| IEI/PID/syndrome (in approximate order of prevalence) | Estimated prevalence | IUIS IEI classification[1] | Hallmarks (of the IEI) | Immunodeficiency features | Possible manifestations of autoimmunity and/or immune dysregulation | Suspected predominant mechanism(s) of autoimmunity or immune dysregulation[2-5] |
| Selective IgA deficiency | 1 to 3:1000 | Predominantly antibody deficiencies | Allergies; may precede CVID or have positive family history | Asymptomatic or recurrent sinopulmonary bacterial infections | Endocrinopathies, cytopenia, SLE | Lacking clearance of antigens from mucosal surfaces, autoreactive B cells due to impaired negative selection and regulation, reduced T regulatory function; reduced debris clearance |
| 22q11 deletion syndrome (DiGeorge) | 2 to 5:10,000 | CID with syndromic features | Cardiac, abnormal facies, thymic hypoplasia, cleft palate, hypoparathyroidism, cognitive and speech problems | Variable, opportunistic infections | Cytopenia, endocrinopathies, arthritis | Impaired T regulatory cell function and diversity, oligoclonal TCR repertoire, residual autoreactive T cells |
| Wiskott-Aldrich syndrome (WAS) | 1:20,000 | CID with syndromic features | Microthrombocytopenia, eczema | Severe, viral, and bacterial opportunistic infections | Skin (eczema, atopic dermatitis), cytopenia, vasculitis, kidney disease (nephritis, IgA nephropathy, glomerulonephritis), arthritis, IBD | Defective T regulatory cell function, impaired lymphocyte migration and activation, loss of inhibitory signaling |
| Common variable immunodeficiency (CVID) | 1 to 10:100,000 | Predominantly antibody deficiencies | Hypogammaglobulinemia | Recurrent infections | Cytopenia, endocrinopathies, IBD, SLE, arthritis, parenchymal lung disease, lymphoproliferation, lymphoma, granuloma formation | BCR editing checkpoint and B cell maturation defects leading to residual autoreactive B cell clones, loss of inhibitory signaling, reduced T regulatory cell function, impaired T helper cell activity |
| Familial hemophagocytic lymphohistiocytosis (FHL), hemophagocytic lymphohistiocytosis (HLH) | Unknown, estimated 1:50,000 | Diseases of immune dysregulation | Hemophagocytosis, fever, hyperferritinemia, syndromes with or without hypopigmentation | EBV or other herpes viruses may be trigger | Cytopenia, lymphoproliferation, hemophagocytosis, neurologic symptoms (CNS infiltration) | Uncontrolled cytokine and interferon-mediated macrophage activation due to impaired cellular cytotoxicity of T and NK cells, apoptosis defects |
| Combined immunodeficiencies (CID)* | Unknown, estimated 1 to 5:100,000 | CID | Depending on subtype/genetic cause | Combined, variable severity | Cytopenia, endocrinopathies, IBD, skin (eczema, rash, other), lymphoproliferation, parenchymal lung disease, lymphoma | Impaired T and T regulatory cell function and diversity, oligoclonal TCR repertoire, residual autoreactive T cells, hypersensitivity to persisting viral antigens |
| Autoimmune lymphoproliferative syndrome (ALPS) | Unknown, estimated >1 to 5:100,000 | Diseases of immune dysregulation | Increased T cell receptor alpha/beta-positive CD4-CD8- double-negative T (DNT) cells | Rare | Cytopenia, endocrinopathies, kidney disease (glomerulonephritis), lymphoproliferation, lymphoma | Apoptosis defect, immature and senescent T cell phenotype, resulting in autoreactive T and B cells, impaired debris clearance |
| X-linked agammaglobulinemia (XLA) | 1:200,000 | Predominantly antibody deficiencies | Agammaglobulinemia | Bacterial, enteroviral | Cytopenia, endocrinopathies, skin (eczema, rash, vitiligo, alopecia, oral ulcerations, mucocutaneous candidiasis), IBD | Unknown |
| Chronic granulomatous disease (CGD) | 1 to 5:500,000 | Congenital defects of phagocyte number, function, or both | May mimic Crohn disease or lymphoproliferative disorders, HLH | Bacterial (Staphylococci), fungal | Granuloma formation, IBD, lymphoproliferation | Ineffective and deregulated phagocyte activation, chemoattraction, impaired T regulatory function, defective clearance of apoptotic cells, hypersensitivity to bacterial antigens (neutrophil, NK-mediated) |
| Hyperimmunoglobulin M syndromes (HIGM) | 1 to 2:500,000 | CID or predominantly antibody deficiencies | Cryptosporidium infection, Pneumocystis pneumonia, sclerosing cholangitis | Bacterial and opportunistic infections | Cytopenia, IBD, primary biliary cirrhosis, sclerosing cholangitis | Disturbed T-B cell interaction, residual autoreactive B cells, T cell-mediated hypersensitivity to parasitic antigens (Cryptosporidium, Pneumocystis) |
| Complement deficiencies¶ | 1 to 5:500,000 | Complement deficiencies | Some have increased risk of neisserial infections | SLE, vasculitis | Ineffective clearance of immune complexes, apoptotic cells, and debris | |
| APECED | 1 to 10:1,000,000 | Diseases of immune dysregulation | Ectodermal dystrophy, 21-hydroxylase autoantibodies | Candidiasis | Endocrinopathies, skin (eczema, rash, vitiligo, alopecia, oral ulcerations, mucocutaneous candidiasis) | Central tolerance defect, anticytokine, enzyme- and tissue-directed autoantibodies |
| XLP1 (SH2D1A deficiency) | 1 to 5:1,000,000 | Diseases of immune dysregulation | Lymphoproliferation, hypo- or agammaglobulinemia, HLH, lymphoma | EBV may be trigger | Lymphoproliferation, hemophagocytosis, lymphoma, cytopenia | Disturbed T-B cell cross-talk, impaired T and NK cytotoxicity |
| IPEX and IPEX-like syndromes | Unknown, estimated <1:1,000,000 | Diseases of immune dysregulation | Early-onset enteropathy, type 1 diabetes mellitus | Combined, variable severity | IBD, endocrinopathies, cytopenia, skin (eczema, rash, vitiligo), autoimmune hepatitis | T regulatory cell deficiency or loss-of-function |
| CTLA4 haploinsufficiency (ALPSV) | Unknown, estimated <1:1,000,000 | Diseases of immune dysregulation | Progressive loss of B cells, hypogammaglobulinemia | Upper and lower respiratory infections | IBD, granuloma formation, pneumonitis, cytopenia, SLE, endocrinopathies, (arthritis, neurologic disease [encephalitis, cerebellitis, CNS lymphoma]), lymphoproliferation, organ infiltration, malignancy | T regulatory cell defect, impaired T cell help for B cells |
| LRBA deficiency | Unknown, estimated <1:1,000,000 | Diseases of immune dysregulation | Enteropathy, ALPS/CVID-overlap syndrome | Bacterial and opportunistic infections | IBD, cytopenia, arthritis, myasthenia gravis, neurologic disease (encephalitis, cerebellitis, CNS lymphoma), lymphoproliferation | CTLA4-dependent T regulatory cell defect, impaired autophagy, autoreactive B cells |
| CD27 deficiency | Unknown, estimated <1:1,000,000 | Diseases of immune dysregulation | Hypogammaglobulinemia, lymphoma | EBV may be a trigger | Lymphoproliferation, hemophagocytosis, lymphoma, cytopenia | Impaired antigen-activated T and B cell expansion and memory development, impaired NK function |
| ITK deficiency | Unknown | Diseases of immune dysregulation | Hodgkin (and rarer non-Hodgkin) lymphoma | EBV may be trigger | Lymphoproliferation, lymphoma, cytopenia | Skewed CD4 T cell differentiation |
| XLP2 (XIAP deficiency) | Unknown, estimated <1:1,000,000 | Diseases of immune dysregulation | Lymphoproliferation, IBD, HLH | EBV may be trigger | IBD, autoimmune hepatitis, lymphoproliferation, cytopenia | T cell apoptosis and activation-induced cell death |
| Activated PI3K-d syndrome | Unknown, estimated <1:1,000,000 | Predominantly antibody deficiency | T and B lymphoid nodules, bronchiectasis, CVID-like | Respiratory tract infections, chronic EBV and CMV infection | Pneumonitis, cytopenia, lymphoproliferation | Immature and terminal effector T cell phenotype, transitional B cells increased, lymphocyte sensitivity to activation-induced death |
| Type 1 interferonopathies | Unknown | Autoinflammatory disorders | Progressive encephalopathy | SLE, cytopenia, vasculopathy | Impaired cellular nucleic debris clearance | |
| Early-onset inflammatory bowel disease syndromes | Unknown | Diseases of immune dysregulation | Respiratory infections | IBD, arthritis, lymphoma | Lacking responses to immune regulatory interleukins | |
| CMC/STAT1 gain-of-function | Unknown | Defects in innate immunity | CMC | Fungal, bacterial, mycobacterial, herpesvirus infections | Endocrinopathies, cytopenia | Impaired development of interleukin-17-producing T cells |
| STAT3 gain-of-function | Unknown | Diseases of immune dysregulation | Early-onset, IPEX-like | IBD, endocrinopathies, cytopenia, pneumonitis, autoimmune hepatitis, lymphoproliferation | Increased T cell differentiation towards interleukin-17 production, perturbed T regulatory cell function |
