Table 3.
Predominantly antibody deficiencies.
| Disease | Serum Ig | Associated features | Inheritance | Genetic defect/presumed pathogenesis | OMIM number | |
|---|---|---|---|---|---|---|
| 1. Severe reduction in all serum immunoglobulin isotypes with profoundly decreased or absent B cells | ||||||
| (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 BTK, a cytoplasmic tyrosine kinase activated by crosslinking of the BCR | 300300 | |
| (b) μ Heavy chain deficiency | All isotypes decreased | Severe bacterial infections; normal numbers of pro-B cells | AR | Mutations in μ heavy chain | 147020 | |
| (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 | 146770 | |
| (d) Igα deficiency* | All isotypes decreased | Severe bacterial infections; normal numbers of pro-B cells | AR | Mutations in Igα (CD79a); part of the pre-BCR and BCR | 112205 | |
| (e) Igβ deficiency* | All isotypes decreased | Severe bacterial infections; normal numbers of pro-B cells | AR | Mutations in Igβ (CD79b); part of the pre-BCR and BCR | 147245 | |
| (f) BLNK deficiency* | All isotypes decreased | Severe bacterial infections; normal numbers of pro-B cells | AR | Mutations in BLNK; a scaffold protein that binds to BTK | 604615 | |
| (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 | ||
| 2. Severe reduction in at least 2 serum immunoglobulin isotypes with normal or low number of B cells | ||||||
| (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 ICOS | 604558 | ||
| (c) CD19 deficiency* | Low IgG and IgA and/or IgM | May have glomerulonephritis | AR | Mutations in CD19; transmembrane protein that amplifies signal through BCR | 107265 | |
| (d) CD81 deficiency* | Low IgG, low or normal IgA, and IgM | May have glomerulonephritis | AR | Mutations in CD81; transmembrane protein that amplifies signal through BCR | 186845 | |
| (e) CD20 deficiency* | Low IgG, normal or elevated IgM, and IgA | AR | Mutations in CD20 | 112210 | ||
| (f) TACI deficiency | Low IgG and IgA and/or IgM | Variable clinical expression | AD or AR or complex | Mutations in TNFRSF13B (TACI) | 604907 | |
| (g) BAFF receptor deficiency* | Low IgG and IgM | Variable clinical expression | AR | Mutations in TNFRSF13C (BAFF-R) | 606269 | |
| 3. Severe reduction in serum IgG and IgA with normal/elevated IgM and normal numbers of B cells | ||||||
| (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 CD40LG (also called TNFSF5 or CD154) | 300386 | |
| (b) CD40 deficiency* | Low IgG and IgA; normal or raised IgM | Opportunistic infections, neutropenia, autoimmune disease | AR | Mutations in CD40 (also called TNFRSF5) | 109535 | |
| (c) AID deficiency | IgG and IgA decreased; IgM increased | Enlarged lymph nodes and germinal centers | AR | Mutations in AICDA gene | 605257 | |
| (d) UNG deficiency | IgG and IgA decreased; IgM increased | Enlarged lymph nodes and germinal centers | AR | Mutations in UNG | 191525 | |
| 4. Isotype or light chain deficiencies with normal numbers of B cells | ||||||
| (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 | 147200 | |
| (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 | ||
| 5. Specific antibody deficiency with normal Ig concentrations and normal numbers of B cells | Normal | Reduced ability to make antibodies to specific antigens | Variable | Unknown | ||
| 6. Transient hypogammaglobulinemia of infancy with normal numbers of B cells | IgG and IgA decreased | Normal ability to make antibodies to vaccine antigens, usually not associated with significant infections | Variable | Unknown | ||
XL, X-linked inheritance; AR, autosomal recessive inheritance; AD, autosomal dominant inheritance; BTK, Bruton tyrosine kinase; BLNK, B cell linker protein; AID, activation-induced cytidine deaminase; UNG, uracil-DNA glycosylase; ICOS, inducible costimulator; Ig(κ), immunoglobulin, or κ light chain type.
*Ten or fewer unrelated cases reported in the literature.
Two new autosomal recessive disorders that might previously have been called CVID have been added to Table 3. CD81 is normally co-expressed with CD19 on the surface of B cells. Like CD19 mutations, mutations in CD81 result in normal numbers of peripheral blood B cells, low serum IgG, and an increased incidence of glomerulonephritis. A single patient with a homozygous mutation in CD20 has been reported.
Common Variable Immunodeficiency Disorders (CVID) include several clinical and laboratory phenotypes that may be caused by distinct genetic and/or environmental factors. Some patients with CVID and no known genetic defect have markedly reduced numbers of B cells as well as hypogammaglobulinemia. Alterations in TNFRSF13B (TACI) and TNFRSF13C (BAFF-R) sequences may represent disease modifying mutations rather than disease causing mutations. CD40L and CD40 deficiency are included in Table 1 as well as this table. A small minority of patients with XLP (Table 4), WHIM syndrome (Table 6), ICF (Table 2), VOD1 (Table 2), thymoma with immunodeficiency (Good syndrome) or myelodysplasia are first seen by an immunologist because of recurrent infections, hypogammaglobulinemia, and normal or reduced numbers of B cells. Patients with GATA2 mutations (Table 5) may have markedly reduced numbers of B cells, as well as decreased monocytes and NK cells and a predisposition to myelodysplasia but they do not have an antibody deficiency.