Edited by: Jordan Orange, Baylor College of Medicine, USA
Reviewed by: Jordan Orange, Baylor College of Medicine, USA; Francisco A. Bonilla, Boston Children’s Hospital, USA; Thomas Arthur Fleisher, National Institutes of Health, USA; Fischer Alain, INSERM, France
This article was submitted to Primary Immunodeficiencies, a section of the journal Frontiers in Immunology.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
We report the updated classification of primary immunodeficiencies (PIDs) compiled by the Expert Committee of the International Union of Immunological Societies. In comparison to the previous version, more than 30 new gene defects are reported in this updated version. In addition, we have added a table of acquired defects that are phenocopies of PIDs. For each disorder, the key clinical and laboratory features are provided. This classification is the most up-to-date catalog of all known PIDs and acts as a current reference of the knowledge of these conditions and is an important aid for the molecular diagnosis of patients with these rare diseases.
The International Union of Immunological Societies (IUIS) Expert Committee on Primary Immunodeficiency met in New York on 19th–21st April 2013 to update the classification of human primary immunodeficiencies (PIDs). This report represents the most current and complete catalog of known PIDs. It serves as a reference for these conditions and provides a framework to help in the diagnostic approach to patients suspected to have PID.
As in previous reports, we have classified the conditions into major groups of PIDs and these are now represented in nine different tables. In each table, we list the condition, its genetic defect if known, and the major immunological and in some conditions the non-immunological abnormalities associated with the disease. The classification this year differs slightly from the previous edition in that Table
Disease | Genetic defect/presumed pathogenesis | Inheritance | Circulating T cells | Circulating B cells | Serum Ig | Associated features | OMIM number |
---|---|---|---|---|---|---|---|
1. T−B+ severe combined immunodeficiency (SCID) | |||||||
(a) γc deficiency | Mutation of |
XL | Markedly decreased | Normal or increased | Decreased | Markedly decreased NK cells | |
Defect in γ chain of receptors for IL-2, -4, -7, -9, -15, -21 | |||||||
(b) JAK3 deficiency | Mutation of |
AR | Markedly decreased | Normal or increased | Decreased | Markedly decreased NK cells | |
Defect in Janus-activating kinase 3 | |||||||
(c) IL7Rα deficiency | Mutation of |
AR | Markedly decreased | Normal or increased | Decreased | Normal NK cells | |
Defect in IL-7 receptor α chain | |||||||
(d) CD45 deficiency |
Mutation of |
AR | Markedly decreased | Normal | Decreased | Normal γ/δ T cells | |
Defect in CD45 | |||||||
(e) CD3δ deficiency | Mutation of |
AR | Markedly decreased | Normal | Decreased | Normal NK cells | |
Defect in CD3δ chain of T cell antigen receptor complex | No γ/δ T cells | ||||||
(f) CD3ε deficiency |
Mutation of |
AR | Markedly decreased | Normal | Decreased | Normal NK cells | |
Defect in CD3ε chain of T cell antigen receptor complex | No γ/δ T cells | ||||||
(g) CD3ζ deficiency |
Mutation of |
AR | Markedly decreased | Normal | Decreased | Normal NK cells | |
Defect in CD3ζ chain of T cell antigen receptor complex | No γ/δ T cells | ||||||
(h) Coronin-1A deficiency |
Mutation of |
AR | Markedly decreased | Normal | Decreased | Detectable thymus EBV associated B cell lymphoproliferation | |
2. T−B−SCID | |||||||
(i) DNA recombination defects | |||||||
(a) RAG 1 deficiency | Mutation of |
AR | Markedly decreased | Markedly decreased | Decreased | ||
Defective VDJ recombination; defect of recombinase activating gene (RAG) 1 | |||||||
(a) RAG 2 deficiency | Mutation of |
AR | Markedly decreased | Markedly decreased | Decreased | ||
Defective VDJ recombination; defect of recombinase activating gene (RAG) 2 | |||||||
(b) DCLRE1C (artemis) deficiency | Mutation of |
AR | Markedly decreased | Markedly decreased | Decreased | Radiation sensitivity | |
Defective VDJ recombination; defect in artemis DNA recombinase repair protein | |||||||
(c) DNA PKcs deficiency |
Mutation of |
AR | Markedly decreased | Markedly decreased | Decreased | Radiation sensitivity, microcephaly, and developmental defects | |
Recombinase repair protein | |||||||
(ii) Reticular dysgenesis, AK2 deficiency | Mutation of |
AR | Markedly decreased | Decreased or normal | Decreased | Granulocytopenia and deafness | |
Defective maturation of lymphoid and myeloid cells (stem cell defect) | |||||||
Defect in mitochondrial adenylate kinase 2 | |||||||
(iii) Adenosine deaminase (ADA) deficiency | Mutation of ADA absent |
AR | 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 | |
3. CD40 ligand deficiency | Mutation of |
XL | Normal; may progressively decrease | sIgM+ and sIgD+ B cells present, other surface isotype positive B cells absent | IgM increased or normal, other isotypes decreased | Neutropenia, thrombocytopenia; hemolytic anemia, biliary tract and liver disease, opportunistic infections | |
4. CD40 deficiency |
Mutation of |
AR | 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 | |
5. Purine nucleoside phosphorylase (PNP) deficiency | Mutation of |
AR | Progressive decrease | Normal | Normal or decreased | Autoimmune hemolytic anemia, neurological impairment | |
6. CD3γ deficiency |
Mutation of |
AR | Normal, but reduced TCR expression | Normal | Normal | ||
7. CD8 deficiency |
Mutation of |
AR | Absent CD8, normal CD4 cells | Normal | Normal | ||
8. ZAP70 deficiency | Mutation in ZAP70 intracellular signaling kinase, acts downstream of TCR | AR | Decreased CD8, normal CD4 cells | Normal | Normal | Autoimmunity in some cases | |
9. MHC class I deficiency | Mutations in |
AR | Decreased CD8, normal CD4 | Normal | Normal | Vasculitis; pyoderma gangrenosum | |
10. MHC class II deficiency | Mutation in transcription factors for MHC class II proteins ( |
AR | Normal number, decreased CD4 cells | Normal | Normal or decreased | Failure to thrive, diarrhea, respiratory tract infections, liver/biliary tract disease | |
11. ITK deficiency |
Mutations in |
AR | Progressive decrease | Normal | Normal or decreased | EBV-associated B cell lymphoproliferation, lymphoma | |
Normal or decreased IgG | |||||||
12. SH2D1A deficiency (XLP1) | Mutations in |
XL | Normal or increased activated T cells | Reduced memory B cells | Partially defective NK cell and CTL cytotoxic activity | Clinical and immunologic features triggered by EBV infection: HLH, lymphoproliferation, aplastic anemia, lymphoma | |
Hypogammaglobulinemia | |||||||
Absent iNKT cells | |||||||
13. Cartilage hair hypoplasia | Mutations in |
AR | Varies from severely decreased (SCID) to normal; impaired lymphocyte proliferation | Normal | Normal or reduced. antibodies variably decreased | Can present just as combined immunodeficiency without other features of short-limbed dwarfism | |
Also see Table |
|||||||
14. MAGT1 deficiency |
Mutations in |
XL | Decreased CD4 cells reduced numbers of RTE, impaired T cell proliferation in response to CD3 | Normal | Normal | EBV infection, lymphoma; viral infections, respiratory, and GI infections | |
15. DOCK8 deficiency | Mutations in |
AR | Decreased impaired T lymphocyte proliferation | Decreased, low CD27+ memory B cells | Low IgM, increased IgE | Low NK cells with impaired function, hypereosinophilia, recurrent infections; severe atopy, extensive cutaneous viral and bacterial (staph.) infections, susceptibility to cancer | |
16. RhoH deficiency |
Mutations in |
AR | Normal | Normal | Normal | HPV infection, lymphoma, lung granulomas, molluscum contagiosum | |
Low naïve T cells and RTE, restricted T cell repertoire and impaired T cells proliferation in response to CD3 stimulation | |||||||
17. MST1 deficiency | Mutations in |
AR | Decreased/increased proportion of terminal differentiated effector memory cells (TEMRA), low naïve T cells, restricted T cell repertoire in the TEMRA population, and impaired T cells proliferation | Decreased | High | Recurrent bacterial, viral, and candidal infections; intermittent neutropenia; EBV-driven lymphoproliferation; lymphoma; congenital heart disease, autoimmune cytopenias; HPV infection | |
18. TCRα deficiency |
Mutations in |
AR | Normal all CD3 T cells expressed TCRγδ (or may be better to say: TCRαβ T cell deficiency), impaired T cells proliferation | Normal | Normal | Recurrent viral, bacterial, and fungal infections, immune dysregulation autoimmunity, and diarrhea | |
19. LCK deficiency |
Defects in |
AR | Normal total numbers but CD4+ T cell lymphopenia, low Treg numbers, restricted T cell repertoire, and impaired TCR signaling | Normal | Normal IgG and IgA and increased IgM | Diarrhea, recurrent infections, immune dysregulation autoimmunity | |
20. MALT1 deficiency |
Mutations in |
AR | Normal impaired T cells proliferation | Normal | Normal | Bacterial, fungal, and viral infections | |
Impaired antibody response | |||||||
21. IL-21R deficiency |
Defects in |
AR | Abnormal T cell cytokine production; abnormal T cell proliferation to specific stimuli | Normal | Normal but impaired specific responses | Susceptibility to cryptosporidium and pneumocystis and cholangitis | |
22. UNC119 deficiency |
Defects in |
AD | Low T cells | Mostly low | Normal | Recurrent bacterial, fungal, and viral infections | |
CD4+ T cell lymphopenia, impaired TCR signaling | |||||||
23. CARD11 deficiency |
Defects in |
AR | Normal predominance of naive T lymphocyte, impaired T cells proliferation | Normal predominance of transitional B lymphocytes | Absent/low | ||
24. OX40 deficiency |
Defects in |
AR | Normal T cell numbers | Normal B cell numbers | Normal | Kaposi’s sarcoma; impaired immunity to HHV8 | |
Low levels of antigen-specific memory CD4+ cells | Lower frequency of memory B cells | ||||||
25. IKBKB deficiency |
Defects in |
AR | Normal total T cells; absent regulatory and gd T cells; impaired TCR activation | Normal B cell numbers; impaired BCR activation | Decreased | Recurrent bacterial, viral, and fungal infections; clinical phenotype of SCID | |
26. Activated PI3K-δ | Mutation in |
AD gain-of-function | Decreased total numbers of T cells | Decreased total peripheral B cell and switched memory B cells; increased transitional B cells | Reduced IgG2 and impaired antibody to pneumococci and hemophilus | Respiratory infections, bronchiectasis; autoimmunity; chronic EBV, and CMV infection | |
27. LRBA deficiency | Mutations in |
AR | 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 | |
28. CD27 deficiency |
Mutations in |
AR | Normal | No memory B cells | Hypogamma globulinemia following EBV infection | Clinical and immunologic features triggered by EBV infection, HLH | |
Aplastic anemia, lymphoma | |||||||
Hypogammaglobulinemia | |||||||
Low iNKT cells | |||||||
29. Omenn syndrome | Hypomorphic mutations in |
Present; restricted T cell repertoire, and impaired function | Normal or decreased | Decreased, except increased IgE | Erythroderma, eosinophilia, adenopathies, hepatosplenomegaly |
Disease | Genetic defect/presumed pathogenesis | Inheritance | Circulating T cells | Circulating B cells | Serum Ig | Associated features | OMIM number |
---|---|---|---|---|---|---|---|
1. Congenital thrombocytopenia | |||||||
(a) Wiskott– Aldrich syndrome (WAS) | Mutations in |
XL | 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 | |
(b) WIP deficiency |
Mutations in |
AR | Reduced, defective lymphocyte responses to anti-CD3 | Low | Normal, except for increased IgE | Recurrent infections; eczema; thrombocytopenia. WAS- |
|
2. DNA repair defects (other than those in Table |
|||||||
(a) Ataxia–telangiectasia | Mutations in |
AR | 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 increased radiosensitivity; chromosomal instability | |
(b) Ataxia–telangiectasia-like disease (ATLD) |
Hypomorphic mutations in |
AR | Progressive decrease | Normal | Antibodies variably decreased | Moderate ataxia; pulmonary infections; severely increased radiosensitivity | |
(c) Nijmegen breakage syndrome | Hypomorphic mutations in |
AR | Progressive decrease | Variably reduced | Often decreased IgA, IgE, and IgG subclasses; increased IgM; antibodies variably decreased | Microcephaly; bird-like face; lymphomas; solid tumors; increased radiosensitivity; chromosomal instability | |
(d) Bloom syndrome | Mutations in |
AR | Normal | Normal | Reduced | Short stature; bird-like face; sun-sensitive erythema; marrow failure; leukemia; lymphoma; chromosomal instability | |
(e) Immunodeficiency with centromeric instability and facial anomalies (ICF) | Mutations in DNA methyltransferase |
AR | Decreased or normal; responses to PHA may be decreased | Decreased or normal | Hypogamma globulinemia; variable antibody deficiency | Facial dysmorphic features; macroglossia; bacterial/opportunistic infections; malabsorption; cytopenias; malignancies; multiradial configurations of chromosomes 1, 9, 16; no DNA breaks | |
(f) Immunodeficiency with centromeric instability and facial anomalies (ICF) | Mutations in |
AR | Decreased or normal; responses to PHA may be decreased | Decreased or normal | Hypogamma globulinemia; variable antibody deficiency | Facial dysmorphic features; macroglossia; bacterial/opportunistic infections; malabsorption; cytopenias; malignancies; multiradial configurations of chromosomes 1, 9, 16 | |
(g) PMS2 deficiency | Mutations in |
AR | 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 | |
(h) RNF168 deficiency |
Mutations in |
AR | Normal | Normal | Low IgG or low IgA | Short stature; mild motor control to ataxia and normal intelligence to learning difficulties; mild facial dysmorphism to microcephaly; increased radiosensitivity | |
(i) MCM4 deficiency | Mutations in |
AR | Normal | Normal | Normal | Viral infections (EBV, HSV, VZV) Adrenal failure Short stature | |
3. Thymic defects with additional congenital anomalies | |||||||
(a) DiGeorge anomaly | Contiguous gene defect in 90% affecting thymic development; may also be due to heterozygous mutation in |
Decreased or normal; 5% have <1500 CD3 T cells/μL | Normal | Normal or decreased | Hypoparathyroidism, conotruncal malformation; abnormal facies; large deletion (3 Mb) in 22q11.2 (or rarely a deletion in 10p) | ||
(b) CHARGE syndrome | Variable defects of the thymus and associated T cell abnormalities often due to deletions or mutations in |
Decreased or normal; some have <1500 CD3 T cells/μL | Normal | Normal or decreased | Coloboma, heart anomaly, choanal atresia, retardation, genital and ear anomalies | ||
4. Immune-osseous dysplasias | |||||||
(a) Cartilage hair hypoplasia | Mutations in |
AR | 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 | |
(b) Schimke syndrome | Mutations in |
AR | Decreased | Normal | Normal | Short stature, spondiloepiphyseal dysplasia, intrauterine growth retardation, nephropathy; bacterial, viral, and fungal infections; may present as SCID; bone marrow failure | |
5. Hyper-IgE syndromes (HIES) | |||||||
(a) AD-HIES (Job’s syndrome) | Dominant-negative heterozygous mutations in |
AD Often |
Normal Th-17 and T follicular helper 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, delay of shedding primary teeth, hyperextensible joints, bacterial infections (skin and pulmonary abscesses, pneumatoceles) due to |
|
(i) Tyk2 deficiency |
Mutation in |
AR | Normal, but multiple cytokine signaling defect | Normal | (±) Elevated IgE | Susceptibility to intracellular bacteria ( |
|
(ii) DOCK8 deficiency | Mutations in |
AR | Decreased impaired T lymphocyte proliferation | Decreased, low CD27+ memory B cells | Low IgM, increased IgE | Low NK cells with impaired function, hypereosinophilia, recurrent infections; severe atopy, extensive cutaneous viral and bacterial (staph.) infections, susceptibility to cancer | |
6. Dyskeratosis congenital (DKC) | |||||||
(a) XL-DKC | Mutations in dyskerin |
XL | Progressive decrease | Progressive decrease | Variable | Intrauterine growth retardation, microcephaly, nail dystrophy, recurrent infections, digestive tract involvement, pancytopenia, reduced number and function of NK cells | |
(b) AR-DKC due to NHP2 deficiency | Mutation in |
AR | Decreased | Variable | Variable | Pancytopenia, sparse scalp hair and eyelashes, prominent periorbital telangiectasia, and hypoplastic/dysplastic nails | |
(c) AR-DKC due to NOP10 deficiency | Mutation in |
AR | Decreased | Variable | Variable | Pancytopenia, sparse scalp hair and eyelashes, prominent periorbital telangiectasia, and hypoplastic/dysplastic nails | |
(d) AR-DKC due to RTEL1 deficiency | Mutation in |
AR | Decreased | Variable | Variable | Pancytopenia, sparse scalp hair and eyelashes, prominent periorbital telangiectasia, and hypoplastic/dysplastic nails | |
(e) AD-DKC due to TERC deficiency | Mutation in |
AD | Variable | Variable | Variable | Reticular hyperpigmentation of the skin, dystrophic nails, osteoporosis premalignant leukokeratosis of the mouth mucosa, palmar hyperkeratosis, anemia, pancytopenia | |
(f) AD-DKC due to TERT deficiency | Mutation in |
AD | Variable | Variable | Variable | Reticular hyperpigmentation of the skin, dystrophic nails, osteoporosis premalignant leukokeratosis of the mouth mucosa, palmar hyperkeratosis, anemia, pancytopenia | |
(g) AD-DKC due to TINF2 deficiency | Mutation in |
AD | Variable | Variable | Variable | Reticular hyperpigmentation of the skin, dystrophic nails, osteoporosis premalignant leukokeratosis of the mouth mucosa, palmar hyperkeratosis, anemia, pancytopenia | |
7. Defects of vitamin B12 and folate metabolism | |||||||
(a) TCN2 deficiency | Mutation in |
AR | Normal | Variable | Decreased | Megaloblastic anemia, pancytopenia, untreated for prolonged periods results in mental retardation | |
(b) SLC46A1 deficiency | Mutation in |
AR | Variable numbers and activation profile | Variable | Decreased | Megaloblastic anemia, failure to thrive untreated for prolonged periods results in mental retardation | |
(c) MTHFD1 |
Mutations in |
AR | Low | Low | Decreased | Megaloblastic anemia, failure to thrive neutropenia, seizures, mental retardation | |
8. Comel–Netherton syndrome | Mutations in |
AR | Normal | Switched and non-switched B cells are reduced | Elevated IgE and IgA | Congenital ichthyosis, bamboo hair, atopic diathesis, increased bacterial infections, failure to thrive | |
Antibody variably decreased | |||||||
9. Winged helix deficiency (Nude) |
Defects in forkhead box N1 transcription factor encoded by |
AR | Markedly decreased | Normal | Decreased | Alopecia, abnormal thymic epithelium, impaired T cell maturation | |
10. ORAI-I deficiency |
Mutation in |
AR | Normal number, but defective TCR-mediated activation | Normal | Normal | Autoimmunity, anhydrotic ectodermic dysplasia, non-progressive myopathy defective TCR-mediated activation | |
11. STIM1 deficiency |
Mutations in |
AR | Normal number, but defective TCR-mediated activation | Normal | Normal | Autoimmunity, anhydrotic ectodermal dysplasia, non-progressive myopathy defective TCR-mediated activation | |
12. STAT5b deficiency |
Mutations in |
AR | Modestly decreased | Normal | Normal | Growth-hormone insensitive dwarfism | |
Dysmorphic features | |||||||
Eczema | |||||||
Lymphocytic interstitial pneumonitis, autoimmunity | |||||||
13. Hepatic veno-occlusive disease with immunodeficiency (VODI) | Mutations in |
AR | 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; |
|
14. IKAROS deficiency |
Mutation in |
AD |
Normal, but impaired lymphocyte proliferation | Absent | Presumably decreased | Anemia, neutropenia, thrombocytopenia | Not assigned |
15. FILS syndrome |
Mutation in |
AR | Low naïve T cells; decreased T cell proliferation | Low memory B cells | Decreased IgM and IgG; lack of antibodies to polysaccharide antigens | Mild facial dysmorphism (malar hypoplasia, high forehead), livedo, short stature; recurrent upper and lower respiratory tract infections, recurrent pulmonary infections, and recurrent meningitis | |
16. Immunodeficiency with multiple intestinal atresias | Mutation in |
AR | Variable, but sometimes absent | Normal | Decreased | Multiple intestinal atresias, often with intrauterine polyhydramnios and early demise; some with SCID phenotype |
Disease | Genetic defect/presumed pathogenesis | Inheritance | Serum Ig | Associated features | OMIM number |
---|---|---|---|---|---|
1. Severe reduction in all serum immunoglobulin isotypes with profoundly decreased or absent B cells | |||||
(a) BTK deficiency | Mutations in |
XL | All isotypes decreased in majority of patients; some patients have detectable immunoglobulins | Severe bacterial infections; normal numbers of pro-B cells | |
(b) μ Heavy chain deficiency | Mutations in μ heavy chain; essential component of the pre-BCR | AR | All isotypes decreased | Severe bacterial infections; normal numbers of pro-B cells | |
(c) λ5 Deficiency |
Mutations in l5; part of the surrogate light chain in the pre-BCR | AR | All isotypes decreased | Severe bacterial infections; normal numbers of pro-B cells | |
(d) Igα deficiency |
Mutations in Iga |
AR | All isotypes decreased | Severe bacterial infections; normal numbers of pro-B cells | |
(e) Igβ deficiency |
Mutations in Igb |
AR | All isotypes decreased | Severe bacterial infections; normal numbers of pro-B cells | |
(f) BLNK deficiency |
Mutations in |
AR | All isotypes decreased | Severe bacterial infections; normal numbers of pro-B cells | |
(g) PI3 kinase deficiency |
Mutations in |
AR | All isotypes decreased | Severe bacterial infections; decreased or absent pro-B cells | |
(h) E47 transcription factor deficiency |
Mutations in |
AD | All isotypes decreased | Recurrent bacterial infections | |
(i) Myelodysplasia with hypogammaglobulinemia | May have monosomy 7, trisomy 8, or dyskeratosis congenita | Variable | One or more isotypes may be decreased | Infections; decreased number of pro-B cells | Not assigned |
(j) Thymoma with immunodeficiency | Unknown | None | One or more isotypes may be decreased | Bacterial and opportunistic infections; autoimmunity; decreased number of pro-B cells | Not assigned |
2. Severe reduction in at least two serum immunoglobulin isotypes with normal or low number of B cells | |||||
(a) Common variable immunodeficiency disorders | 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 | Not assigned |
(b) ICOS deficiency |
Mutations in |
AR | Low IgG and IgA and/or IgM | Recurrent infections; autoimmunity, gastroenteritis, granuloma in some | |
(c) CD19 deficiency |
Mutations in |
AR | Low IgG and IgA and/or IgM | Recurrent infections; may have glomerulonephritis | |
(d) CD81 deficiency |
Mutations in |
AR | Low IgG, low or normal IgA and IgM | Recurrent infections; may have glomerulonephritis | |
(e) CD20 deficiency |
Mutations in |
AR | Low IgG, normal or elevated IgM and IgA | Recurrent infections | |
(f) CD21 deficiency |
Mutations in |
AR | Low IgG; impaired anti-pneumococcal response | Recurrent infections | |
(g) TACI deficiency | Mutations in |
AD or AR or complex | Low IgG and IgA and/or IgM | Variable clinical expression | |
(h) LRBA deficiency | Mutations in |
AR | Reduced I IgG and IgA in most | Recurrent infections, inflammatory bowel disease, autoimmunity; EBV infections | |
(i) BAFF receptor deficiency |
Mutations in |
AR | Low IgG and IgM | Variable clinical expression | |
(j) TWEAK |
Mutations in |
AD | Low IgM and IgA; lack of anti-pneumococcal antibody | Pneumonia, bacterial infections, warts; thrombocytopenia. neutropenia | |
(k) NFKB2 deficiency |
Mutations in |
AD | Low IgG and IgA and IgM | Recurrent infections | |
(l) Warts, hypogammaglobulinemia, infections, myelokathexis (WHIM) syndrome | Gain-of-function mutations of |
AD | Panhypogammaglobulinemia, decreased B cells | Warts/human papilloma virus (HPV) infection Neutropenia Reduced B cell number Hypogammaglobulinemia | |
3. Severe reduction in serum IgG and IgA with normal/elevated IgM and normal numbers of B cells | |||||
(a) CD40L deficiency | Mutations in |
XL | IgG and IgA decreased; IgM may be normal or increased; B cell numbers may be normal or increased | Bacterial and opportunistic infections, neutropenia, autoimmune disease | |
(b) CD40 deficiency |
Mutations in |
AR | Low IgG and IgA; normal or raised IgM | Bacterial and opportunistic infections, neutropenia, autoimmune disease | |
(c) AID deficiency | Mutations in |
AR | IgG and IgA decreased; IgM increased | Bacterial infections, enlarged lymph nodes, and germinal centers | |
(d) UNG deficiency | Mutations in |
AR | IgG and IgA decreased; IgM increased | Enlarged lymph nodes and germinal centers | |
4. Isotype or light chain deficiencies with generally normal numbers of B cells | |||||
(a) 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 | Not assigned |
(b) κ Chain deficiency |
Mutations in Kappa constant gene | AR | All immunoglobulins have lambda light chain | Asymptomatic | |
(c) Isolated IgG subclass deficiency | Unknown | Variable | Reduction in one or more IgG subclass | Usually asymptomatic; a minority may have poor antibody response to specific antigens and recurrent viral/bacterial infections | Not assigned |
(d) IgA with IgG subclass deficiency | Unknown | Variable | Reduced IgA with decrease in one or more IgG subclass | Recurrent bacterial infections | Not assigned |
(e) PRKC δ deficiency |
Mutation in |
AR | Low IgG levels; IgA and IgM above the normal range | Recurrent infections; EBV chronic infection Lymphoproliferation SLE-like autoimmunity (nephrotic and antiphospholipid syndromes) | |
(f) Activated PI3K-δ | Mutation in |
AD gain-of-function | Reduced IgG2 and impaired antibody to pneumococci and hemophilus | Respiratory infections, bronchiectasis; autoimmunity; chronic EBV, CMV infection | |
(g) Selective IgA deficiency | Unknown | Variable | 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 | |
5. Specific antibody deficiency with normal Ig concen-trations and normal numbers of B cells | Unknown | Variable | Normal | Reduced ability to produce antibodies to specific antigens | Not assigned |
6. Transient hypogammaglobulinemia of infancy with normal numbers of B cells | Unknown | Variable | IgG and IgA decreased | Normal ability to produce antibodies to vaccine antigens, usually not associated with significant infections | Not assigned |
Disease | Genetic defect/presumed pathogenesis | Inheritance | Circulating T cells | Circulating B cells | Functional defect | Associated features | OMIM number |
---|---|---|---|---|---|---|---|
1. Familial hemophagocytic lymphohistiocytosis (FHL) syndromes | |||||||
1.1 FHL syndromes without hypopigmentation | |||||||
(a) Perforin deficiency (FHL2) | Mutations in |
AR | Increased activated T cells | Normal | Decreased to absent NK and CTL activities (cytotoxicity) | Fever, hepatosplenomegaly (HSMG), hemophagocytic lymphohistiocytosis (HLH), cytopenias | |
(b) UNC13D/Munc13-4 deficiency (FHL3) | Mutations in |
AR | Increased activated T cells | Normal | Decreased to absent NK and CTL activities (cytotoxicity and/or degranulation) | Fever, HSMG, HLH, cytopenias | |
(c) Syntaxin 11 deficiency (FHL4) | Mutations in |
AR | Increased activated T cells | Normal | Decreased NK activity (cytotoxicity and/or degranulation) | Fever, HSMG, HLH, cytopenias | |
(d) STXBP2/Munc18-2 deficiency (FHL5) | Mutations in |
AR | Increased activated T cells | Normal | Decreased NK and CTL activities (cytotoxicity and/or degranulation) | Fever, HSMG, HLH, cytopenias | |
1.2. FHL syndromes with hypopigmentation | |||||||
(a) Chediak–Higashi syndrome | Mutations in |
AR | Increased activated T cells | Normal | Decreased NK and CTL activities (cytotoxicity and/or degranulation) | Partial albinism |
|
(b) Griscelli syndrome, type 2 | Mutations in |
AR | Normal | Normal | Decreased NK and CTL activities (cytotoxicity and/or degranulation) | Partial albinism, fever, HSMG, HLH, cytopenias | |
(c) Hermansky–Pudlak syndrome, type 2 | Mutations in |
AR | Normal | Normal | Decreased NK and CTL activities (cytotoxicity and/or degranulation) | Partial albinism |
|
2. Lymphoproliferative syndromes | |||||||
(a) SH2D1A deficiency (XLP1) | Mutations in |
XL | Normal or increased activated T cells | Reduced memory B cells | Partially defective NK cell and CTL cytotoxic activity | Clinical and immunological features triggered by EBV infection: HLH |
|
(b) XIAP deficiency (XLP2) | Mutations in |
XL | Normal or increased activated T cells; low/normal iNK T 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 | |
(c) ITK deficiency |
Mutations in |
AR | Progressive decrease | Normal | Decreased T cell activations | EBV-associated B cell lymphoproliferation, lymphoma |
|
(d) CD27 deficiency |
Mutations in |
AR | Normal | No memory B cells | Low T and NK cells functions | Clinical and immunological features triggered by EBV infection: HLH |
|
3. Genetic defects of regulatory T cells | |||||||
(a) IPEX, immune dysregulation, polyendocrinopathy, enteropathy X-linked | Mutations in |
XL | Normal | Normal | Lack of (and/or impaired function of) CD4+ CD25+ FOXP3+ regulatory T cells (Tregs) | Autoimmune enteropathy |
|
(b) CD25 deficiency |
Mutations in |
AR | Normal to decreased | Normal | No CD4+ C25+ cells with impaired function of Tregs cells | Lymphoproliferation, autoimmunity. Impaired T cell proliferation | |
(c) STAT5b deficiency |
Mutations in |
AR | Modestly decreased | Normal | Impaired development and function of γδT cells, Tregs, and NK cells Low T cell proliferation | Growth-hormone insensitive dwarfism | |
Dysmorphic features | |||||||
Eczema | |||||||
Lymphocytic interstitial pneumonitis, autoimmunity | |||||||
4. Autoimmunity without lymphoproliferation | |||||||
(a) APECED (APS-1), autoimmune polyendocrinopathy with candidiasis and ectodermal dystrophy | Mutations in |
AR | Normal | Normal | AIRE-1 serves as checkpoint 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 | |||||||
(b) ITCH deficiency |
Mutations in |
AR | 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) | |
Autoimmune disorder (thyroiditis, type I diabetes, chronic diarrhea/enteropathy, and hepatitis) | |||||||
Failure to thrive, developmental delay, dysmorphic facial features | |||||||
5. Autoimmune lymphoproliferative syndrome (ALPS) | |||||||
(a) ALPS–FAS | Germinal mutations in |
AD | Increased CD4−CD8− TCRα/β double negative (DN) T cells | Normal, low memory B cells | Apoptosis defect FAS mediated | Splenomegaly, adenopathies, autoimmune cytopenias | |
AR |
Increased lymphoma risk | ||||||
IgG and A normal or increased | |||||||
Elevated FasL and IL-10, vitamin B12 | |||||||
(b) ALPS– FASLG | Mutations in |
AR | Increased DN T cells | Normal | Apoptosis defect FAS mediated | Splenomegaly, adenopathies, autoimmune cytopenias, SLE | |
Soluble FasL is not elevated | |||||||
(c) ALPS–caspase 10 |
Mutations in |
AD | Increased DN T cells | Normal | Defective lymphocyte apoptosis | Adenopathies, splenomegaly, autoimmunity | |
(d) ALPS–caspase 8 |
Mutations in |
AR | Slightly increased DN T cells | Normal | Defective lymphocyte apoptosis and activation | Adenopathies, splenomegaly, bacterial and viral infections, hypogammaglobulinemia | |
(e) FADD deficiency |
Mutations in |
AR | Increased DN T cells | Normal | Defective lymphocyte apoptosis | Functional hyposplenism, bacterial and viral infections | |
Recurrent episodes of encephalopathy and liver dysfunction | |||||||
(f) CARD11 gain-of-function (GOF) mutations |
GOF mutations in |
AD | Normal | Increased M+D+CD19+ CD20+ B cells | Constitutive activation of NF-κB in B & T | Lymphoproliferation | |
Bacterial and viral infections | |||||||
EBV chronic infection | |||||||
Autoimmune cytopenia | |||||||
Hypogammaglobulinemia | |||||||
(g) PRKCδ deficiency |
Mutations in |
AR | Normal | Low memory B cells and elevation of CD5 B cells | Apoptotic defect in B cells | Recurrent infections; EBV chronic infection | |
Lymphoproliferation | |||||||
SLE-like autoimmunity (nephrotic and antiphospholipid syndromes) | |||||||
HypoIgG | |||||||
6. Immune dysregulation with colitis | |||||||
(a) IL-10 deficiency |
Mutations in |
AR | Normal | Normal | No functional IL-10 secretion | Inflammatory bowel disease (IBD) folliculitis | Not assigned |
Recurrent respiratory diseases | |||||||
Arthritis | |||||||
(b) IL-10Rα deficiency | Mutations in |
AR | Normal | Normal | Leukocytes, no response to IL-10 | IBD, folliculitis | |
Recurrent respiratory diseases | |||||||
Arthritis, lymphoma | |||||||
(c) IL-10Rβ deficiency | Mutations in |
AR | Normal | Normal | Leukocytes, no response to IL-10, IL-22, IL-26, IL-28A, IL-28B, and IL-29 | IBD, folliculitis | |
Recurrent respiratory diseases | |||||||
Arthritis, lymphoma | |||||||
7. Type 1 interferonopathies | |||||||
(a) TREX1 deficiency, Aicardi–Goutieres syndrome 1 (AGS1) | Mutations in |
AR | Not assessed | Not assessed | Intracellular accumulation of abnormal single-stranded (ss) DNA species leading to increased CSF alpha-IFN production | Progressive encephalopathy intracranial calcifications | |
AD |
Cerebral atrophy, leukodystrophy | ||||||
HSMG, thrombocytopenia | |||||||
Elevated hepatic transaminases | |||||||
Chronic cerebrospinal fluid (CSF) lymphocytosis | |||||||
(b) RNASEH2B deficiency, AGS2 | Mutations in |
AR | Not assessed | Not assessed | Intracellular accumulation of abnormal ss-DNA species leading to increased CSF alpha-IFN production | Progressive encephalopathy intracranial calcifications | |
Cerebral atrophy, leukodystrophy | |||||||
HSMG, thrombocytopenia | |||||||
Elevated hepatic transaminases | |||||||
Chronic CSF lymphocytosis | |||||||
(c) RNASEH2C deficiency, AGS3 | Mutations in |
AR | Not assessed | Not assessed | Intracellular accumulation of abnormal ss-DNA species leading to increased CSF alpha-IFN production | Progressive encephalopathy intracranial calcifications | |
Cerebral atrophy, leukodystrophy | |||||||
HSMG, thrombocytopenia | |||||||
Elevated hepatic transaminases | |||||||
Chronic CSF lymphocytosis | |||||||
(d) RNASEH2A deficiency, AGS4 |
Mutations in |
AR | Not assessed | Not assessed | Intracellular accumulation of abnormal ss-DNA species leading to increased CSF alpha-IFN production | Progressive encephalopathy intracranial calcifications | |
Cerebral atrophy, leukodystrophy | |||||||
HSMG, thrombocytopenia | |||||||
Elevated hepatic transaminases | |||||||
Chronic CSF lymphocytosis | |||||||
(e) SAMHD1 deficiency, AGS5 | Mutations in |
AR | Not assessed | Not assessed | Induction of the cell intrinsic antiviral response, apoptosis, and mitochondrial DNA destruction leading to increased CSF alpha-IFN production | Progressive encephalopathy intracranial calcifications | |
Cerebral atrophy, leukodystrophy | |||||||
HSMG, thrombocytopenia, anemia elevated lactates | |||||||
Chronic CSF lymphocytosis | |||||||
Skin vasculitis, mouth ulcers, arthropathy | |||||||
(f) ADAR1 deficiency, AGS6 | Mutations in |
AR | Not assessed | Not assessed | Catalyzes the deamination of adenosine to inosine in dsRNA substrates markedly elevated CSF IFN-alpha | Progressive encephalopathy intracranial calcification Severe developmental delay, leukodystrophy | |
(g) Spondyloenchondro-dysplasia with immune dysregulation (SPENCD) | Mutations in |
AR | Not assessed | Not assessed | Upregulation of IFN-alpha and type I IFN-stimulated genes | Recurrent bacterial and viral infections, intracranial calcification | |
SLE-like autoimmunity (Sjögren’s syndrome, hypothyroidism, inflammatory myositis, Raynaud’s disease and vitiligo), hemolytic anemia, thrombocytopenia, skeletal dysplasia, short stature |
Disease | Genetic defect/presumed pathogenesis | Inheritance | Affected cells | Affected function | Associated features | OMIM number |
---|---|---|---|---|---|---|
1. Defects of neutrophil function | ||||||
(a) Severe congenital neutropenia 1 (ELANE deficiency) | Mutation in |
AD | N | Myeloid differentiation | Susceptibility to MDS/leukemia | |
(b) SCN2 |
Mutation in |
AD | N | Myeloid differentiation | B/T lymphopenia | |
(c) SCN3 (Kostmann disease) | Mutation in |
AR | N | Myeloid differentiation | Cognitive and neurological defects in patients with defects in both HAX1 isoforms, susceptibility to MDS/leukemia | |
(d) SCN4 (G6PC3 deficiency) | Mutation in |
AR | N + F | Myeloid differentiation, chemotaxis, O2−production | Structural heart defects, urogenital abnormalities, inner ear deafness, and venous angiectasias of trunks and limbs | |
(e) SCN5 | Mutation in |
AR | N + F | Myeloid differentiation, migration | Extramedullary hematopoiesis, bone marrow fibrosis, nephromegaly | |
(f) Glycogen storage disease type 1b | Mutation in |
AR | N + M | Myeloid differentiation, chemotaxis, O2−production | Fasting hypoglycemia, lactic acidosis, hyperlipidemia, hepatomegaly | |
(g) Cyclic neutropenia | Mutation in |
AD | N | Differentiation | Oscillations of other leukocytes and platelets | |
(h) X-linked neutropenia/ |
Mutation in |
XL, gain-of-function | N + M | Mitosis | Monocytopenia | |
(i) P14/LAMTOR2 deficiency |
Mutation in |
AR | N + L Mel | Endosome biogenesis | Neutropenia | |
Hypogammaglobulinemia | ||||||
↓CD8 cytotoxicity | ||||||
Partial albinism | ||||||
Growth failure | ||||||
(j) Barth syndrome | Mutation in tafazzin |
XL | N | Myeloid differentiation | Cardiomyopathy, myopathy, growth retardation | |
(k) Cohen syndrome | Mutation in |
AR | N | Myeloid differentiation | Retinopathy, developmental delay, facial dysmorphisms | |
(l) Clericuzio syndrome poikiloderma with neutropenia | Mutation in |
AR | N | Myeloid differentiation | Poikiloderma, neutropenia, MDS | |
2. Defects of motility | ||||||
(a) Leukocyte adhesion deficiency type 1 (LAD1) | Mutation in |
AR | N + M + L + NK | Adherence, chemotaxis, endocytosis, T/NK cytotoxicity | Delayed cord separation, skin ulcers Periodontitis Leukocytosis | |
(b) Leukocyte adhesion deficiency type 2 (LAD2) |
Mutation in |
AR | N + M | Rolling, chemotaxis | Mild LAD type 1 features plus hh-blood group plus mental and growth retardation | |
(c) Leukocyte adhesion deficiency type 3 (LAD3) | Mutation in |
AR | N + M + L + NK | Adherence, chemotaxis | LAD type 1 plus bleeding tendency | |
(d) Rac 2 deficiency |
Mutation in |
AD | N | Adherence, chemotaxis, O2−production | Poor wound healing, leukocytosis | |
(e) β-Actin deficiency |
Mutation in |
AD | N + M | Motility | Mental retardation, short stature | |
(f) Localized juvenile periodontitis | Mutation in |
AR | N | Formylpeptide induced chemotaxis | Periodontitis only | |
(g) Papillon–Lefèvre syndrome | Mutation in |
AR | N + M | Chemotaxis | Periodontitis, palmoplantar hyperkeratosis in some patients | |
(h) Specific granule deficiency |
Mutation in |
AR | N | Chemotaxis | Neutrophils with bilobed nuclei; absent secondary granules and defensins | |
(i) Shwachman–Diamond syndrome | Mutation in |
AR | N | Chemotaxis | Pancytopenia, exocrine pancreatic insufficiency, chondrodysplasia | |
3. Defects of respiratory burst | ||||||
(a) X-linked chronic granulomatous disease (CGD) | Mutation in |
XL | N + M | Killing (faulty O2−production) | Recurrent bacterial infection, susceptibility to fungal infection, inflammatory gut manifestations McLeod phenotype in patients with deletions extending into the contiguous Kell locus | |
(b) Autosomal recessive CGD – p22 phox deficiency | Mutation in |
AR | N + M | Killing (faulty O2−production) | Recurrent bacterial infection, susceptibility to fungal infection, and inflammatory gut manifestations | |
(c) Autosomal recessive CGD – p47 phox deficiency | Mutation in |
AR | N + M | Killing (faulty O2−production) | Recurrent bacterial infection, susceptibility to fungal infection, and inflammatory gut manifestations | |
(d) Autosomal recessive CGD – p67 phox deficiency | Mutation in |
AR | N + M | Killing (faulty O2−production) | Recurrent bacterial infection, susceptibility to fungal infection, inflammatory gut manifestations | |
(e) Autosomal recessive CGD – p40 phox deficiency |
Mutation in |
AR | N + M | Killing (faulty O2−production) | Inflammatory gut manifestations only | |
4. Mendelian susceptibility to mycobacterial disease (MSMD) | ||||||
(a) IL-12 and IL-23 receptor β1 chain deficiency | Mutation in |
AR | L + NK | IFN-γ secretion | Susceptibility to |
|
(b) IL-12p40 deficiency | Mutation in |
AR | M | IFN-γ secretion | Susceptibility to |
|
(c) IFN-γ receptor 1 deficiency | Mutation in |
AR, AD | M + L | IFN-γ binding and signaling | Susceptibility to |
|
(d) IFN-γ receptor 2 deficiency | Mutation in |
AR | M + L | IFN-γ signaling | Susceptibility to |
|
(e) STAT1 deficiency (AD form) |
Mutation in |
AD | M + L | IFN-γ signaling | Susceptibility to |
|
(f) Macrophage gp91 phox deficiency |
Mutation in |
XL | Mf only | Killing (faulty O2−production) | Isolated susceptibility to |
|
(g) IRF8-deficiency (AD form) |
Mutation in |
AD | CD1c+ MDC | Differentiation of CD1c+ MDC subgroup | Susceptibility to |
|
(h) ISG15 | Mutation in |
AR | M + N + L | IFN-γ secretion | Susceptibility to |
|
5. Other defects | ||||||
(a) IRF 8-deficiency (AR form) |
Mutation in |
AR | Monocytes peripheral DC | Cytopenias | Susceptibility to |
|
(b) GATA2 deficiency (Mono MAC syndrome) | Mutation in |
AD | Monocytes peripheral DC + NK + B | Multilineage cytopenias | Susceptibility to |
|
(c) Pulmonary alveolar proteinosis |
Mutation in |
Biallelic mutations in pseudo-autosomal gene | Alveolar macro-phages | GM-CSF signaling | Alveolar proteinosis |
Disease | Genetic defect/presumed pathogenesis | Inheritance | Affected cell | Functional defect | Associated features | OMIM number |
---|---|---|---|---|---|---|
1. Anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) | ||||||
(a) EDA-ID, X-linked (NEMO deficiency) | Mutations of |
XL | Lymphocytes + monocytes | NF-κB signaling pathway | Various infections (bacteria, |
|
Colitis | ||||||
EDA (not in all patients) | ||||||
Hypogammaglobulinemia to specific antibody polysaccharides deficiency | ||||||
(b) EDA-ID, autosomal-dominant |
Gain-of-function mutations of |
AD | Lymphocytes + monocytes | NF-κB signaling pathway | Various infections (bacteria, viruses, and fungi) | |
EDA | ||||||
T cell defect | ||||||
2. TIR signaling pathway deficiency | ||||||
(a) IRAK-4 deficiency | Mutations of |
AR | Lymphocytes + granulocytes + monocytes | TIR–IRAK signaling pathway | Bacterial infections (pyogenes) | |
(b) MyD88 deficiency | Mutations of |
AR | Lymphocytes + granulocytes + monocytes | TIR–MyD88 signaling pathway | Bacterial infections (pyogenes) | |
3. HOIL1 deficiency |
Mutation of |
AR | Lymphocytes + granulocytes + monocytes | NF-κB signaling pathway | Bacterial infections (pyogenes) | Not assigned |
Autoinflammation | ||||||
Amylopectinosis | ||||||
4. WHIM (Warts, hypogammaglobulinemia, infections, myelokathexis) syndrome | Gain-of-function mutations of |
AD | Granulocytes + lymphocytes | Increased response of the CXCR4 chemokine receptor to its ligand CXCL12 (SDF-1) | Warts/human papilloma virus (HPV) infection | |
Neutropenia | ||||||
Reduced B cell number | ||||||
Hypogammaglobulinemia | ||||||
5. Epidermodysplasia verruciformis | ||||||
EVER1 deficiency | Mutations of |
AR | Keratinocytes and leukocytes | EVER proteins may be involved in the regulation of cellular zinc homeostasis in lymphocytes | HPV (group B1) infections and cancer of the skin (typical EV) | |
EVER2 deficiency | Mutations of |
AR | Keratinocytes and leukocytes | EVER proteins may be involved in the regulation of cellular zinc homeostasis in lymphocytes | HPV (group B1) infections and cancer of the skin (typical EV) | |
6. Predisposition to severe viral infection | ||||||
(a) STAT2 deficiency |
Mutations of |
AR | T and NK cells | STAT2-dependent | Severe viral infections (disseminated vaccine-strain measles) | Not assigned |
IFN-α and -β response | ||||||
(b) MCM4 deficiency |
Mutations in |
AR | NK cells | DNA repair disorder | Viral infections (EBV, HSV, VZV) | |
Adrenal failure | ||||||
Short stature | ||||||
7. Herpes simplex encephalitis (HSE) | ||||||
(a) TLR3 deficiency |
(b) Mutations of |
AD | Central nervous system (CNS) resident cells and fibroblasts | TLR3-dependent | Herpes simplex virus 1 encephalitis (incomplete clinical penetrance for all etiologies listed here) | |
AR | IFN-α, -β, and -λ induction | |||||
(b) UNC93B1 deficiency |
(a) Mutations of |
AR | CNS resident cells and fibroblasts | UNC-93B-dependent | Herpes simplex virus 1 encephalitis | |
IFN-α, -β, and -λ induction | ||||||
(c) TRAF3 deficiency |
(c) Mutations of |
AD | CNS resident cells and fibroblasts | TRAF3-dependent | Herpes simplex virus 1 encephalitis | |
IFN-α, -β, and -λ induction | ||||||
(d) TRIF deficiency |
(c) Mutations of |
AD | CNS resident cells and fibroblasts | TRIF-dependent | Herpes simplex virus 1 encephalitis | |
AR | IFN-α, -β, and -λ induction | |||||
(e) TBK1 deficiency |
(c) Mutations of |
AD | CNS resident cells and fibroblasts | TBK1-dependent | Herpes simplex virus 1 encephalitis | Not assigned |
IFN-α, -β, and -λ induction | ||||||
8. Predisposition to invasive fungal diseases |
||||||
CARD9 deficiency | Mutations of |
AR | Mononuclear phagocytes | CARD9 signaling pathway | Invasive candidiasis infection Deep dermatophytoses | |
9. Chronic mucocutaneous candidiasis (CMC) | ||||||
(a) IL-17RA deficiency |
(a) Mutations in |
AR | Epithelial cells, fibroblasts, mononuclear phagocytes | IL-17RA signaling pathway | CMC Folliculitis | |
(b) IL-17F deficiency |
(b) Mutations in |
AD | T cells | IL-17F-containing dimers | CMC Folliculitis | |
(c) STAT1 gain-of-function | (c) Gain-of-function mutations in |
AD | T cells | 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, cytopenia) | ||||||
Enteropathy | ||||||
(d) ACT1 deficiency |
(c) Mutations in |
AR | 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 | ||||||
10. Trypanosomiasis |
Mutations in |
AD | APOL-I | Trypanosomiasis | ||
11. Isolated congenital asplenia (ICA) | Mutations in |
AD | Spleen | RPSA encodes ribosomal protein SA, a component of the small subunit of the ribosome | Bacteremia (encapsulated bacteria) No spleen |
Disease | Genetic defect/presumed pathogenesis | Inheritance | Affected cells | Functional defects | Associated features | OMIM number |
---|---|---|---|---|---|---|
1. Defects effecting the inflammasome | ||||||
(a) Familial Mediterranean fever | Mutations of |
AR | 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 | |
(b) Mevalonate kinase deficiency (hyper IgD syndrome) | Mutations of |
AR | Affecting cholesterol synthesis; pathogenesis of disease is unclear | Periodic fever and leukocytosis with high IgD levels | ||
(c) Muckle–Wells syndrome | Mutations of |
AD | PMNs monocytes | Defect in cryopyrin, involved in leukocyte apoptosis and NF-κB signaling and IL-1 processing | Urticaria, SNHL, amyloidosis | |
(d) Familial cold autoinflammatory syndrome | Mutations of |
AD | PMNs, monocytes | Same as above | Non-pruritic urticaria, arthritis, chills, fever, and leukocytosis after cold exposure | |
5. Neonatal onset multisystem inflammatory disease (NOMID) or chronic infantile neurologic cutaneous and articular syndrome (CINCA) | Mutations of |
AD | PMNs, chondrocytes | Same as above | Neonatal onset rash, chronic meningitis, and arthropathy with fever and inflammation | |
2. Non inflammasome-related conditions | ||||||
(a) TNF receptor-associated periodic syndrome (TRAPS) | Mutations of |
AD | PMNs, monocytes | Mutations of 55-kDa 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 | |
(b) Early-onset inflammatory bowel disease | Mutations in |
AR | Monocyte/macrophage, activated T cells | IL-10 deficiency leads to increase of TNFγ and other proinflammatory cytokines | Early-onset enterocolitis enteric fistulas, perianal abscesses, chronic folliculitis | |
(b) Early-onset inflammatory bowel disease | Mutations in |
AR | Monocyte/macrophage, activated T cells | Mutation in IL-10 receptor alpha leads to increase of TNFγ and other proinflammatory cytokines | Early-onset enterocolitis enteric fistulas, perianal abscesses, chronic folliculitis | |
(b) Early-onset inflammatory bowel disease | Mutations in |
AR | Monocyte/macrophage, activated T cells | Mutation in IL-10 receptor beta leads to increase of TNFγ and other proinflammatory cytokines | Early-onset enterocolitis enteric fistulas, perianal abscesses, chronic folliculitis | |
(c) Pyogenic sterile arthritis, pyoderma gangrenosum, acne (PAPA) syndrome | Mutations of |
AD | Hematopoietic tissues, upregulated in activated T cells | Disordered actin reorganization leading to compromised physiologic signaling during inflammatory response | Destructive arthritis, inflammatory skin rash, myositis | |
(d) Blau syndrome | Mutations of |
AD | 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 | |
10. Chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anemia (Majeed syndrome) |
Mutations of |
AR | Neutrophils, bone marrow cells | Undefined | Chronic recurrent multifocal osteomyelitis, transfusion-dependent anemia, cutaneous inflammatory disorders | |
11. DIRA (deficiency of the interleukin 1 receptor antagonist) |
Mutations of |
AR | PMNs, monocytes | Mutations in the IL-1 receptor antagonist allow unopposed action of Interleukin 1 | Neonatal onset of sterile multifocal osteomyelitis, periostitis, and pustulosis | |
12. DITRA – deficiency of IL-36 receptor antagonist | Mutation in |
AR | Keratinocyte leukocytes | Mutations in IL-36RN leads to increase IL-8 production | Pustular psoriasis | |
13. SLC29A3 mutation | Mutation in SLC29A3 (?) | AR | Leukocyte, bone cells | Macrophage activation? | Hyperpigmentation hypertrichosis | |
14. CAMPS (CARD14 mediated psoriasis) | Mutation in |
AD | Mainly in keratinocyte | Mutations in CARD14 activate the NF-κB pathway and production of IL-8 | Psoriasis | |
15. Cherubism | Mutation in |
AD | Stroma cells, bone cells | Hyperactivated macrophage and increased NF-κB | Bone degeneration in jaws | |
16. CANDLE (chronic atypical neutrophilic dermatitis with lipodystrophy) | Mutation in |
AD | Keratinocyte, B cell adipose cells | Mutations cause increase IL-6 production | Dystrophy, panniculitis | |
17. HOIL1 deficiency | Mutation in |
AR | PMNs, fibroblast | Mutation in |
Immunodeficiency autoinflammation amylopectinosis | |
18. PLAID (PLCγ2 associated antibody deficiency and immune dysregulation) | Mutation in |
AD | B cells, NK, mast cells | Mutations cause activation of IL-1 pathways | Cold urticaria hypogammaglobulinemia |
Disease | Genetic defect; presumed pathogenesis | Inheritance | Functional defect | Associated features | OMIM number |
---|---|---|---|---|---|
1. C1q deficiency | Mutation in |
AR | Absent CH50 hemolytic activity, defective activation of the classical pathway | SLE, infections with encapsulated organisms | |
Diminished clearance of apoptotic cells | |||||
2. C1r deficiency | Mutation in |
AR | Absent CH50 hemolytic activity, defective activation of the classical pathway | SLE, infections with encapsulated organisms | |
3. C1s deficiency | Mutation in |
AR | Absent CH50 hemolytic activity, defective activation of the classical pathway | SLE, infections with encapsulated organisms | |
4. C4 deficiency | Mutation in |
AR | Absent CH50 hemolytic activity, defective activation of the classical pathway, defective humoral immune response to carbohydrate antigens in some patients | SLE, infections with encapsulated organisms | |
5. C2 deficiency | Mutation in |
AR | Absent CH50 hemolytic activity, defective activation of the classical pathway | SLE, infections with encapsulated organisms, atherosclerosis | |
6. C3 deficiency | Mutation in |
AR, gain-of-function AD | Absent CH50 and AH50 hemolytic activity defective opsonization | Infections; glomerulonephritis | |
Defective humoral immune response | Atypical hemolytic–uremic syndrome with gain-of-function mutations | ||||
7. C5 deficiency | Mutation in |
AR | Absent CH50 and AH50 hemolytic activity; defective bactericidal activity | Neisserial infections | |
8. C6 deficiency | Mutation in |
AR | Absent CH50 and AH50 hemolytic activity; defective bactericidal activity | Neisserial infections | |
9. C7 deficiency | Mutation in |
AR | Absent CH50 and AH50 hemolytic activity; defective bactericidal activity | Neisserial infections | |
10. C8 α–γ deficiency | Mutation in |
AR | Absent CH50 and AH50 hemolytic activity; defective bactericidal activity | Neisserial infections | |
11. C8b deficiency | Mutation in |
AR | Absent CH50 and AH50 hemolytic activity; defective bactericidal activity | Neisserial infections | |
12. C9 deficiency | Mutation in |
AR | Reduced CH50 and AP50 hemolytic activity; deficient bactericidal activity | Mild susceptibility to Neisserial infections | |
13. C1 inhibitor deficiency | Mutation in |
AD | Spontaneous activation of the complement pathway with consumption of C4/C2 | Hereditary angioedema | |
Spontaneous activation of the contact system with generation of bradykinin from high molecular weight kininogen | |||||
14. Factor B |
Mutation in |
AD | Gain-of-function mutation with increased spontaneous AH50 | aHUS | |
15. Factor D deficiency | Mutation in |
AR | Absent AH50 hemolytic activity | Neisserial infections | |
16. Properdin deficiency | Mutation in |
XL | Absent AH50 hemolytic activity | Neisserial infections | |
17. Factor I deficiency | Mutation in |
AR | Spontaneous activation of the alternative complement pathway with consumption of C3 | Infections, Neisserial infections, aHUS, preeclampsia, membranoproliferative glomerulonephritis (MPGN) | |
18. Factor H deficiency | Mutation in |
AR | Spontaneous activation of the alternative complement pathway with consumption of C3 | Infections, Neisserial infections, aHUS, preeclampsia, membranoproliferative glomerulonephritis (MPGN) | |
19. Factor H-related protein deficiencies | Mutation in |
AR | Normal CH50, AH50, autoantibodies to Factor H | aHUS | |
20. Thrombomodulin |
Mutation in |
AD | Normal CH50, AH50 | aHUS | |
21. MASP1 deficiency | Mutation in |
AR | Deficient activation of the lectin activation pathway, cell migration | Infections, 3MC syndrome | |
22. MASP2 deficiency |
AR | Deficient activation of the lectin activation pathway | Pyogenic infections; inflammatory lung disease, autoimmunity | ||
23. 3MC syndrome COLEC11 deficiency |
Mutation in |
AR | Loss of neural crest cell migration signals | A developmental syndrome of facial dysmorphism, cleft lip and/or palate, craniosynostosis, learning disability, and genital, limb, and vesicorenal anomalies (3MC syndrome) | |
24. Complement receptor 2 (CR2) deficiency |
Mutation in |
AR | See CD21 deficiency in Table |
||
25. Complement receptor 3 (CR3) deficiency | Mutation in |
AR | See LAD1 in Table |
||
Membrane cofactor protein (CD46) deficiency | Mutation in |
AD | Inhibitor of complement alternate pathway, decreased C3b binding | aHUS, infections, preeclampsia | |
Membrane Attack Complex inhibitor (CD59) deficiency |
Mutation in |
AR | Erythrocytes highly susceptible to complement-mediated lysis | Hemolytic anemia, polyneuropathy | |
Ficolin 3 deficiency |
Mutation in |
AR | Absence of complement activation by the Ficolin 3 pathway | Respiratory infections, abscesses |
In this updated version, we have added a new category in Table
Disease | Genetic defect/presumed pathogenesis | Circulating T cells | Circulating B cells | Serum Ig | Associated features/similar PID |
---|---|---|---|---|---|
(a) Autoimmune lymphoproliferative syndrome (ALPS–SFAS) | Somatic mutation in |
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/ |
|||||
(b) RAS-associated autoimmune leukoproliferative disease (RALD) | Somatic mutation in |
Normal | B cell lymphocytosis | Normal or increased | Splenomegaly, lymphadenopathy, autoimmune cytopenias, granulocytosis, monocytosis/ |
(c) RAS-associated autoimmune leukoproliferative disease (RALD) | Somatic mutation in |
Increased CD4−CD8−double negative (DN) T alpha/beta cells | Lymphocytosis | Splenomegaly, lymphadenopathy, autoantibodies/ |
|
(a) Chronic mucocutaneous candidiasis (isolated or with APECED syndrome) | Germline mutation in |
Normal | Normal | Normal | Endocrinopathy, chronic mucocutaneous candidiasis/ |
(b) Adult-onset immunodeficiency | AutoAb to IFN gamma | Decreased naive T cells | Normal | Normal | Mycobacterial, fungal, |
(c) Recurrent skin infection | AutoAb to IL-6 | Normal | Normal | Normal | Staphylococcal infections/ |
(d) Pulmonary alveolar proteinosis | AutoAb to GM-CSF | Normal | Normal | Normal | Pulmonary alveolar proteinosis, cryptococcal meningitis/ |
(e) Acquired angioedema | AutoAb to CI inhibitor | Normal | Normal | Normal | Angioedema/ |
As with all complex diseases, any classification cannot be strictly adhered to. Certain conditions fall into more than one category and so appear in more than one table. For example, CD40L ligand deficiency is reported in both Tables
The rapid advances in gene identification technology, including the widespread use of whole exome and whole genome sequencing, has meant that the ability to identify gene defects in affected families and even single individuals with inherited diseases has grown enormously. In this report, over 30 new gene defects have been added that were identified since the previous classification in November, 2011. These defects can be found in all major groups of PIDs included in this report. In many cases, the mutations are not necessarily in genes formally implicated in immune cell function but are genes involved in essential cell processes. The more detailed analysis and functional consequences of such defects as illustrated by these PIDs will increase our understanding of the interplay between different cellular processes in the development and function of the immune system.
Among the newly identified, gene defects are many that are to date particular to a single pedigree or individual; such defects may prove exceedingly rare, or indeed may not necessarily be found to recur in other individuals. We have marked conditions for which there are 10 or fewer reported individuals with an asterisk, although historically, following the description of the first few cases, additional individuals with a similar PID phenotype and genotype have often been recognized. It is likely that we will uncover many more “personal” or very rare gene defects over time and that the spectrum of PIDs will become increasingly diverse and complex, due to contributions of both environmental exposures and genetic modifiers to each affected individual. The value of this report therefore to capture and catalog the full spectrum at any one time point becomes increasingly important.
The goal of the IUIS Expert Committee on PIDs is to increase awareness, facilitate recognition, and promote optimal treatment for patients with PIDs. In addition to the current report and previous “classification table” publications, the committee has also produced a “Phenotypic Approach for IUIS PID Classification and Diagnosis: Guidelines for Clinicians at the Bedside,” which aims to lead physicians to particular groups of PIDs starting from clinical features and combining routine immunological investigations. Together, these contributions will hopefully allow a practical clinical framework for PID diagnosis. The committee also aims to establish a classification of PIDs based on other aspects and will work on publishing further guidelines in due course.
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.