR 612688 Normal Normal Low IgG or IgA Short stature, mild defect of motor control to ataxia, normal intelligence to learning difficulties, mild facial dysmorphism to microcephaly, increased radiosensitivity
MCM4 deficiency MCM4 AR 602638 Normal Normal Normal NK cells: low number and function. Viral infections (EBV, HSV, VZV), short stature, B cell lymphoma, adrenal failure
POLE1 (polymerase ε subunit 1) deficiency (FILS syndrome) POLE AR 174762 Decreased T cell proliferation Low memory B cells Low IgG2 and IgM, lack of antibody to PPS Recurrent respiratory infections, meningitis, facial dysmorphism, livido, short stature
POLE2 (polymerase ε subunit 2) deficiency POLE2 AR 602670 Lymphopenia, lack of TRECS, absent proliferation in response to antigens Very low Hypogammaglobulinemia Recurrent infections, disseminated BCG infections, autoimmunity (type 1 diabetes, hypothyroidism, facial dysmorphism
Ligase I deficiency LIG1 AR 126391 Lymphopenia, decreased mitogen response Normal Low IgA and IgGReduced antibody responses Recurrent respiratory infections, growth retardation, sun sensitivity, lymphoma, radiation sensitivity
NSMCE3 deficiency NSMCE3 AR 608243 Number decreased, poor response to mitogens and antigens Normal NormalDecreased Ab responses to PPS normal IgG, IgA, elevated IgM Severe lung disease (possibly viral), thymic hypoplasia, chromosomal breakage, radiation sensitivity
ERCC6L2 (Hebo deficiency) ERCC6L2 AR 615667 Lymphopenia Low Normal Facial dysmorphism, microcephaly, bone marrow failure
GINS1 deficiency GINS1 AR 610608 Low or normal Low or normal High IgA, low IgM and IgG Neutropenia, IUGR, NK cells very low
3. Thymic defects with additional congenital anomalies
DiGeorge/velocardiofacial syndromeChromosome 22q11.2 deletion syndrome (22q11.2DS) Large deletion (3 Mb) typically in chromosome 22 AD 602054 Decreased or normal, 5% have < 1500 CD3T cells/μL in neonatal period Normal Normal or decreased Hypoparathyroidism, conotruncal cardiac malformation, velopalatal insufficiency, abnormal facies, intellectual disability
DiGeorge/velocardiofacial syndrome Unknown Sporadic Decreased or normal Normal Normal or decreased Hypoparathyroidism, conotruncal cardiac malformation, velopalatal insufficiency, abnormal facies, intellectual disability
TBX1 deficiency TBX1 AD 602054 Decreased or normal Normal Normal or decreased Hypoparathyroidism, conotruncal cardiac malformation, velopalatal insufficiency, abnormal facies, intellectual disability
CHARGE syndrome due to CHD7 deficiency CHD7 AD 608892 Decreased or normal, response to PHA may be decreased Normal Normal or decreased Coloboma, heart anomaly, choanal atresia, intellectual disability, genital and ear anomalies, CNS malformation, some are SCID-like and have low TRECs
CHARGE syndrome due to SEMA3E deficiency SEMA3E AD 608166 Decreased or normal, response to PHA may be decreased Normal Normal or decreased Coloboma, heart anomaly, choanal atresia, intellectual retardation, genital and ear anomalies, CNS malformation, some are SCID-like and have low TRECs
CHARGE syndrome Unknown Decreased or normal, response to PHA may be decreased Normal Normal or decreased Coloboma, heart anomaly, choanal atresia, intellectual disability, genital and ear anomalies, CNS malformation, some are SCID-like and have low TRECs
Winged helix nude FOXN1 deficiency FOXN1 AR 600838 Very low Normal Decreased Severe infections, abnormal thymic epithelium, immunodeficiency, congenital alopecia, nail dystrophy, neural tube defect
Chromosome 10p13-p14 deletion Syndrome (10p13-p14DS) Del10p13-p14 AD 601362 Normal, rarely lymphopenia and decreased lymphoproliferation to mitogens and antigens, hypolastic thymus may be present Normal Normal Hypoparathyroidism, renal disease, deafness, growth retardation, facial dysmorphism, cardiac defects may be present, recurrent infections +/−
4. Immuno-osseous dysplasias
Cartilage hair hypoplasia (CHH) RMRP AR 157660 Varies from severely decreased (SCID) to normal, impaired lymphocyte proliferation Normal Normal or reduced, antibodies variably decreased Short-limbed dwarfism with metaphyseal dysostosis, sparse hair, bone marrow failure, autoimmunity, susceptibility to lymphoma and other cancers, impaired spermatogenesis, neuronal dysplasia of the intestine
Schimke immuno-osseous dysplasia SMARCAL1 AR 606622 Decreased Normal Normal Short stature, spondiloepiphyseal dysplasia, intrauterine growth retardation, nephropathy, bacterial, viral, fungal infections, may present as SCID, bone marrow failure
MYSM1 deficiency MYSM1 AR 612176 T cell lymphopenia, reduced naïve T cells Immature B cells Hypogammaglobulinemia Short stature, recurrent infections, congenital bone marrow failure, myelodysplasia, immunodeficiency affecting B cells and granulocytes, skeletal anomalies, cataracts, developmental delay.
MOPD1 deficiency RNU4ATAC AR 601428 Normal Normal Normal, specific antibodies variably decreased Recurrent bacterial infections, lymphadenopathy, spondyloepiphyseal dysplasia, extreme intrauterine growth retardation, retinal dystrophy, facial dysmorphism, may present with microcephaly
EXTL3 deficiency EXTL3 AR Reduced Normal Variably decreased Platyspondyly, kyphosis, variable skeletal dysplasias, developmental delay
5. Hyper IgE syndromes (HIES)
AD-HIESSTAT3 deficiency(Job syndrome) STAT3 AD LOF 102582 Normal overall, Th-17 and T-follicular helper cells decreased Normal, reduced switched and non-switched memory B cells, BAFF expression increased High IgE, specific antibody production decreased Distinctive facial features (broad nasal bridge), bacterial infections (boils and pulmonary abscesses, pneumatoceles) due to S. aureus, pulmonary aspergillus, Pneumocystis jirovecii, eczema, mucocutaneous candidiasis, hyperextensible joints, osteoporosis and bone fractures, scoliosis, retention of primary teeth, coronary and cerebral aneurysm formation
Comel-Netherton syndrome SPINK5 AR 605010 Normal Low Switched and non-switched B cells High IgE and IgAAntibody variably decreased Congenital ichthyosis, bamboo hair, atopic diathesis, increased bacterial infections, failure to thrive
PGM3 deficiency PGM3 AR 172100 CD8 and CD4 T cells may be decreased Low B and memory B cells Normal or elevated IgG and IgA, most high IgE, eosinophilia Severe atopy, autoimmunity, bacterial and viral infections, skeletal anomalies dysplasia: short stature, brachydactyly, dysmorphic facial features, and intellectual disability cognitive impairment, hypomyelination
6. Dyskeratosis congenita (DKC), myelodysplasia, short telomeres
XL-DKC due to dyskerin deficiency DKC1 XL 300126 Progressive decrease Progressive decrease Variable hypogammaglobulinemia Intrauterine growth retardation, microcephaly, nail dystrophy, sparse scalp hair and eyelashes, hyperpigmentation of skin, palmar hyperkeratosis, premalignant oral leukoplakia, pancytopenia, myelodysplasia, +/− recurrent infections. A severe phenotype with developmental delay and cerebellar hypoplasia known as Hoyeraal-Hreidarsson syndrome (HHS) may occur in some DKC patients
AR-DKC due to nucleolar protein family A member 2 (NHP2) deficiency NHP2 AR 606470 Decreased Variable Variable
AR-DKC due to nucleolar protein family A member 3 (NHP3) or NOP10 deficiency NOP10 AR 606471 Decreased Variable Variable
AD/AR-DKC due to regulator of telomere elongation (RTEL1) deficiency RTEL1 AD or AR 608833 Decreased Variable Variable
AD-DKC due to TERC deficiency TERC AD 602322 Variable Variable Variable
AD/AR-DKC due to TERT deficiency TERT AD or AR 187270 Variable Variable Variable
AD-DKC due to TINF2 deficiency TINF2 AD 604319 Variable Variable Variable
AD/AR-DKC due to TPP1 deficiency TPP1 AD or AR 609377 Variable Variable Variable
AR-DKC due to DCLRE1B deficiency DCLRE1B/SNM1/APOLLO: AR 609683 Variable Variable Variable
AR-DKC due to PARN deficiency PARN AR (AD?) 604212 Variable Variable Variable
AR-DKC due to WRAP53 deficiency WRAP53 AR 612661 Not reported Not reported Not reported
Coats plus syndrome due to STN1 deficiency STN1 AR 613128 Variable Variable Not known Intrauterine growth retardation, premature aging, pancytopenia, hypocellular bone marrow, gastrointestinal hemorrhage due to vascular ectasia, intracranial calcification, abnormal telomeres
Coats plus syndrome due to CTC1 deficiency CTC1 AR 613129 Normal Normal Normal Intrauterine growth retardation, sparse graying hair, dystrophic nails, trilinear bone marrow failure, osteopenia, gastrointestinal hemorrhage due to vascular ectasia, retinal telangiectasia, intracranial calcification, abnormal telomeres
SAMD9 SAMD9 AD (GOF) 617053 Not reported Not reported Not reported IUGR with gonadal abnormalities, adrenal failure, MDS with chromosome 7 aberrations, predisposition to infections, enteropathy, absent spleen
SAMD9L SAMD9L AD (GOF) 159550 Normal Low Not reported Cytopenia, predisposition to MDS with chromosome 7 aberrations, immunodeficiency, and progressive cerebellar dysfunction
7. Defects of vitamin B12 and folate metabolism
Transcobalamin 2 deficiency TCN2 AR 613441 Normal Variable Decreased Megaloblastic anemia, pancytopenia, if untreated for prolonged periods results in intellectual disability
SLC46A1/PCFT deficiency causing hereditary folate malabsorption SLC46A1 AR 229050 Variable numbers and activation profile Variable Decreased Megaloblastic anemia, if untreated for prolonged periods results in intellectual disability
Methylene-tetrahydrofolate dehydrogenase 1 (MTHFD1) deficiency MTHFD1 AR 172460 Low thymic output, normal in vitro proliferation Low Decreased/poor antibody responses to conjugated polysaccharide antigens Recurrent bacterial infection, Pneumocystis jirovecii, megaloblastic anemia, neutropenia, seizures, intellectual disability, folate-responsive
8. Anhidrotic ectodermodysplasia with immunodeficiency (EDA-ID))
EDA-ID due to NEMO /IKBKG deficiency (ectodermal dysplasia, immune deficiency) NEMO (IKBKG) XL 300248 Normal or decreased, TCR activation impaired NormalLow memory and isotype switched B cells Decreased, some with elevated IgA, IgM, poor specific antibody responses, absent antibody to polysaccharide antigens Anhidrotic ectodermal dysplasia (in some), various infections (bacteria, mycobacteria, viruses and fungi), colitis, conical teeth, variable defects of skin, hair and teeth, monocyte dysfunction
EDA-ID due to IKBA GOF mutation IKBA (NFKBIA) AD GOF 164008 Normal total T cells, TCR activation impaired Normal B cell numbers, impaired BCR activation, low memory and isotype switched B cells Decreased IgG and IgA, elevated IgM, poor specific antibody responses, absent antibody to polysaccharide antigens Anhidrotic ectodermal dysplasia, various infections (bacteria, mycobacteria, viruses and fungi), colitis, variable defects of skin, hair and teeth, T cell and monocyte dysfunction
9. Calcium channel defects
ORAI-1 deficiency ORAI1 AR 610277 Normal, defective TCR mediated activation Normal Normal Autoimmunity, EDA, non-progressive myopathy
STIM1 deficiency STIM1 AR 605921 Normal, defective TCR mediated activation Normal Normal Autoimmunity, EDA, non-progressive myopathy
10. Other defects
Purine nucleoside phosphorylase (PNP) deficiency PNP AR 164050 Progressive decrease Normal Normal or low Autoimmune hemolytic anemia, neurological impairment
Immunodeficiency with multiple intestinal atresias TTC7A AR 609332 Variable, but sometimes absent low TRECs Normal or low Markedly decreased IgG, IgM, IgA Bacterial (sepsis), fungal, viral infections, multiple intestinal atresias, often with intrauterine polyhydramnios and early demise, some with SCID phenotype
Hepatic veno-occlusive disease with immunodeficiency (VODI) SP110 AR 604457 Normal (decreased memory T cells) Normal (decreased memory B cells) Decreased IgG, IgA, IgM, absent germinal centers and tissue plasma cells Hepatic veno-occlusive disease, Susceptibility to Pneumocystis jirovecii pneumonia, CMV, candida, thrombocytopenia, hepatosplenomegaly, cerebrospinal leukodystrophy
Vici syndrome due to EPG5 deficiency EPG5 AR 615068 Profound depletion of CD4+ cells Defective Decreased (particularly IgG2) Agenesis of the corpus callosum, cataracts, cardiomyopathy, skin hypopigmentation, intellectual disability, microcephaly, recurrent infections, chronic mucocutaneous candidiasis
HOIL1 deficiency HOIL1 (RBCK1) AR 610924 Normal numbers Normal, decreased memory B cells Poor antibody responses to polysaccharides Bacterial infections, autoinflammation, amylopectinosis
HOIP deficiency RNF31 AR 612487 Normal numbers Normal, decreased memory B cells decreased Bacterial infections, autoinflammation, amylopectinosis, lymphangiectasia
Hennekam-lymphangiectasia-lymphedema syndrome due to CCBE1 deficiency CCBE1 AR 612753 Low/variable Low/variable decreased Lymphangiectasia and lymphedema with facial abnormalities and other dysmorphic features
Hennekam-lymphangiectasia-lymphedema syndrome due to FAT4 deficiency FAT4 AR 612411 Low/variable Low/variable decreased Lymphangiectasia and lymphedema with facial abnormalities and other dysmorphic features
STAT5b deficiency STAT5B AR 604260 Modestly decreased Normal Normal Growth-hormone insensitive dwarfism, dysmorphic features, eczema, lymphocytic interstitial pneumonitis, autoimmunity
Kabuki syndrome 1 due to KMT2D deficiency KMT2D (MLL2) AD 602113 Normal Normal Low IgA and occasionally low IgG Typical facial abnormalities, cleft or high arched palate, skeletal abnormalities, short stature, intellectual disability, congenital heart defects, recurrent infections (otitis media, pneumonia) in 50% of patients. Autoimmunity may be present
Kabuki syndrome 2 due to KDM6A deficiency KDM6A XL (females may be affected) 300128 Normal Normal Low IgA and occasionally IgG

Table 5.

Congenital defects of phagocyte number or function

Disease Genetic defect Inheritance OMIM Affected cells Affected function Associated features
1. Congenital neutropenias
Elastase deficiency (SCN1) ELANE AD 130130 N Myeloid differentiation Susceptibility to MDS/leukemiaSevere congenital neutropenia or cyclic neutropenia
GFI 1 deficiency (SCN2) GFI1 AD 600871 N Myeloid differentiation B/T lymphopenia
HAX1 deficiency (Kostmann disease) (SCN3) HAX1 AR 605998 N Myeloid differentiation Cognitive and neurological defects in patients with defects in both HAX1 isoforms, susceptibility to MDS/leukemia
G6PC3 deficiency (SCN4) G6PC3 AR 611045 N Myeloid differentiation, chemotaxis, O2 − production Structural heart defects, urogenital abnormalities, inner ear deafness, and venous angiectasias of trunks and limbs
VPS45 deficiency (SCN5) VPS45 AR 610035 N Myeloid differentiation, migration Extramedullary hematopoiesis, bone marrow fibrosis, nephromegaly
Glycogen storage disease type 1b G6PT1 AR 602671 N + M Myeloid differentiation, chemotaxis, O2 − production Fasting hypoglycemia, lactic acidosis, hyperlipidemia, hepatomegaly
X-linked neutropenia/myelodysplasia WAS GOF WAS XL 300392 N Differentiation, mitosis Neutropenia, myeloid maturation arrest, monocytopenia, variable lymphoid anomalies
P14/LAMTOR2 deficiency LAMTOR2 AR 610389 N + M Endosomal biogenesis NeutropeniaHypogammaglobulinemia ↓CD8 cytotoxicity, partial albinism, growth failure
Barth syndrome (3-methylglutaconic aciduria type II) TAZ XL 300394 N + L Mel Mitochondrial function Cardiomyopathy, myopathy, growth retardation, neutropenia
Cohen syndrome VPS13B AR 607817 N Myeloid differentiation Dysmorphism, mental retardation, obesity, deafness, neutropenia
Clericuzio syndrome (poikiloderma with neutropenia) USB1 AR 613276 N Myeloid differentiation Retinopathy, developmental delay, facial dysmorphisms, poikiloderma
JAGN1 deficiency JAGN1 AR 616012 N Myeloid differentiation Myeloid maturation arrest, osteopenia
3-Methylglutaconic aciduria CLPB AR 616254 N Myeloid differentiationMitochondrial protein Neurocognitive developmental aberrations, microcephaly, hypoglycemia, hypotonia, ataxia, seizures, cataracts, IUGR
G-CSF receptor deficiency CSF3R AR 138971 N Stress granulopoiesis disturbed
SMARCD2 deficiency SMARCD2 AR 601736 N Chromatin remodeling, myeloid differentiation and neutrophil functional defect Neutropenia, developmental aberrations, skeletal abnormalities, hematopoietic stem cells, myelodysplasia
HYOU1 deficiency HYOU1 AR 601746 N Unfolded protein response Hypoglycemia, inflammatory complications
2. Defects of motility
Leukocyte adhesion deficiency type 1 (LAD1) ITGB2 AR 600065 N + M +L + NK Adherence, chemotaxis, endocytosis, T/NK cytotoxicity Delayed cord separation, skin ulcers, periodontitis, leukocytosis
Leukocyte adhesion deficiency type 2 (LAD2) SLC35C1 AR 605881 N + M Rolling, chemotaxis Mild LAD type 1 features with hh-blood group, growth retardation, developmental delay
Leukocyte adhesion deficiency type 3 (LAD3) FERMT3 AR 607901 N + M + L + NK Adherence, chemotaxis LAD type 1 plus bleeding tendency
Rac 2 deficiency RAC2 AD 602049 N Adherence, chemotaxis O2 − production Poor wound healing, leukocytosis
β actin deficiency ACTB AD 102630 N + M Motility Mental retardation, short stature
Localized juvenile periodontitis FPR1 AR 136537 N Formylpeptide induced chemotaxis Periodontitis only
Papillon-Lefèvre syndrome CTSC AR 602365 N + M Chemotaxis Periodontitis, palmoplantar hyperkeratosis in some patients
Specific granule deficiency CEBPE AR 189965 N Chemotaxis Neutrophils with bilobed nuclei
Shwachman-Diamond syndrome SBDS AR 607444 N Chemotaxis Pancytopenia, exocrine pancreatic insufficiency, chondrodysplasia
WDR1 deficiency WDR1 AR 604734 N Spreading, survival, chemotaxis Mild neutropenia, poor wound healing, severe stomatitis, neutrophil nuclei herniate
Cystic fibrosis CFTR AR 602421 M only Chemotaxis Respiratory infections, pancreatic insufficiency, elevated sweat chloride
Schwachman Diamond syndrome due to DNAJC21 deficiency DNAJC21 AR 617048 N Motility, ribosome biogenesis Metaphyseal changes, short stature, developmental delay, pancreatic dysfunction, bone marrow failure
Neutropenia with combined immune deficiency due to MKL1 deficiency MKL1 AR 606078 N + M +L + NK Impaired expression of cytoskeletal genes Mild thrombocytopenia
3. Defects of respiratory burst
X-linked chronic granulomatous disease (CGD), gp91phox CYBB XL 300481 N + M Killing (faulty O2 − production) Infections, autoinflammatory phenotype, IBDMcLeod phenotype in patients with deletions extending into the contiguous Kell locus
Autosomal recessive CGD p22phox CYBA AR 608508 N + M Killing (faulty O2 − production) Infections, autoinflammatory phenotype
Autosomal recessive CGD p47phox NCF1 AR 608,512 N + M Killing (faulty O2 − production) Infections, autoinflammatory phenotype
Autosomal recessive CGD p67phox NCF2 AR 608515 N + M Killing (faulty O2 − production) Infections, autoinflammatory phenotype
Autosomal recessive CGD p40phox NCF4 AR 601488 N + M Killing (faulty O2 − production) Infections, autoinflammatory phenotype
G6PD deficiency class I G6PD XL 305900 N Reduced O2 − production Infections
4. Other non-lymphoid defects
GATA2 deficiency (MonoMac syndrome) GATA2: loss of stem cells AD 137295 Monocytes + peripheral DC Multi lineage cytopenias Susceptibility to mycobacteria, HPV, histoplasmosis, alveolar proteinosis, MDS/AML/CMMoL, lymphedema
Congenital pulmonary alveolar proteinosis due to CSF2RB mutations CSF2RB AR 138981 Alveolar macrophages GM-CSF signaling Alveolar proteinosis
Congenital pulmonary alveolar proteinosis due to CSF2RA mutations CSF2RA XL (pseudoautosomal) 306250 Alveolar macrophages GM-CSF signaling Alveolar proteinosis

Table 6.

Defects in intrinsic and innate immunity

Disease Genetic defect Inheritance OMIM Affected cells Affected function Associated features
1. Mendelian susceptibility to mycobacterial disease (MSMD)
IL-12 and IL-23 receptor β1 chain deficiency IL12RB1 AR 601604 L + NK IFN-γ secretion Susceptibility to mycobacteria and Salmonella
IL-12p40 (IL-12 and IL-23) deficiency IL12B AR 161561 M IFN-γ secretion Susceptibility to mycobacteria and Salmonella
IFN-γ receptor 1 deficiency IFNGR1 AR/AD 107470 M + L IFN-γ binding and signaling Susceptibility to mycobacteria and Salmonella
IFN-γ receptor 2 deficiency IFNGR2 AR 147569 M + L IFN-γ signaling Susceptibility to mycobacteria and Salmonella
STAT1 deficiency (AD LOF) STAT1 AD 600555 M + L IFN-γsignaling Susceptibility to mycobacteria, Salmonella
Macrophage gp91 phox deficiency CYBB XL 300481 Macrophage only Killing (faulty O2 − production) Isolated susceptibility to mycobacteria
IRF8 deficiency (AD) IRF8 AD 601565 CD1c+ MDC Differentiation of CD1c+ MDC subgroup Susceptibility to mycobacteria
IRF8 deficiency (AR) IRF8 AR 601565 CD1c+ MDC Differentiation of CD1c+ MDC subgroup Susceptibility to mycobacteria and multiple other infectious agents
Tyk2 deficiency TYK2 AR 176941 Normal, but multiple cytokine signaling defect Normal Susceptibility to intracellular bacteria (mycobacteria, Salmonella), viruses, +/− elevated IgE
ISG15 deficiency ISG15 AR 147571 IFNγ production defect Susceptibility to mycobacteria (BCG), brain calcification
RORc deficiency RORC AR 602943 L + NK Lack of functional RORγT protein, IFNγ production defect, complete absence of IL-17A/F-producing T cells Susceptibility to mycobacteria and candida
JAK1 (LOF) JAK1 AR 147795 N + L IFNγ production Susceptibility to mycobacteria and viruses, urothelial carcinoma
2. Epidermodysplasia verruciformis (HPV)
EVER1 deficiency TMC6 AR 605828 Keratinocytes and leukocytes EVER proteins may be involved in the regulation of cellular zinc homeostasis in lymphocytes Human papillomavirus (HPV) (group B1) infections and cancer of the skin (typical EV)
EVER2 deficiency TMC8 AR 605829 Keratinocytes and leukocytes EVER proteins may be involved in the regulation of cellular zinc homeostasis in Ly HPV (group B1) infections and cancer of the skin (typical EV)
WHIM (warts, hypogammaglobulinemia, infections, myelokathexis) syndrome CXCR4 AD GOF 162643 Granulocytes + lymphocytes Increased response of the CXCR4 chemokine receptor to its ligand CXCL12 (SDF-1) Warts, neutropenia, low B cell number, hypogammaglobulinemia
3. Predisposition to severe viral infection
STAT1 deficiency (AR LOF) STAT1 AR 600555 T and NK cells and monocytes STAT1-dependent IFN-α, β, and γ response Severe viral infections, mycobacterial infection
STAT2 deficiency STAT2 AR 600556 T and NK cells STAT2-dependent IFN-α, β, and γ response Severe viral infections (disseminated vaccine-strain measles)
IRF7 deficiency IRF7 AR 605047 Leukocytes, plasmacytoid dendritic cells, non-hematopoietic cells IFN-α, β, and γ production and IFN-λ production Severe influenza disease
IFNAR2 deficiency IFNAR2 AR 602376 Broadly expressed No response to IFN-α Severe viral infections (disseminated vaccine-strain measles, HHV6)
CD16 deficiency FCGR3A AR 146740 NK cells Altered NK cells function Severe herpes viral infections, particularly VZV, Epstein-Barr virus (EBV), and (HPV)
MDA5 deficiency (LOF) IFIH1 AR 606951 Somatic and hematopoietic Viral recognition Rhinovirus and other RNA viruses
4. Herpes simplex encephalitis (HSE)
TLR3 deficiency TLR3 AD or AR 603029 Central nervous system (CNS) resident cells and fibroblasts TLR3-dependent IFN-α, β, and γ response Herpes simplex virus 1 encephalitis (incomplete clinical penetrance for all etiologies listed here)
UNC93B1 deficiency UNC93B1 AR 608204 CNS resident cells and fibroblasts UNC-93B-dependent IFN-α, β, and γ response Herpes simplex virus 1 encephalitis
TRAF3 deficiency TRAF3 AD 601896 CNS resident cells and fibroblasts TRAF3-dependent IFN-α, β, and γ response Herpes simplex virus 1 encephalitis
TRIF deficiency TICAM1 AD or AR 607601 CNS resident cells and fibroblasts TRIF-dependent IFN-α, β, and γ response Herpes simplex virus 1 encephalitis
TBK1 deficiency TBK1 AD 604834 CNS resident cells and fibroblasts TBK1-dependent IFN-α, β, and γ response Herpes simplex virus 1 encephalitis
IRF3 deficiency IRF3 AD 616532 CNS resident cells and fibroblasts Low IFN-α/β production in response to HSV1 and decreased IRF3 phosphorylation Herpes simplex virus 1 encephalitis
5. Predisposition to invasive fungal diseases
CARD9 deficiency CARD9 AR 607212 Mononuclear phagocytes CARD9 signaling pathway Invasive candidiasis infection, deep dermatophytoses, other invasive fungal infections
6. Predisposition to mucocutaneous candidiasis
IL-17RA deficiency IL17RA AR 605461 Epithelial cells, fibroblasts, mononuclear phagocytes IL-17RA signaling pathway CMC, folliculitis
IL-17RC deficiency IL17RC AR 610925 Epithelial cells, fibroblasts, mononuclear phagocytes IL-17RC signaling pathway CMC
IL-17F deficiency IL17F AD 606496 T cells IL-17F-containing dimers CMC, folliculitis
STAT1 GOF STAT1 AD GOF 600555 T cells, B cells, monocytes Gain-of-function STAT1 mutations that impair the development of IL-17-producing T cells CMC, various fungal, bacterial and viral (HSV) infections, autoimmunity (thyroiditis, diabetes, cytopenias), enteropathy
ACT1 deficiency TRAF3IP2 AR 607043 T cells, fibroblasts Fibroblasts fail to respond to IL-17A and IL-17F, and their T cells to IL-17E CMC, blepharitis, folliculitis and macroglossia
7. TLR signaling pathway deficiency with bacterial susceptibility
IRAK-4 deficiency IRAK4 AR 606883 Lymphocytes + granulocytes + monocytes TIR-IRAK4 signaling pathway Bacterial infections (pyogens)
MyD88 deficiency MYD88 AR 602170 Lymphocytes + granulocytes + monocytes TIR-MyD88 signaling pathway Bacterial infections (pyogens)
IRAK1 deficiency IRAK1 XL Not yet attributed Lymphocytes + granulocytes + monocytes TIR-IRAK1 signaling pathway Bacterial infections, X-linked MECP2 deficiency-related syndrome due to a large de novo Xq28 chromosomal deletion encompassing both MECP2 and IRAK1
TIRAP deficiency TIRAP AR 614382 Lymphocytes + granulocytes+ monocytes TIRAP- signaling pathway, TLR1/2, TLR2/6, and TLR4 agonists were impaired in the fibroblasts and leukocytes Staphylococcal disease during childhood
8. Other inborn errors of immunity related to non-hematopoietic tissues
Isolated congenital asplenia (ICA) due to RPSA deficiency RPSA AD 271400 No spleen RPSA encodes ribosomal protein SA, a component of the small subunit of the ribosome Bacteremia (encapsulated bacteria)
Isolated congenital asplenia (ICA) due to HMOX deficiency HMOX AR 141250 Macrophages HO-1 regulates iron recycling and heme-dependent damage occurs Hemolysis, nephritis, inflammation
Trypanosomiasis APOL1 AD 603743 Somatic Lipid Trypanosomiasis
Acute liver failure due to NBAS deficiency NBAS AR 608025 Somatic and hematopoietic ER stress Fever induces liver failure
Acute necrotizing encephalopathy RANBP2 AD 601181 Ubiquitous expression Nuclear pore Fever induces acute encephalopathy
CLCN7 deficiency associated osteopetrosis CLCN7 AR 602727 Osteoclasts Secretory lysosomes Osteopetrosis with hypocalcemia, neurologic features
SNX10 deficiency associated osteopetrosis SNX10 AR 614780 Osteoclasts Secretory lysosomes Osteopetrosis with visual impairment
OSTM1 deficiency associated osteopetrosis OSTM1 AR 607649 Osteoclasts Secretory lysosomes Osteopetrosis with hypocalcemia, neurologic features
PLEKHM1 deficiency associated osteopetrosis PLEKHM1 AR 611466 Osteoclasts Secretory lysosomes Osteopetrosis
TCIRG1 deficiency associated osteopetrosis TCIRG1 AR 604592 Osteoclasts Secretory lysosomes Osteopetrosis with hypocalcemia
TNFRSF11A deficiency associated osteopetrosis TNFRSF11A AR 603499 Osteoclasts Osteoclastogenesis Osteopetrosis
TNFSF11 deficiency associated osteopetrosis TNFSF11 AR 602642 Stromal Osteoclastogenesis Osteopetrosis with severe growth retardation
NCSTN deficiency hidradenitis suppurativa NCSTN AD 605254 Epidermis Gamma-secretase in hair follicle regulates keratinization Hidradenitis suppurativa with acne
PSEN deficiency hidradenitis suppurativa PSEN AD 104311 Epidermis Gamma-secretase in hair follicle regulates keratinization Hidradenitis suppurative with cutaneous hyperpigmentation
PSENEN deficiency hidradenitis suppurativa PSENEN AD 607632 Epidermis Gamma-secretase in hair follicle regulates keratinization Hidradenitis suppurativa

Table 7.

Autoinflammatory disorders

1. Type 1 interferonopathies
Disease Genetic defect Inheritance OMIM T cells B cells Functional defect Associated features
TREX1 deficiency, Aicardi-Goutieres syndrome 1 (AGS1) TREX1 AR or AD 606609 Not assessed Not assessed Intracellular accumulation of abnormal ss DNA species leading to increased type I IFN production Classical AGS, SLE, FCL
RNASEH2B deficiency, AGS2 RNASEH2B AR 610326 Not assessed Not assessed Intracellular accumulation of abnormal RNA-DNA hybrid species leading to increased type I IFN production Classical AGS, SP
RNASEH2C deficiency, AGS3 RNASEH2C AR 610330 Not assessed Not assessed Intracellular accumulation of abnormal RNA-DNA hybrid species leading to increased type I IFN production Classical AGS
RNASEH2A deficiency, AGS4 RNASEH2A AR 606034 Not assessed Not assessed Intracellular accumulation of abnormal RNA-DNA hybrid species leading to increased type I IFN production Classical AGS
SAMHD1 deficiency, AGS5 SAMHD1 AR 606754 Not assessed Not assessed Controls dNTPs in the cytosol, failure of which leads to increased type I IFN production Classical AGS, FCL
ADAR1 deficiency, AGS6 ADAR1 AR 146920 Not assessed Not assessed Catalyzes the deamination of adenosine to inosine in dsRNA substrates, failure of which leads to increased type I IFN production Classical AGS, BSN, SP
Aicardi-Goutieres syndrome 7 (AGS7) IFIH1 (GOF) AD 606951 Not assessed Not assessed IFIH1 gene encodes a cytoplasmic viral RNA receptor that activates type I interferon signaling through the MAVS adaptor molecule Classical AGS, SLE, SP, SMS
Spondyloenchondro-dysplasia with immune dysregulation (SPENCD) ACP5 AR 171640 Not assessed Not assessed Upregulation of IFN through mechanism possibly relating to pDCS Short stature, SP, ICC, SLE, thrombocytopenia and autoimmune hemolytic anemia, possibly recurrent bacterial and viral infections
STING-associated vasculopathy, infantile-onset TMEM173 AR 612374 Not assessed Not assessed STING activates both the NF-kappa-B and IRF3 transcription pathways to induce expression of IFN Skin vasculopathy, inflammatory lung disease, systemic autoinflammation and ICC, FCL
X-linked reticulate pigmentary disorder POLA1 XL 301220 Not assessed Not assessed POLA1 is required for synthesis of cytosolic RNA:DNA and its deficiency leads to increase production of type I interferon Hyperpigmentation, characteristic facies, lung and GI involvement
USP18 deficiency USP18 AR 607057 Not assessed Not assessed Defective negative regulation of ISG15 leading to increased IFN TORCH like syndrome
CANDLE (chronic atypical neutrophilic dermatitis with lipodystrophy) PSMB8 a AR and AD 256040 Not assessed Not assessed Mutations cause increased IFN signaling through an undefined mechanism Contractures, panniculitis, ICC, fevers
Singleton-Merten syndrome DDX58 AD 609631 Not assessed Not assessed Recognizes double stranded RNA Dental dysplasia), calcifications in the aorta, osteoporosis, especially in the hands and feet
2. Defects affecting the inflammasome
Disease Genetic defect Inheritance OMIM Affected cells Functional defects Associated features
Familial Mediterranean fever MEFV AR or AD 249100134610 Mature granulocytes, cytokine-activated monocytes Decreased production of pyrin permits ASC-induced IL-1 processing and inflammation following subclinical serosal injury, macrophage apoptosis decreased Recurrent fever, serositis and inflammation responsive to colchicine. Predisposes to vasculitis and inflammatory bowel disease
Mevalonate kinase deficiency (Hyper IgD syndrome) MVK AR 260920 Somatic and hemaotpoietic Affecting cholesterol synthesis, pathogenesis of disease unclear Periodic fever and leukocytosis with high IgD levels
Muckle-Wells syndrome NLRP3 (also called NALP3 CIAS1 or PYPAF1) AD GOF 191900 PMNs Monocytes Defect in cryopyrin, involved in leukocyte apoptosis and NFkB signaling and IL-1 processing Urticaria, SNHL, amyloidosis
Familial cold autoinflammatory syndrome 1 NLRP3 AD GOF 120100 PMNs, monocytes As above Non-pruritic urticaria, arthritis, chills, fever and leukocytosis after cold exposure
Familial cold autoinflammatory syndrome 2 NLRP12 AD GOF 611762 PMNs, monocytes As above Non-pruritic urticaria, arthritis, chills, fever and leukocytosis after cold exposure
Neonatal onset multisystem inflammatory disease (NOMID) or chronic infantile neurologic cutaneous and articular syndrome (CINCA) NLRP3 AD GOF 607115 PMNs, chondrocytes As above Neonatal onset rash, chronic meningitis, and arthropathy with fever and inflammation
NLRC4-MAS (macrophage activating syndrome) or familial cold autoinflammatory syndrome 4 NLRC4 AD GOF 616050616115 PMNs monocytes macrophages Gain-of-function mutation in NLRC4 results in elevated secretion of IL-1β and IL-18 as well as macrophage activation Severe enterocolitis and macrophage activation syndrome
PLAID (PLCγ2 associated antibody deficiency and immune dysregulation) or familial cold autoinflammatory syndrome 3 or APLAID (c2120A>C) PLCG2 AD GOF 614468 B cells, NK, mast cells Mutations cause activation of IL-1 pathways Cold urticaria hypogammaglobulinemia, autoinflammation
NLRP1 deficiency NLRP1 AR 606579 Leukocytes Systemic elevation of IL-18 and caspase 1, suggesting involvement of NLRP1 inflammasome Dyskeratosis, autoimmunity and arthritis
3. Non-inflammasome-related conditions
Disease Genetic defect Inheritance OMIM Affected cells Functional defects Associated Features
TNF receptor-associated periodic syndrome (TRAPS) TNFRSF1A AD 142680 PMNs, monocytes Mutations of 55-kD TNF receptor leading to intracellular receptor retention or diminished soluble cytokine receptor available to bind TNF Recurrent fever, serositis, rash, and ocular or joint inflammation
Pyogenic sterile arthritis, pyoderma gangrenosum, acne (PAPA) syndrome, hyperzincemia, and hypercalprotectinemia PSTPIP1 (also called C2BP1) AD 604416 Hematopoietic tissues, upregulated in activated T cells Disordered actin reorganization leading to compromised physiologic signaling during inflammatory response Destructive arthritis, inflammatory skin rash, myositis
Blau syndrome NOD2 (also called CARD15) AD 186580 Monocytes Mutations in nucleotide binding site of CARD15, possibly disrupting interactions with lipopolysaccharides and NF-kB signaling Uveitis, granulomatous synovitis, camptodactyly, rash and cranial neuropathies, 30% develop Crohn colitis
ADAM17 deficiency ADAM17 AR 614328 Leukocytes and epithelial cells Defective TNFα production Early-onset diarrhea and skin lesions
Chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anemia (Majeed syndrome) LPIN2 AR 609628 Neutrophils, bone marrow cells Undefined Chronic recurrent multifocal osteomyelitis, transfusion-dependent anemia, cutaneous inflammatory disorders
DIRA (deficiency of the interleukin-1 receptor antagonist) IL1RN AR 612852 PMNs, Monocytes Mutations in the IL-1 receptor antagonist allow unopposed action of interleukin-1 Neonatal onset of sterile multifocal osteomyelitis, periostitis and pustulosis
DITRA (deficiency of IL-36 receptor antagonist) IL36RN AR 614204 Keratinocytes, leukocytes Mutations in IL-36RN leads to increase IL-8 production Pustular psoriasis
SLC29A3 mutation SLC29A3 AR 602782 Leukocytes, bone cells Hyperpigmentation hypertrichosis, histiocytosis-lymphadenopathy plus syndrome
CAMPS (CARD14 mediated psoriasis) CARD14 AD 602723 Mainly in keratinocytes Mutations in CARD14 activate the NF-kB pathway and production of IL-8 Psoriasis
Cherubism SH3BP2 AD 118400 Stroma cells, bone cells Hyperactived macrophage and increase NF-kB Bone degeneration in jaws
COPA defect COPA AD 6011924 PMN and tissue specific cells Defective intracellular transport via the coat protein complex I (COPI) Autoimmune inflammatory arthritis and interstitial lung disease with Th17 dysregulation and autoantibody production
Otulipenia/ORAS OTULIN AR 615712 Leukocytes Increase LUBAC induction of NF-KB activation leading to high proinflammatory cytokines levels Fever, diarrhea, dermatitis
A20 deficiency TNFAIP3 AD LOF 616744 Lymphocytes Defective inhibition of NF-KB signaling pathway Arthralgia, mucosal ulcers, ocular inflammation
ADA2 deficiency CECR1 AR 607575 Lymphocytes ADAs deactivate extracellular adenosine and terminate signaling through adenosine receptors Polyarteritis nodosa, childhood-onset, early-onset recurrent ischemic stroke and fever
AP1S3 deficiency AP1S3 AR 615781 Keratinocytes Disrupted TLR3 translocation Pustular psoriasis

Table 8.

Complement deficiencies

1. Complement deficiencies
Disease Genetic defect Inheritance Gene OMIM Laboratory features Associated features
C1q deficiency due to defects in C1QA C1QA AR 120550 Absent CH50 hemolytic activity, defective activation of the classical pathway, diminished clearance of apoptotic cells SLE, infections with encapsulated organisms
C1q deficiency due to defects in C1QB C1QB AR 120570 Absent CH50 hemolytic activity, Defective activation of the classical pathway, diminished clearance of apoptotic cells SLE, infections with encapsulated organisms
C1q deficiency due to defects in C1QC C1QC AR 120575 Absent CH50 hemolytic activity, Defective activation of the classical pathway, diminished clearance of apoptotic cells SLE, infections with encapsulated organisms
C1r deficiency C1R AR 613785 Absent CH50 hemolytic activity, defective activation of the classical pathway SLE, infections with encapsulated organisms, Ehlers-Danlos phenotype
C1s deficiency C1S AR 120580 Absent CH50 hemolytic activity, defective activation of the classical pathway SLE, infections with encapsulated organisms, Ehlers-Danlos phenotype
Complete C4 deficiency C4A + C4B AR 120810 Absent CH50 hemolytic activity, defective activation of the classical pathway, complete deficiency requires biallelic mutations/deletions/conversions of both C4A and C4B SLE, infections with encapsulated organisms, partial deficiency is common (either C4A or C4B) and appears to have a modest effect on host defense
C2 deficiency C2 AR 217000 Absent CH50 hemolytic activity, defective activation of the classical pathway SLE, infections with encapsulated organisms, atherosclerosis
C3 deficiency (LOF) C3 AR 120700 Absent CH50 and AH50 hemolytic activity, defective opsonization, defective humoral immune response Infections, glomerulonephritis, atypical hemolytic-uremic syndrome with GOF mutations
C3 GOF C3 AD 120700 Increased activation of complement Atypical hemolytic-uremic syndrome
C5 deficiency C5 AR 120900 Absent CH50 and AH50 hemolytic activity Defective bactericidal activity Disseminated neisserial infections
C6 deficiency C6 AR 217050 Absent CH50 and AH50 hemolytic activity, defective bactericidal activity Disseminated neisserial infections
C7 deficiency C7 AR 217070 Absent CH50 and AH50 hemolytic activity, defective bactericidal activity Disseminated neisserial infections
C8α deficiency C8A AR 120950 Absent CH50 and AH50 hemolytic activity, defective bactericidal activity Disseminated neisserial infections
C8γ deficiency C8G AR 120930 Absent CH50 and AH50 hemolytic activity, defective bactericidal activity Disseminated neisserial infections
C8β-deficiency C8B: AR 120960 Absent CH50 and AH50 hemolytic activity, defective bactericidal activity Disseminated neisserial infections
C9 deficiency C9 AR 120940 Reduced CH50 and AP50 hemolytic activity, deficient bactericidal activity Mild susceptibility to disseminated neisserial infections
MASP2 deficiency MASP2 AR 605102 Deficient activation of the lectin activation pathway Pyogenic infections, inflammatory lung disease, autoimmunity
Ficolin 3 deficiency FCN3 AR 604973 Absence of complement activation by the Ficolin 3 pathway. Respiratory infections, abscesses
C1 inhibitor deficiency SERPING1 AD 606860 Spontaneous activation of the complement pathway with consumption of C4/C2, spontaneous activation of the contact system with generation of bradykinin from high molecular weight kininogen Hereditary angioedema
Factor B GOF CFB AD 138470 Gain-of-function mutation with increased spontaneous AH50 Atypical hemolytic-uremic syndrome
Factor B LOF CFB AR 138470 Deficient activation of the alternative pathway Infections with encapsulated organisms
Factor D deficiency CFD AR 134350 Absent AH50 hemolytic activity Neisserial infections
Properdin deficiency CFP XL 300383 Absent AH50 hemolytic activity Neisserial infections
Factor I deficiency CFI AR 217030 Spontaneous activation of the alternative complement pathway with consumption of C3 Infections, disseminated neisserial infections, atypical hemolytic-uremic syndrome, preeclampsia
Factor H deficiency CFH AR or AD 134370 Spontaneous activation of the alternative complement pathway with consumption of C3 Infections, disseminated neisserial infections, atypical hemolytic-uremic syndrome, preeclampsia
Factor H-related protein deficiencies CFHR1-5 AR or AD 134371, 600889, 605336, 605337, 608593 Normal CH50, AH50, autoantibodies to factor H, linked deletions of one or more CFHR genes leads to susceptibility autoantibody-mediated aHUS Older onset atypical hemolytic-uremic syndrome, disseminated neisserial infections
Thrombomodulin deficiency THBD AD 188040 Normal CH50, AH50 Atypical hemolytic-uremic syndrome
Membrane cofactor protein (CD46) deficiency CD46 AD 120920 Inhibitor of complement alternate pathway, decreased C3b binding Atypical hemolytic-uremic syndrome, infections, preeclampsia
Membrane attack Complex inhibitor (CD59) deficiency CD59 AR 107271 Erythrocytes highly susceptible to complement-mediated lysis Hemolytic anemia, polyneuropathy
CD55 deficiency (CHAPEL disease) CD55 AR 125240 Hyperactivation of complement on endothelium Protein losing enteropathy, thrombosis

Table 9.

Phenocopies of inborn errors of immunity

1. Phenocopies of inborn errors of immunity
Disease Genetic defect/presumed pathogenesis Circulating T cells Circulating B cells Serum Ig Associated features/similar PID
Associated with somatic mutations
Autoimmune lymphoproliferative syndrome (ALPS–SFAS) Somatic mutation in TNFRSF6 Increased CD4−CD8− double negative (DN) T alpha/beta cells Normal, but increased number of CD5+ B cells Normal or increased Splenomegaly, lymphadenopathy, autoimmune cytopenias, defective lymphocyte apoptosis/ALPS–FAS (=ALPS type Im)
RAS-associated autoimmune leukoproliferative disease (RALD) Somatic mutation in KRAS (GOF) Normal B cell lymphocytosis Normal or increased Splenomegaly, lymphadenopathy, autoimmune cytopenias, granulocytosis, monocytosis/ALPS-like
RAS-associated autoimmune leukoproliferative disease (RALD) Somatic mutation in NRAS (GOF) Increased CD4−CD8− double negative (DN) T alpha/beta cells Lymphocytosis Normal or increased Splenomegaly, lymphadenopathy, autoantibodies/ALPS-like
Cryopyrinopathy, (Muckle-Wells/CINCA/NOMID-like syndrome) Somatic mutation in NLRP3 Normal Normal Normal Urticaria-like rash, arthropathy, neurological signs
Hypereosinophilic syndrome due to somatic mutations in STAT5b Somatic mutation in STAT5b (GOF) Normal Normal Normal Eosinophilia, atopic dermatitis, urticarial rash, diarrhea
Large granular lymphocytosis Somatic mutations in STAT3 (GOF) Clonal expansion of large T cells Normal Normal Anemia, neutropenia, splenomegaly
Associated with autoantibodies
Chronic mucocutaneous candidiasis (isolated or with APECED syndrome) Germline mutation in AIRE AutoAb to IL-17 and/or IL-22 Normal Normal Normal Endocrinopathy, chronic mucocutaneous candidiasis/CMC
Adult-onset immunodeficiency with susceptibility to mycobacteria AutoAb to IFNγ Decreased naive T cells Normal Normal Mycobacterial, fungal, Salmonella VZV infections/MSMD, or CID
Recurrent skin infection AutoAb to IL-6 Normal Normal Normal Staphylococcal infections/STAT3 deficiency
Pulmonary alveolar proteinosis AutoAb to GM-CSF Normal Normal Normal Pulmonary alveolar proteinosis, cryptococcal meningitis, disseminated nocardiosis/CSF2RA deficiency
Acquired angioedema AutoAb to CI inhibitor Normal Normal Normal Angioedema/C1 INH deficiency (hereditary angioedema)
Atypical hemolytic-uremic syndrome AutoAb to complement factor H Normal Normal Normal aHUS = spontaneous activation of the alternative complement pathway
Thymoma with hypogammaglobulinemia (Good syndrome) AutoAb to various cytokines Increased CD8+ T cells No B cells Decreased Invasive bacterial, viral or opportunistic infections, autoimmunity, PRCA, lichen planus, cytopenia, colitis, chronic diarrhea

The goal of the IUIS Expert Committee on Primary Immunodeficiencies is to increase awareness, facilitate recognition, promote optimal treatment, and support research in the field of immune deficiency disorders. Thus, the “IUIS PID Committee Report on Inborn Errors of Immunity” and “Update of the Phenotypical IUIS Classification for Primary Immunodeficiencies” publications are important resources for clinicians and researchers. In addition, these tables form the basis of lists used for sequencing panels and are used to monitor health utilization which will influence health services funding by federal or state governments and/or insurance companies in various global settings. The addition of ICD10 codes for the online version will promote a harmonization between the diagnostic tables and coding items that will facilitate bioinformatics research going forward.

Acknowledgements

The authors wish to thank Dawn Westerfer for the expert secretarial support and Ulrika Smrekova for the administrative support.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflicts of interest.

References