Edited by: Eric Meffre, Yale University School of Medicine, USA
Reviewed by: Eric Meffre, Yale University School of Medicine, USA
*Correspondence: Mary Ellen Conley, Department of Pediatrics, University of Tennessee College of Medicine, Memphis, TN, USA; Department of Immunology MS 351, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA. e-mail:
This article was submitted to Frontiers in Primary Immunodeficiencies, a specialty of Frontiers in Immunology.
This is an open-access article subject to a non-exclusive license between the authors and Frontiers Media SA, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and other Frontiers conditions are complied with.
We report the updated classification of primary immunodeficiency diseases, compiled by the
The International Union of Immunological Societies (IUIS) Expert Committee on Primary Immunodeficiency met in New York City, May 31–June 1, 2011 to update the classification of human primary immunodeficiencies (PIDs). Novel developments in gene discovery and increased knowledge in the mechanisms that govern immune system development and function have resulted in the identification of several novel PIDs in the last 2 years.
The classification of primary immunodeficiencies (PIDs) provides a framework to help in the diagnostic approach to patients. As in recent classifications, eight major groups of PIDs have been included in the Tables; however the order of the Tables has been changed with Table
Disease | Circulating T cells | Circulating B cells | Serum Ig | Associated features | Inheritance | Genetic defect/presumed pathogenesis | OMIM number |
---|---|---|---|---|---|---|---|
(a) γc deficiency | Markedly decreased | Normal or increased | Decreased | Markedly decreased NK cells; leaky cases may present with low to normal T and/or NK cells or Omenn syndrome | XL | Defect in γ chain of receptors for IL-2, -4, -7, -9, -15, -21 | |
(b) JAK3 deficiency | Markedly decreased | Normal or increased | Decreased | Markedly decreased NK cells; leaky cases may present with variable T and/or NK cells | AR | Defect in Janus activating kinase 3 | |
(c) IL7Rα deficiency | Markedly decreased | Normal or increased | Decreased | Normal NK cells | AR | Defect in IL-7 receptor α chain | |
(d) CD45 deficiency* | Markedly decreased | Normal | Decreased | Normal γ/δ T cells | AR | Defect in CD45 | |
(e) CD3δ*/CD3ε*/CD3ζ* deficiency | Markedly decreased | Normal | Decreased | Normal NK cells Noγ/δT cells | AR | Defect in CD3δ, CD3ε, or CD3ζ chains of T cell antigen receptor complex | |
(f) Coronin-1A deficiency* | Markedly decreased | Normal | Decreased | Detectable thymus | AR | Defective thymic egress of T cells and defective T cell locomotion | |
(a) RAG 1/2 deficiency | Markedly decreased | Markedly decreased | Decreased | May present with Omenn syndrome, expanded γ/δT cells, autoimmunity, and/or granulomas | AR | Defective VDJ recombination; defect of recombinase activating gene (RAG) 1 or 2 | |
(b) |
Markedly decreased | Markedly decreased | Decreased | Defective VDJ recombination, radiation sensitivity; may present with Omenn syndrome | AR | Defective VDJ recombination; defect in Artemis DNA recombinase repair protein | |
(c) DNA-PKcs deficiency* | Markedly decreased | Markedly decreased | Decreased | (Widely studied |
AR | Defective VDJ recombination; defect in DNA-PKcs recombinase repair protein | |
(d) Reticular dysgenesis, AK2 deficiency | Markedly decreased | Decreased or normal | Decreased | Deficiency of T, B, and NK cells with granulocytopenia, deafness | AR | Defective maturation of lymphoid and myeloid cells (stem cell defect) defect in mitochondrial adenylate kinase 2 | |
(e) Adenosine deaminase (ADA) deficiency | Absent from birth (null mutations) or progressive decrease | Absent from birth of progressive decrease | Progressive decrease | Decreased NK cells, often with costochondral junction flaring, neurological features, hearing impairment, lung, and liver manifestations; partial ADA deficiency may lead to delayed or milder presentation | AR | Absent ADA activity, elevated lymphotoxic metabolites (dATP, |
|
Present; restricted heterogeneity | Normal or decreased | Decreased, except increased IgE | Erythroderma, eosinophilia, adenopathies, hepatosplenomegaly | AR | Hypomorphic mutations in RAG1/2, Artemis, IL7Rα, RMRP, ADA, DNA Ligase IV, γc, or associated with DiGeorge syndrome; some cases have no defined gene mutation | ||
Decreased | Decreased | Decreased | Microcephaly, facial dysmorphisms, radiation sensitivity; may present with Omenn syndrome or with a delayed clinical onset | AR | DNA ligase IV defect, impaired non-homologous end joining (NHEJ) | ||
Decreased | Decreased | Decreased | Microcephaly, |
AR | Cernunnos ( |
||
Normal; may progressively decrease | IgM+ and IgD+ B cells present, other isotypes absent | IgM increased or normal, other isotypes decreased | Neutropenia, thrombocytopenia; hemolytic anemia, biliary tract, and liver disease, opportunistic infections | XL | Defects in CD40 ligand (CD40L) cause defective isotype switching and impaired dendritic cell signaling | ||
Normal | IgM+ and IgD+ B cells present, other isotypes absent | IgM increased or normal, other isotypes decreased | Neutropenia, gastrointestinal, and liver/biliary tract disease, opportunistic infections | AR | Defects in CD40 cause defective isotype switching and impaired dendritic cell signaling | ||
Progressive decrease | Normal | Normal or decreased | Autoimmune hemolytic anemia, neurological impairment | AR | Absent PNP, T cell and neurologic defects from elevated toxic metabolites, especially dGTP | ||
Normal, but reduced TCR expression | Normal | Normal | AR | Defect in CD3 γ | |||
Absent CD8, normal CD4 cells | Normal | Normal | AR | Defects of CD8 α chain | |||
Decreased CD8, normal CD4 cells | Normal | Normal | AR | Defects in ZAP-70 signaling kinase | |||
(a) ORAI-I deficiency* | Normal number, but defective TCR-mediated activation | Normal | Normal | Autoimmunity, anhydrotic ectodermic dysplasia, non-progressive myopathy | AR | Defect in ORAI-1, a Ca++ release-activated channel (CRAC) modulatory component | |
(b) STIM-1 deficiency* | Normal number, but defective TCR-mediated activation | Normal | Normal | Autoimmunity, anhydrotic ectodermic dysplasia, non-progressive myopathy | AR | Defect in STIM-1, a stromal interaction molecule Ca++sensor | |
Decreased CD8, normal CD4 | Normal | Normal | Vasculitis | AR | Mutations in |
||
Normal number, decreased CD4 cells | Normal | Normal or decreased | Failure to thrive, diarrhea, respiratory tract infections | AR | Mutation in transcription factors for MHC class II proteins ( |
||
Markedly decreased | Normal | Decreased | Alopecia, abnormal thymic epithelium, impaired T cell maturation (widely studied nude mouse defect) | AR | Defects in forkhead box N1 transcription factor encoded by |
||
Profoundly decreased | Low to normal | Decreased | Lymphoproliferation (lymphadenopathy, hepatosplenomegaly), autoimmunity (may resemble IPEX syndrome), impaired T cell proliferation | AD | Deletion of chromosome 22q11.2 or in a minority of cases other chromosomal regions, including 10p; heterozygous defects in transcription factor |
||
Decreased or 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 | AR | Mutations in |
||
Normal, but impaired lymphocyte proliferation | Absent | Presumably decreased | Anemia, neutropenia, thrombocytopenia | AD |
Mutation in |
||
Modestly decreased | Normal | Normal | Growth-hormone insensitive dwarfism, dysmorphic features, eczema, lymphocytic interstitial pneumonitis, autoimmunity | AR | Defects of STAT5b, impaired development and function of γδT cells, Treg, and NK cells, impaired T cell proliferation | ||
Modestly decreased | Normal | Normal or decreased | AR | Defects in |
|||
Decreased CD4 cells | Normal | Normal | EBV infection, lymphoma; viral infections, respiratory and GI infections | XL | Mutations in |
||
Decreased | Decreased | Low IgM, increased IgE | Low NK cells, hypereosinophilia, recurrent infections; severe atopy, extensive cutaneous viral, and bacterial (staph.) infections, susceptibility to cancer | AR | Defect in |
Disease | Circulating T cells | Circulating B cells | Serum Ig | Associated features | Inheritance | Genetic defect/presumed pathogenesis | OMIM number |
---|---|---|---|---|---|---|---|
Progressive decrease, abnormal lymphocyte responses to anti-CD3 | Normal | Decreased IgM: antibody to polysaccharides particularly decreased; often increased IgA and IgE | Thrombocytopenia with small platelets; eczema; lymphoma; autoimmune disease; IgA nephropathy; bacterial and viral infections. XL thrombocytopenia is a mild form of WAS, and XL neutropenia is caused by missense mutations in the GTPase binding domain of WASP | XL | Mutations in |
||
(a) Ataxia–telangiectasia | Progressive decrease | Normal | Often decreased IgA, IgE, and IgG subclasses; increased IgM monomers; antibodies variably decreased | Ataxia; telangiectasia; pulmonary infections; lymphoreticular and other malignancies; increased alpha fetoprotein and X-ray sensitivity; chromosomal instability | AR | Mutations in |
|
(b) Ataxia–telangiectasia-like disease (ATLD)* | Progressive decrease | Normal | Antibodies variably decreased | Moderate ataxia; pulmonary infections; severely increased radiosensitivity | AR | Hypomorphic mutations in |
|
(c) Nijmegen breakage syndrome | Progressive decrease | Variably reduced | Often decreased IgA, IgE, and IgG subclasses; increased IgM; antibodies variably decreased | Microcephaly; bird like face; lymphomas; solid tumors; ionizing radiation sensitivity; chromosomal instability | AR | Hypomorphic mutations in |
|
(d) Bloom syndrome | Normal | Normal | Reduced | Short stature; bird like face; sun-sensitive erythema; marrow failure; leukemia; lymphoma; chromosomal instability | AR | Mutations in |
|
(e) Immunodeficiency with centromeric instability and facial anomalies (ICF) | Decreased or normal; Responses to PHA may be decreased | Decreased or normal | Hypogammaglobulinemia; variable antibody deficiency | Facial dysmorphic features; macroglossia; bacterial/opportunistic infections; malabsorption; cytopenias; malignancies; multiradial configurations of chromosomes 1, 9, 16; no DNA breaks | AR | Mutations in DNA methyltransferase |
|
(f) PMS2 deficiency (class switch recombination deficiency due to impaired mismatch repair) | Normal | Switched and non-switched B cells are reduced | Low IgG and IgA, elevated IgM, abnormal antibody responses | Recurrent infections; café-au-lait spots; lymphoma, colorectal carcinoma, brain tumor | AR | Mutations in |
|
(g) Riddle syndrome* | Normal | Normal | Low IgG | Mild motor control and learning difficulties, mild facial dysmorphism, and short stature | AR | Mutations in |
|
DiGeorge anomaly (chromosome 22q11.2 deletion syndrome) | Decreased or normal | Normal | Normal or decreased | Hypoparathyroidism, conotruncal malformation; abnormal facies; large deletion (3 Mb) in 22q11.2 (or rarely a deletion in 10p) | Contiguous gene defect in 90% affecting thymic development; mutation in |
||
(a) Cartilage hair hypoplasia | Decreased or 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 | AR | Mutations in |
|
(b) Schimke syndrome | Decreased | Normal | Normal | Short stature, spondyloepiphyseal dysplasia, intrauterine growth retardation, nephropathy; bacterial, viral, fungal infections; may present as SCID; bone marrow failure | AR | Mutations in |
|
Normal | Switched and non-switched B cells are reduced | Elevated IgE and IgA antibody variably decreased | Congenital ichthyosis, bamboo hair, atopic diathesis, increased bacterial infections, failure to thrive | AR | Mutations in |
||
(a) AD-HIES (Job syndrome) | Normal Th-17 cells decreased | Normal (switched and non-switched memory B cells are reduced; BAFF level increased) | Elevated IgE; specific antibody production decreased | Distinctive facial features (broad nasal bridge), eczema, osteoporosis, and fractures, scoliosis, failure/delay of shedding primary teeth, hyperextensible joints, bacterial infections (skin and pulmonary abscesses, pneumatoceles) due to |
AD, often |
Dominant-negative heterozygous mutations in |
|
(b) AR-HIES | No skeletal and connective tissue abnormalities; no pneumatoceles | AR | |||||
(i) TYK2 deficiency* | Normal, but multiple cytokine signaling defect | Normal | (±) Elevated IgE | Susceptibility to intracellular bacteria (mycobacteria, |
Mutation in |
||
(ii) DOCK8 deficiency | Reduced | Reduced | (±) Elevated IgE, low IgM | Recurrent respiratory infections; extensive cutaneous viral and staphylococcal infections, increased risk of cancer, severe atopy with anaphylaxis | Mutation in |
||
(iii) Unknown origin | Normal | Normal | Elevated IgE | CNS hemorrhage, fungal, and viral infections | Unknown | ||
Normal (decreased memory T cells) | Normal (decreased memory B cells) | Decreased IgG, IgA, IgM absent germinal centers absent tissue plasma cells | Hepatic veno-occlusive disease; |
AR | Mutations in |
||
(a) XL-DKC (Hoyeraal-Hreidarsson syndrome) | Progressive decrease | Progressive decrease | Variable | Intrauterine growth retardation, microcephaly, nail dystrophy, recurrent infections, digestive tract involvement, pancytopenia, reduced number and function of NK cells | XL | Mutations in dyskerin ( |
|
(b) AR-DKC* | Abnormal | Variable | Variable | Pancytopenia, sparse scalp hair and eyelashes, prominent periorbital telangiectasia, and hypoplastic/dysplastic nails | AR | Mutation in |
|
(c) AD-DKC | Variable | Variable | Variable | Reticular hyperpigmentation of the skin, dystrophic nails, osteoporosis, premalignant leukokeratosis of the mouth mucosa, palmar hyperkeratosis, anemia, pancytopenia | AD | Mutation in |
|
Normal, but impaired lymphocyte proliferation | Absent | Presumably decreased | Anemia, neutropenia, thrombocytopenia | AD |
Mutation in |
Disease | Serum Ig | Associated features | Inheritance | Genetic defect/presumed pathogenesis | OMIM number | |
---|---|---|---|---|---|---|
(a) BTK deficiency | All isotypes decreased in majority of patients; some patients have detectable immunoglobulins | Severe bacterial infections; normal numbers of pro-B cells | XL | Mutations in |
||
(b) μ Heavy chain deficiency | All isotypes decreased | Severe bacterial infections; normal numbers of pro-B cells | AR | Mutations in μ heavy chain | ||
(c) λ5 deficiency* | All isotypes decreased | Severe bacterial infections; normal numbers of pro-B cells | AR | Mutations in λ5; part of the surrogate light chain in the pre-BCR | ||
(d) Igα deficiency* | All isotypes decreased | Severe bacterial infections; normal numbers of pro-B cells | AR | Mutations in Igα ( |
||
(e) Igβ deficiency* | All isotypes decreased | Severe bacterial infections; normal numbers of pro-B cells | AR | Mutations in Igβ ( |
||
(f) BLNK deficiency* | All isotypes decreased | Severe bacterial infections; normal numbers of pro-B cells | AR | Mutations in |
||
(g) Thymoma with immunodeficiency | One or more isotypes may be decreased | Bacterial and opportunistic infections; autoimmunity; decreased number of pro-B cells | None | Unknown | ||
(h) Myelodysplasia with hypogammaglobulinemia | One or more isotypes may be decreased | Infections; decreased number of pro-B cells | Variable | May have monosomy 7, trisomy 8, or dyskeratosis congenita | ||
(a) Common variable immunodeficiency disorders | Low IgG and IgA and/or IgM | Clinical phenotypes vary: most have recurrent infections, some have polyclonal lymphoproliferation, autoimmune cytopenias, and/or granulomatous disease | Variable | Unknown | ||
(b) ICOS deficiency* | Low IgG and IgA and/or IgM | AR | Mutations in |
|||
(c) CD19 deficiency* | Low IgG and IgA and/or IgM | May have glomerulonephritis | AR | Mutations in |
||
(d) CD81 deficiency* | Low IgG, low or normal IgA, and IgM | May have glomerulonephritis | AR | Mutations in |
||
(e) CD20 deficiency* | Low IgG, normal or elevated IgM, and IgA | AR | Mutations in |
|||
(f) TACI deficiency | Low IgG and IgA and/or IgM | Variable clinical expression | AD or AR or complex | Mutations in |
||
(g) BAFF receptor deficiency* | Low IgG and IgM | Variable clinical expression | AR | Mutations in |
||
(a) CD40L deficiency | IgG and IgA decreased; IgM may be normal or increased; B cell numbers may be normal or increased | Opportunistic infections, neutropenia, autoimmune disease | XL | Mutations in |
||
(b) CD40 deficiency* | Low IgG and IgA; normal or raised IgM | Opportunistic infections, neutropenia, autoimmune disease | AR | Mutations in |
||
(c) AID deficiency | IgG and IgA decreased; IgM increased | Enlarged lymph nodes and germinal centers | AR | Mutations in |
||
(d) UNG deficiency | IgG and IgA decreased; IgM increased | Enlarged lymph nodes and germinal centers | AR | Mutations in |
||
(a) Ig heavy chain mutations and deletions | One or more IgG and/or IgA subclasses as well as IgE may be absent | May be asymptomatic | AR | Mutation or chromosomal deletion at 14q32 | ||
(b) κ chain deficiency* | All immunoglobulins have lambda light chain | Asymptomatic | AR | Mutations in κ constant gene | ||
(c) Isolated IgG subclass deficiency | Reduction in one or more IgG subclass | Usually asymptomatic; a minority may have poor antibody response to specific antigens and recurrent viral/bacterial infections | Variable | Unknown | ||
(d) IgA with IgG subclass deficiency | Reduced IgA with decrease in one or more IgG subclass | Recurrent bacterial infections in majority | Variable | Unknown | ||
(e) Selective IgA deficiency | IgA decreased/absent | Usually asymptomatic; may have recurrent infections with poor antibody responses to carbohydrate antigens; may have allergies or autoimmune disease. A very few cases progress to CVID, others coexist with CVID in the family | Variable | Unknown | ||
Normal | Reduced ability to make antibodies to specific antigens | Variable | Unknown | |||
IgG and IgA decreased | Normal ability to make antibodies to vaccine antigens, usually not associated with significant infections | Variable | Unknown |
Disease | Circulating T cells | Circulating B cells | Serum Ig | Associated features | Inheritance | Genetic defect/presumed pathogenesis | OMIM number |
---|---|---|---|---|---|---|---|
(a) Chediak–Higashi syndrome | Normal | Normal | Normal | Partial albinism, recurrent infections, late-onset primary encephalopathy, increased lymphoma risk. Neutropenia, Giant lysosomes, low NK, and CTL activities, elevation of acute phase markers | AR | Mutations in |
|
(b) Griscelli syndrome, type2 | Normal | Normal | Normal | Partial albinism, elevation of acute phase markers, encephalopathy in some patients. Low NK and CTL activities | AR | Mutations in |
|
(c) Hermansky–Pudlak syndrome, type 2* | Normal | Normal | Normal | Partial albinism, increased bleeding. Neutropenia, low NK, and CTL activity | AR | Mutations in the |
|
(a) Perforin deficiency, FHL2 | Normal | Normal | Normal | Severe inflammation, persistent fever, cytopenias, splenomegaly. Hemophagocytosis, decreased to absent NK and CTL activities | AR | Mutations in |
|
(b) UNC13D (Munc13-4) deficiency, FHL3 | Normal | Normal | Normal | Severe inflammation, persistent fever, splenomegaly, hemophagocytosis, decreased NK and CTL activities | AR | Mutations in |
|
(c) Syntaxin 11 deficiency, FHL4 | Normal | Normal | Normal | Severe inflammation, persistent fever, splenomegaly. Hemophagocytosis, decreased to absent NK activity | AR | Mutations in |
|
(d) STXBP2 (Munc 18-2) deficiency, FHL5 | Normal | Normal | Normal or low | Severe inflammation, fever, splenomegaly, hemophagocytosis possible bowel disease. Decreased NK and CTL activities with partial restoration after IL-2 stimulation | AR | Mutations in |
|
(a) SH2D1A deficiency, XLP1 | Normal | Normal or reduced | Normal or low | Clinical and immunologic abnormalities triggered by EBV infection, including hepatitis, hemophagocytic syndrome, aplastic anemia, and lymphoma. Dysgammaglobulinemia or hypogammaglobulinemia, low to absent NKT cells | XL | Mutations in |
|
(b) XIAP deficiency, XLP2 | Normal | Normal or reduced | Normal or low | Clinical and immunologic abnormalities triggered by EBV infection, including splenomegaly, hepatitis, hemophagocytic syndrome colitis | XL | Mutations in |
|
(a) Autoimmune lymphoproliferative syndrome (ALPS) | |||||||
(i) ALPS-FAS | Increased CD4− CD8− double negative (DN) T cells | Normal, but increased number of CD5+ B cells | Normal or increased | Splenomegaly, adenopathies, autoimmune cytopenias, increased lymphoma risk. Defective lymphocyte apoptosis | AD (AR cases are rare and severe) | Mutations in |
|
(ii) ALPS-FASLG | Increased DN T cells | Normal | Normal | Splenomegaly, adenopathies, autoimmune cytopenias, SLE defective lymphocyte apoptosis | AD AR | Mutations in |
|
(iii) ALPS-CASP10* | Increased DN T cells | Normal | Normal | Adenopathies, splenomegaly, autoimmunity. Defective lymphocyte apoptosis | AD | Mutations in |
|
(iv) Caspase 8 defect* | Slightly increased DN T cells | Normal | Normal or decreased | Adenopathies, splenomegaly, recurrent bacterial, and viral infections. Defective lymphocyte apoptosis and activation, hypogammaglobulinemia | AD | Mutations in |
|
(v) Activating N-RAS defect, activating K-RAS defect* | Increased or normal DN T cells | Elevation of CD5 B cells | Normal | Adenopathies, splenomegaly, leukemia, lymphoma. Defective lymphocyte apoptosis following IL-2 withdrawal | Sporadic | Somatic mutations in |
|
(vi) FADD deficiency* | Increased DN T cells | Normal | Normal | Functional hyposplenism, recurrent bacterial, and viral infections, recurrent episodes of encephalopathy and liver dysfunction. Defective lymphocyte apoptosis | AR | Mutations in |
|
(b) APECED (APS-1), autoimmune polyendocrinopathy with candidiasis and ectodermal dystrophy | Normal | Normal | Normal | Autoimmunity, particularly of parathyroid, adrenal, and other endocrine organs, chronic candidiasis, dental enamel hypoplasia, and other abnormalities | AR | Mutations in |
|
(c) IPEX, immune dysregulation, polyendocrinopathy, enteropathy (X-linked) | Lack of (and/or impaired function of) CD4+ CD25+ FOXP3+ regulatory T cells | Normal | Elevated IgA, IgE | Autoimmune enteropathy, early onset diabetes, thyroiditis hemolytic anemia, thrombocytopenia, eczema | XL | Mutations in |
|
(d) CD25 deficiency | Normal to modestly decreased | Normal | Normal | Lymphoproliferation, autoimmunity. Impaired T cell proliferation | AR | Mutations in IL-2Rα chain | |
(e) ITCH deficiency* | Not assessed (Th2 skewing in |
Not assessed (B cells are dysfunctional in |
Not assessed (elevated in |
Multi-organ autoimmunity, chronic lung disease, failure to thrive, developmental delay, macrocephaly | AR | Mutations in |
Any classification of human disorders is somewhat arbitrary, and the classification of PIDs is no exception. Some disorders might well belong to more than one group. CD40 ligand deficiency, for example, is reported both in Tables
Although this updated classification reports on the most typical immunological findings and associated clinical and genetic features for the various PIDs, there is extensive clinical, immunological, and molecular heterogeneity that can not be easily recapitulated in a brief summary. To facilitate a more rigorous analysis of each disease, a column has been added on the right with a hyperlink to refer to its catalog number in the Online Mendelian Inheritance in Man (OMIM) publicly accessible database (
The prevalence of the various PIDs varies in different countries. For this reason, in this new classification, we have elected to avoid giving a comment on the relative frequency of PID disorders. However, an asterisk has been placed in the first column, after the disease name, to identify disorders for which fewer than 10 unrelated cases have been reported in the literature. Some of these forms of PID can be considered extremely rare. Others have only recently been identified and it may be that more patients will be detected over time.
Finally, it is increasingly recognized that different mutations in the same gene may result in different phenotypes and may be associated with different patterns of inheritance. This concept of clinical, immunological, and genetic heterogeneity is assuming foremost importance. Notes in the text or in the footnotes identify such heterogeneity, when known.
The scope of the IUIS Expert Committee on Primary Immunodeficiency is to increase awareness, facilitate recognition, and promote optimal treatment for patients with Primary Immunodeficiency disorders worldwide. For this reason, in addition to periodically revising the Classification of PIDs, the Expert Committee is also actively involved in the development of diagnostic criteria and in providing, upon request, advice with regard to therapeutic guidelines.
Disease | Affected cells | Affected function | Associated features | Inheritance | Genetic defect/presumed pathogenesis | OMIM number |
---|---|---|---|---|---|---|
(a) Severe congenital neutropenia1 (ELANE deficiency) | N | Myeloid differentiation | Subgroup with myelodysplasia | AD | ||
(b) SCN2* (GFI 1 deficiency) | N | Myeloid differentiation | B/T lymphopenia | AD | ||
(c) SCN3 (Kostmann disease) | N | Myeloid differentiation | Cognitive and neurological defects in some patients | AR | ||
(d) SCN4 (G6PC3 deficiency) | N + F | Myeloid differentiation, chemotaxis, |
Structural heart defects, urogenital abnormalities, and venous angiectasis of trunks and limbs | AR | ||
(e) Glycogen storage disease type 1b | N + M | Myeloid differentiation, chemotaxis, |
Fasting hypoglycemia, lactic acidosis, hyperlipidemia, hepatomegaly | AR | ||
(f) Cyclic neutropenia | N | ? | Oscillations in the number of other leukocytes and platelets | AD | ||
(g) X-linked neutropenia/*myelodysplasia | N + M | Mitosis | Monocytopenia | XL | ||
(h) P14 deficiency* | N + L Mel | Endosome biogenesis | Neutropenia Hypogammaglobulinemia ↓CD8 cytotoxicity partial albinism growth failure | AR | ||
(i) Barth syndrome | N | Myeloid differentiation | Cardiomyopathy, growth retardation | XL | Tafazzin ( |
|
(j) Cohen syndrome | N | Myeloid differentiation | Retinopathy, developmental delay, facial dysmorphisms | AR | ||
(k) Poikiloderma with neutropenia | N | Myeloid differentiation, |
Poikiloderma, MDS | AR | ||
(a) Leukocyte adhesion deficiency type 1 (LAD1) | N + M + L + NK | Adherence, chemotaxis, endocytosis, T/NK cytotoxicity | Delayed cord separation, skin ulcers periodontitis leukocytosis | AR | ||
(b) Leukocyte adhesion deficiency type 2 (LAD2)* | N + M | Rolling, chemotaxis | Mild LAD type 1 features plus hh-blood group plus mental and growth retardation | AR | ||
(c) Leukocyte adhesion deficiency type 3 (LAD3) | N + M + L + NK | Adherence, chemotaxis | LAD type 1 plus bleeding tendency | AR | ||
(d) Rac 2 deficiency* | N | Adherence, chemotaxis |
Poor wound healing, leukocytosis | AD | ||
(e) β-actin deficiency* | N + M | Motility | Mental retardation, short stature | AD | ||
(f) Localized juvenile periodontitis | N | Formyl peptide induced chemotaxis | Periodontitis only | AR | ||
(g) Papillon–Lefèvre syndrome | N + M | Chemotaxis | Periodontitis, palmoplantar hyperkeratosis in some patients | AR | ||
(h) Specific granule deficiency* | N | Chemotaxis | Neutrophils with bilobed nuclei | AR | ||
(i) Shwachman–Diamond syndrome | N | Chemotaxis | Pancytopenia, exocrine pancreatic insufficiency, chondrodysplasia | AR | ||
(a) X-linked chronic granulomatous disease (CGD) | N + M | Killing (faulty |
McLeod phenotype in patients with deletions extending into the contiguous Kell locus | XL | ||
(b-e) Autosomal CGD’s | N + M | Killing (faulty |
AR | |||
(a) IL12 and IL23 receptor β1 chain deficiency | L + NK | IFN-γ secretion | Susceptibility to |
AR | ||
(b) IL12p40 deficiency | M | IFN-γ secretion | Susceptibility to |
AR | ||
(c) IFN-γ receptor 1 deficiency | M + L | IFN-γ binding and signaling | Susceptibility to |
AR, AD | ||
(d) IFN-γ receptor 2 deficiency | M + L | IFN-γsignaling | Susceptibility to |
AR | ||
(e) STAT1 deficiency (AD form)* | M + L | IFN-γsignaling | Susceptibility to |
AD | ||
(f) Macrophage gp91 phox deficiency* | MΦ only | Killing (faulty O2- production) | Isolated susceptibility to mycobacteria | XL | ||
(g) IRF8 deficiency (AD form)* | CD1c+ MDC | Differentiation of CD1c+ MDC subgroup | Susceptibility to |
AD | ||
(a) IRF 8-deficiency (AR form)* | Monocytes peripheral DC | Cytopenias | Susceptibility to |
AR | ||
(b) GATA2 deficiency (Mono MAC Syndrome) | Monocytes peripheral DC + NK + B | Multilineage cytopenias | Susceptibility to |
AD | ||
(c) Pulmonary alveolar proteinosis* | Alveolar macrophages | GM-CSF signaling | Alveolar proteinosis | Biallelic mutations in pseudoautosomal gene |
Disease | Affected cell | Functional defect | Associated features | Inheritance | Genetic defect/presumed pathogenesis | OMIM number |
---|---|---|---|---|---|---|
(a) EDA-ID, X-linked (NEMO deficiency) | Lymphocytes + monocytes | NFκB signaling pathway | Anhidrotic ectodermal dysplasia + specific antibody deficiency (lack of Ab response to polysaccharides) + various infections (mycobacteria and pyogenes) | XL | Mutations of NEMO ( |
|
(b) EDA-ID, autosomal dominant* | Lymphocytes + monocytes | NFκB signaling pathway | Anhidrotic ectodermal dysplasia + T cell defect + various infections | AD | Gain-of-function mutation of |
|
Lymphocytes + monocytes | TIR-IRAK signaling pathway | Bacterial infections (pyogenes) | AR | Mutation of |
||
Lymphocytes + monocytes | TIR-MyD88 signaling pathway | Bacterial infections (pyogenes) | AR | Mutation of |
||
Granulocytes + lymphocytes | Increased response of the CXCR4 chemokine receptor to its ligand CXCL12 (SDF-1) | Hypogammaglobulinemia, reduced B cell number, severe reduction of neutrophil count, warts/HPV infection | AD | Gain-of-function mutations of |
||
Keratinocytes and leukocytes | Human Papilloma virus (group B1) infections and cancer of the skin | AR | Mutations of |
|||
(a) TLR3 deficiency* | Central nervous system (CNS) resident cells and fibroblasts | TLR3-dependent IFN-α, -β, and -λ induction | Herpes simplex virus 1 encephalitis | AD | Mutations of |
|
(b) UNC93B1 deficiency | CNS resident cells and fibroblasts | UNC-93B-dependent IFN-α, -β, and -λ induction | Herpes simplex virus 1 encephalitis | AR | Mutations of |
|
(c) TRAF3 deficiency | CNS resident cells and fibroblasts | TRAF3-dependent IFN-α, -β, and -λ induction | Herpes simplex virus 1 encephalitis | AD | Mutation of |
|
Mononuclear phagocytes | CARD9 signaling pathway | Invasive candidiasis and peripheral dermatophytosis | AR | Mutations of |
||
(a) IL-17RA deficiency* | Epithelial cells, fibroblasts, mononuclear phagocytes | IL-17RA signaling pathway | CMC | AR | Mutation in |
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(b) IL-17F deficiency* | T cells | IL-17F-containing dimers | CMC | AD | Mutation in |
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(c) STAT1 gain-of-function | T cells | Gain-of-function STAT1 mutations that impair the development of IL-17-producing T cells | CMC | AD | Mutations in |
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APOL-I | Trypanosomiasis | AD | Mutation in |
Disease | Affected cells | Functional defects | Associated Features | Inheritance | Genetic defect/presumed pathogenesis | OMIM number |
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(a) Familial Mediterranean fever | 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 | AR | Mutations of |
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(b) Hyper IgD syndrome | Mevalonate kinase deficiency affecting cholesterol synthesis; pathogenesis of disease unclear | Periodic fever and leukocytosis with high IgD levels | AR | Mutations of |
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(c) Muckle–Wells syndrome | PMNs monocytes | Defect in cryopyrin, involved in leukocyte apoptosis and NFkB signaling and IL-1 processing | Urticaria, SNHL, amyloidosis | AD | Mutations of |
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(d) Familial cold autoinflammatory syndrome | PMNs, monocytes | same as above | Non-pruritic urticaria, arthritis, chills, fever, and leukocytosis after cold exposure | AD | Mutations of |
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(e) Neonatal onset multisystem inflammatory disease (NOMID) or chronic infantile neurologic cutaneous and articular syndrome (CINCA) | PMNs, chondrocytes | same as above | Neonatal onset rash, chronic meningitis, and arthropathy with fever and inflammation | AD | Mutations of |
|
(a) TNF receptor-associated periodic syndrome (TRAPS) | 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 | AD | Mutations of |
|
(b) Early onset inflammatory bowel disease | Monocyte/macrophage, activated T cells | Mutation in IL-10 or IL-10 receptor leads to increase of TNFγ and other proinflammatory cytokines | Early onset enterocolitis enteric fistulas, perianal abscesses, chronic folliculitis | AR | Mutations in |
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(c) Pyogenic sterile arthritis, pyoderma gangrenosum, acne (PAPA) syndrome | Hematopoietic tissues, upregulated in activated T cells | Disordered actin reorganization leading to compromised physiologic signaling during inflammatory response | Destructive arthritis, inflammatory skin rash, myositis | AD | Mutations of |
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(d) Blau syndrome | Monocytes | Mutations in nucleotide binding site of CARD15, possibly disrupting interactions with lipopolysaccharides and NF-κB signaling | Uveitis, granulomatous synovitis, camptodactyly, rash, and cranial neuropathies, 30% develop Crohn’s disease | AD | Mutations of |
|
(e) Chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anemia (Majeed syndrome)* | Neutrophils, bone marrow cells | Undefined | Chronic recurrent multifocal osteomyelitis, transfusion-dependent anemia, cutaneous inflammatory disorders | AR | Mutations of |
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(f) DIRA (Deficiency of the interleukin 1 receptor antagonist)* | PMNs, monocytes | Mutations in the IL1 receptor antagonist allows unopposed action of interleukin 1 | Neonatal onset of sterile multifocal osteomyelitis, periostitis, and pustulosis | AR | Mutations of |
Disease | Functional defect | Associated features | Inheritance | Genetic defect/presumed pathogenesis | OMIM number |
---|---|---|---|---|---|
C1q deficiency | Absent CH50 hemolytic activity, defective MAC, faulty dissolution of immune complexes, faulty clearance of apoptotic cells | SLE-like syndrome, rheumatoid disease, infections | AR | Mutations in |
|
C1r deficiency | Absent CH50 hemolytic activity, defective MAC, faulty dissolution of immune complexes | SLE-like syndrome, rheumatoid disease, multiple autoimmune diseases, infections | AR | Mutations in C1r and loss of early complement activation | |
C1s deficiency | Absent CH50 hemolytic activity | SLE-like syndrome; multiple autoimmune diseases | AR | Mutations in C1s and loss of early complement activation | |
C4 deficiency | Absent CH50 hemolytic activity, defective MAC, faulty dissolution of immune complexes, defective humoral immune response to carbohydrate antigens in some patients | SLE-like syndrome, rheumatoid disease, infections |
AR | Mutations in |
|
C2 deficiency | Absent CH50 hemolytic activity, defective MAC, faulty dissolution of immune complexes | SLE-like syndrome, vasculitis, atherosclerosis, polymyositis, pyogenic infections; glomerulonephritis | AR | Mutations in |
|
C3 deficiency | Absent CH50 and AP50 hemolytic activity, defective MAC, defective bactericidal activity, defective humoral immune response | Life threatening pyogenic infections; SLE-like disease; glomerulonephritis; atypical hemolytic–uremic syndrome; selected SNPs with age related macular degeneration | AR | Mutations in |
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C5 deficiency | Absent CH50 and AP50 hemolytic activity, defective MAC, defective bactericidal activity | Neisserial infections, SLE | AR | Mutations in |
|
C6 deficiency | Absent CH50 and AP50 hemolytic activity, defective MAC, defective bactericidal activity | Neisserial infections, SLE | AR | Mutations in |
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C7 deficiency | Absent CH50 and AP50 hemolytic activity, defective MAC, defective bactericidal activity | Neisserial infections, SLE, vasculitis | AR | Mutations in |
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C8a deficiency | Absent CH50 and AP50 hemolytic activity, defective MAC, defective bactericidal activity | Neisserial infections, SLE | AR | Mutations in |
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C8b deficiency | Absent CH50 and AP50 hemolytic activity, defective MAC, defective bactericidal activity | Neisserial infections, SLE | AR | Mutations in |
|
C9 deficiency | Reduced CH50 and AP50 hemolytic activity, defective MAC, defective bactericidal activity | Neisserial infections, weaker association than in C5, C6, C7, or C8 deficiency | AR | Mutations in |
|
C1 inhibitor deficiency | 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 | AD | Mutations in |
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Factor D deficiency | Absent AP50 hemolytic activity | Severe neisserial infection | AR | Mutations in factor D ( |
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Properdin deficiency | Absent AP50 hemolytic activity | Severe neisserial infection | XL | Mutations in properdin ( |
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Factor I deficiency | Spontaneous activation of the alternative complement pathway with consumption of C3 | Recurrent pyogenic infections, glomerulonephritis, SLE; hemolytic–uremic syndrome; selected SNPS: severe pre-eclampsia | AR | Mutations in factor I( |
|
Factor H deficiency | Spontaneous activation of the alternative complement pathway with consumption of C3 | Hemolytic–uremic syndrome, membranoproliferative glomerulonephritis; neisserial infections; selected SNPS: severe pre-eclampsia | AR | Mutations in factor H( |
|
MASP1 deficiency | Potential loss of embryonic cell migration signals | A developmental syndrome of facial dysmorphism, cleft lip, and/or palate, craniosynostosis, learning disability and genital, limb and vesicorenal anomalies | AR | Mutations in |
|
3MC syndrome COLEC11 deficiency | Potential loss of embryonic cell migration signals | A developmental syndrome of facial dysmorphism, cleft lip and/or palate, craniosynostosis, learning disability and genital, limb and vesicorenal anomalies | AR | Gene product CL-K1, a C-type lectin that may serve as a chemoattractant | |
MASP2 deficiency* | Absent hemolytic activity by the lectin pathway | Pyogenic infections; inflammatory lung disease | AR | Mutations in |
|
Complement receptor 3 (CR3) deficiency | See LAD1 in Table |
AR | Mutations in |
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Membrane cofactor protein (CD46) deficiency | Inhibitor of complement alternate pathway, decreased C3b binding | Glomerulonephritis, atypical hemolytic–uremic syndrome; selected SNPS: severe pre-eclampsia | AD | Mutations in |
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Membrane attack complex inhibitor (CD59) deficiency | Erythrocytes highly susceptible to complement-mediated lysis | Hemolytic anemia, thrombosis | AR | Mutations in |
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Paroxysmal nocturnal hemoglobinuria | Complement-mediated hemolysis | Recurrent hemolysis; hemoglobinuria, abdominal pain, smooth muscle dystonias, fatigue, and thrombosis | Acquired X-linked mutation | Disease results from the expansion of hematopoietic stem cells bearing mutations in |
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Immunodeficiency associated with Ficolin 3 deficiency* | Absence of complement activation by the Ficolin 3 pathway. | Recurrent severe pyogenic infections mainly in the lungs; necrotizing enterocolitis in infancy; selective antibody defect to pneumococcal polysaccharides | AR | Mutations in |
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.