In Table 1 of the original manuscript, two gene defects were inadvertently omitted. These two defects (Cernunnos and DNA ligase IV deficiency) fall into the category of DNA recombination defects and lead to a radiosensitive form of SCID associated with microcephaly and developmental defects. These two genes have now been added to a revised Table 1.
Table 1.
Combined immunodeficiencies.
| 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 IL2RG Defect in γ chain of receptors for IL-2, -4, -7, -9, -15, -21 | XL | Markedly decreased | Normal or increased | Decreased | Markedly decreased NK cells | 300400 |
| (b) JAK3 deficiency | Mutation of JAK3 Defect in Janus activating kinase 3 | AR | Markedly decreased | Normal or increased | Decreased | Markedly decreased NK cells; | 600173 |
| (c) IL7Rα deficiency | Mutation of IL7RA Defect in IL-7 receptor α chain | AR | Markedly decreased | Normal or increased | Decreased | Normal NK cells | 146661 |
| (d) CD45 deficiencya | Mutation of PTPRC Defect in CD45 | AR | Markedly decreased | Normal | Decreased | Normal γ/δ T cells | 151460 |
| (e) CD3δ deficiency | Mutation of CD3D Defect in CD3δ, chain of T cell antigen receptor complex | AR | Markedly decreased | Normal | Decreased | Normal NK cells No γ/δ T cells | 186790 |
| (f) CD3ε deficiencya | Mutation of CD3E Defect in CD3ε chain of T cell antigen receptor complex | AR | Markedly decreased | Normal | Decreased | Normal NK cells No γ/δ T cells | 186830 |
| (g) CD3ζ deficiencya | Mutation of CD3Z Defect in CD3ζ chain of T-cell antigen receptor complex | AR | Markedly decreased | Normal | Decreased | Normal NK cells No γ/δ T cells | 186740 |
| (h) Coronin-1A deficiencya | Mutation of CORO1A Defective thymic egress of T cells and defective T cell locomotion | AR | Markedly decreased | Normal | Decreased | Detectable thymus EBV-associated B-cell lymphoproliferation | 605000 |
| 2. T−B−SCID | |||||||
| (i) DNA recombination defects | |||||||
| (a) RAG 1 deficiency | Mutation of RAG1 Defective VDJ recombination Defect of recombinase activating gene (RAG) 1 | AR | Markedly decreased | Markedly decreased | Decreased | 601457 | |
| (a) RAG 2 deficiency | Mutation of RAG2 Defective VDJ recombination; defect of recombinase activating gene (RAG) 2 | AR | Markedly decreased | Markedly decreased | Decreased | 601457 | |
| (b) DCLRE1C (Artemis) deficiency | Mutation of ARTEMIS Defective VDJ recombination; defect in Artemis DNA recombinase-repair protein | AR | Markedly decreased | Markedly decreased | Decreased | Radiation sensitivity | 602450 |
| (c) DNA PKcs deficiencya | Mutation of PRKDC Defective VDJ recombination; defect in DNA PKcs; Recombinase repair protein | AR | Markedly decreased | Markedly decreased | Decreased | Radiation sensitivity, microcephaly, and developmental defects | 600899 |
| d) Cernunnos/XLF deficiency | Mutation of Cernunnos Defective VDJ recombination; defect in Cernunnos | AR | Markedly decreased | Markedly decreased | Decreased | Radiation sensitivity, microcephaly, and developmental defects | 611291 |
| e) DNA ligase IV deficiency | Mutation of LIG4 Defective VDJ recombination; defect in DNA ligase IV | AR | Markedly decreased | Markedly decreased | Decreased | Radiation sensitivity, microcephaly, and developmental defects | 601837 |
| (ii) Reticular dysgenesis, AK2 deficiency | Mutation of AK2 Defective maturation of lymphoid and myeloid cells (stem cell defect) Defect in mitochondrial adenylate kinase 2. | AR | Markedly decreased | Decreased or normal | Decreased | Granulocytopenia and deafness | 103020 |
| (iii) Adenosine deaminase (ADA) deficiency | Mutation of ADA Absent ADA activity, elevated lymphotoxic metabolites (dATP, S-adenosyl homocysteine) | 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 | 102700 |
| Combined immunodeficiencies generally less profound than severe combined immunodeficiency | |||||||
| 3. CD40 ligand deficiency | Mutation of CD40LG Defects in CD40 ligand (CD40L; also called TNFSF5 or CD154) cause defective isotype switching and impaired dendritic cell signaling | 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 | 300386 |
| 4. CD40 deficiencya | Mutation of CD40 (also called TNFRSF5); defects in CD40 cause defective isotype switching and impaired dendritic cell signaling | 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 | 109535 |
| 5. Purine nucleoside phosphorylase (PNP) deficiency | Mutation of PNP Absent PNP, T cell and neurologic defects from elevated toxic metabolites, especially dGTP | AR | Progressive decrease | Normal | Normal or decreased | Autoimmune hemolytic anemia, neurological impairment | 164050 |
| 6. CD3γ deficiencya | Mutation of CD3G Defect in CD3 γ-component of the T cell antigen receptor complex | AR | Normal, but reduced TCR expression | Normal | Normal | 186740 | |
| 7. CD8 deficiencya | Mutation of CD8A Defects of CD8 α chain – important for maturation and function of CD8 T cells | AR | Absent CD8, normal CD4 cells | Normal | Normal | 186910 | |
| 8. ZAP-70 deficiency | Mutation in ZAP70 intracellular signaling kinase, acts downstream of TCR | AR | Decreased CD8, normal CD4 cells | Normal | Normal | Autoimmunity in some cases | 176947 |
| 9. MHC class I deficiency | Mutations in TAP1, TAP2 or TAPBP (tapasin) genes giving MHC class I deficiency | AR | Decreased CD8, normal CD4 | Normal | Normal | Vasculitis; pyoderma gangrenosum | 604571 |
| 10. MHC class II deficiency | Mutation in transcription factors for MHC class II proteins (CIITA, RFX5, RFXAP, RFXANK genes) | AR | Normal number, decreased CD4 cells | Normal | Normal or decreased | Failure to thrive, diarrhea, respiratory tract infections liver/biliary tract disease | 209920 |
| 11. ITK deficiencya | Mutations in ITK encoding IL-2 inducible T cell kinase required for TCR-mediated activation | AR | Progressive decrease | Normal | Normal or decreased | EBV associated B cell lymphoproliferation, lymphoma; normal or decreased IgG | 613011 |
| 12. SH2D1A deficiency (XLP1) | Mutations in SH2D1A encoding an adaptor protein regulating intracellular signals | 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 cell | 308240 |
| 13. Cartilage hair hypoplasia | Mutations in RMRP (RNase MRP RNA) Involved in processing of mitochondrial RNA and cell cycle control | 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 2 | 250250 |
| 14. MAGT1 deficiencya | Mutations in MAGT1, impaired Mg++ flux leading to impaired TCR signaling | 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 | 300715 |
| 15. DOCK8 deficiency | Mutations in DOCK8 – regulator of intracellular actin reorganization | 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 | 243700 |
| 16. RhoH Deficiencya | Mutations in RHOH – an atypical Rho GTPase transducing signals downstream of various membrane receptors | AR | Normal low naïve T cells and RTE, restricted T cell repertoire and impaired T cells proliferation in response to CD3 stimulation | Normal | Normal | HPV infection, lymphoma, lung granulomas, molluscum contagiosum | 602037 |
| 17. MST1 deficiency | Mutations in STK4 – a serine/threonine kinase | 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 | 614868 |
| 18. TCRα deficiencya | Mutations in TRAC – essential component of the T cell receptor | 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. | 615387 |
| 19. LCK deficiencya | Defects in LCK – a proximal tyrosine kinase that interacts with TCR | 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 | 153390 |
| 20. MALT1 deficiencya | Mutations in MALT1 – a caspase-like cysteine protease that is essential for nuclear factor-kappa-B activation | AR | Normal impaired T cells proliferation | Normal | Normal; impaired antibody response | Bacterial, fungal, and viral infections | 604860 |
| 21. IL21R deficiencya | Defects in IL21R – together with common gamma chain binds IL-21 | AR | Abnormal T cell cytokine production; Abnormal T cell proliferation to specific stimuli | Normal | Normal but impaired specific responses | Susceptibility to cryptoporidia and pneumocystis and cholangitis | 605383 |
| 22. UNC119 deficiencya | Defects in UNC119 – an activator of src tyrosine kinases | AD | Low T cells; CD4+ T-cell lymphopenia, impaired TCR signaling | Mostly low | Normal | Recurrent bacterial, fungal, and viral infections | 604011 |
| 23. CARD11 deficiencya | Defects in CARD11 – acts as a scaffold for NF-κB activity in the adaptive immune response | AR | Normal predominance of naive T-lymphocyte, impaired T cells proliferation | Normal predominance of transitional B lymphocytes | Absent/low | Pneumocystis jirovicii pneumonia, bacterial infections | 615206 |
| 24. OX40 deficiencya | Defects in OX40 – a co stimulatory molecule expressed on activated T cells | AR | Normal T cell numbers; low levels of antigen specific memory CD4+ cells | Normal B cell numbers; lower frequency of memory B cells | Normal | Kaposi’s sarcoma; impaired immunity to HHV8 | 615593 |
| 25. IKBKB deficiencya | Defects in IKBKB – encodes IκB kinase 2, a component of the NF-κB pathway | AR | Normal total T cells; absent regulatory and γδ T cells; impaired TCR activation | Normal B cell numbers; impaired BCR activation | Decreased | Recurrent bacterial, viral and fungal infections; clinical phenotype of SCID | 615592 |
| 26. Activated PI3K-δ | Mutation in PIK3CD, PI3K-δ | 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 | 602839 |
| 27. LRBA deficiency | Mutations in LRBA (lipopolysaccharide responsive beige-like anchor protein) | 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 | 606453 |
| 28. CD27 deficiencya | Mutations in CD27, encoding TNF-R member superfamily required for generation and long-term maintenance of T cell immunity | 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 | 615122 |
| 29. Omenn syndrome | Hypomorphic mutations in RAG1, RAG2, Artemis, IL7RA, RMRP, ADA, DNA Ligase IV, IL2RG, AK2, or associated with DiGeorge syndrome; some cases have no defined gene mutation | Present; restricted T cell repertoire and impaired function | Normal or decreased | Decreased, except increased IgE | Erythroderma, eosinophilia, adenopathies, hepatosplenomegaly | 603554 | |
XL, X-linked inheritance; AR, autosomal recessive inheritance; AD, autosomal dominant inheritance; SCID, severe combined immune deficiencies; EBV, Epstein–Barr virus; Ca++, calcium; MHC, major histocompatibility complex, RTE, recent thymic emigrants, HPV, human papillomavirus.
aTen or fewer unrelated cases reported in the literature.
Infants with SCID who have maternal T cells engraftment may have T cells that do not function normally; these cells may cause autoimmune cytopenias or graft versus host disease. Hypomorphic mutations in several of the genes that cause SCID may result in Omenn syndrome (OS), or “leaky” SCID or a less profound CID phenotype. Both OS and leaky SCID can be associated with higher numbers of T cells and reduced rather than absent activation responses when compared with typical SCID caused by null mutations. A spectrum of clinical findings including typical SCID, OS, leaky SCID, granulomas with T lymphopenia, autoimmunity, and CD4+ T lymphopenia can be found with RAG gene defects. RAC2 deficiency is a disorder of leukocyte motility and is reported in Table 5; however, one patient with RAC2 deficiency was found to have absent T cell receptor excision circles (TRECs) by newborn screening, but T cell numbers and mitogen responses were not impaired. For additional syndromic conditions with T cell lymphopenia, such as DNA repair defects, cartilage hair hypoplasia, IKAROS deficiency, and NEMO syndrome, see Table 2 and 6; however, it should be noted that individuals with the most severe manifestations of these disorders could have clinical signs and symptoms of SCID. Severe folate deficiency (such as with malabsorption due to defects in folate carrier or transporter genes SLC10A1 or PCFT) and some metabolic disorders, such as methylmalonic aciduria, may present with reversible profound lymphopenia in addition to their characteristic presenting features.
Conflict of Interest Statement
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.