Table 1.
Immunodeficiency | Molecular defect | Laboratory findings | GI manifestation | Other clinical findings |
---|---|---|---|---|
Selective IgA deficiency | Gene defect unknown; defective maturation of B cells into IgA-secreting plasma cells | Serum IgA absent or near absent, usually <10 mg/dL; normal IgG and IgM levels although IgG2 subclass deficiency may be present; impaired specific antibody response in some patients | Diarrhea, celiac sprue, NLH | Usually asymptomatic; some with recurrent bacterial infections, atopy, and autoimmunity |
Agammaglobulinemia, X-linked or AR | X-linked (BTK), autosomal-recessive (μ, heavy chain, λ5, Igα, Igβ, BLNK) | Absent IgM, IgG, and IgA; B cells <1% of lymphocytes; absent specific antibody response | GI disorders rare, chronic diarrhea, malabsorption | Recurrent and severe bacterial infections, enteroviral infections, absent lymphoid tissue, autoimmunity |
Hyper-IgM syndrome | Mutations in CD40L, CD40, AICDA, UNG | Low IgG and IgA; normal or increased IgM; normal or increased B-cell numbers; impaired specific antibody response; decreased T-cell responses in CD40L/CD40 deficiency | Diarrhea, progressive liver disease, sclerosing cholangitis | Recurrent bacterial infections, opportunistic infections, neutropenia, autoimmune disease |
CVID | Mutations in ICOS, CD19, CD20, CD81, TNFRSF13B; TNFRSF13C; mostly unknown | Low IgG and IgA and/or IgM; absent specific antibody response; normal or decreased B-cell numbers; variably decreased T-cell responses | Diarrhea, NLH, flat villous lesions, IBD-like disease, pernicious anemia, hepatitis | Variable clinical phenotype: recurrent bacterial infections, autoimmune disease, lymphoproliferative ann/or granulomatous disease |
SCID | Multiple defects: RAG1/2, JAK3, CD45, CD3 chain, ZAP70, Artemis, ligase 4, Cernunnos, IL-2RG, IL-7Rα, ADA → defects in T and B cells | Decreased serum immunoglobulins; marked diminished/absent T-cell, B-cell, and NK cell numbers depending on functional deficiency; diminished response to mitogens PHA, ConA, PWM | Chronic diarrhea, oral candidiasis, IBD | Failure to thrive, recurrent and severe bacterial, viral, and/or fungal infections early in life |
CGD | Multiple defects: X-linked owing to defects in CYBB encoding the gp91 phox component of NADPH oxidase autosomal recessive owing to defects in NCF1, NCF2, or CYBA defects in components of NADPH oxidase | Defective oxidative burst in neutrophils by DHR or NBT equivalent | Granulomatous colitis, perianal fistulae, hepatic abscess, gastric outlet obstruction, small-bowel obstruction, granulomatous stomatitis, oral ulcers, esophageal dysmotility, hepatomegaly splenomegaly | Recurrent abscess, skin infections, recurrent bacterial and fungal infections (particularly S aureus and Aspergillus) |
WAS | Mutations in WAS; cytoskeletal defect affecting hematopoietic stem cell derivatives | Immunoglobulins variable in concentration secondary to accelerated synthesis and catabolism (decreased IgM; normal or slightly low IgG; often increased IgA and IgE); antibody response to polysaccharides decreased; normal B-cell numbers; progressive decrease in T-cell numbers with abnormal lymphocyte responses to anti-CD3; platelet numbers are reduced and small in size | Colitis, bloody diarrhea, malabsorption | Thrombocytopenia, eczema, autoimmune disease, bacterial and viral infections, lymphoreticular malignancy |
IPEX | Defects in F0XP3, encoding a T-cell transcription factor | Increased IgA and IgE; normal B-cell numbers; lack of CD4+CD25+F0XP3+ regulatory T cells; eosinophilia | Severe enteropathy with watery, often bloody, diarrhea associated with eosinophilic inflammation | Early onset diabetes, thyroiditis, hemolytic anemia, thrombocytopenia, eczema |
X-linked anhidrotic ectodermal dysplasia with immunodeficiency | Mutations of NEMO (IKBKG), a modulator of NF-κB activation | Impaired response to polysaccharides in most cases; high serum levels of IgM, and low serum levels of IgG, IgA, or IgG2 in several cases | Failure to thrive, recurrent diarrhea, colitis | Severe, recurrent infections (mycobacteria and pyogenic bacteria) with an early onset; ectodermal dysplasia, hypohydrosis, widely spaced cone- or peg-shaped teeth, and hypotrichosis; some with osteopetrosis and lymphedema |
DiGeorge syndrome (chromosome 22q11.2 deletion syndrome) | Contiguous gene defect in 90% affecting thymic development; evidence that point mutations in the TBX1 gene are involved | Immunoglobulins usually normal although occasionally IgE increased and IgA reduced; normal B-cell numbers; low to absent T-cell numbers in complete forms; varying degrees of T-cell function according to thymic deficiency | Mucocutaneous candidiasis | Conotruncal malformation; hypoparathryoidism; abnormal facies; absent thymus in complete forms |
Hermansky–Pudlak syndrome, type 1 | Mutation in the HPS1 gene on chromosome 10q23 that forms part of BLOC-3 | Normal platelet count; prolonged bleeding time, with abnormal platelet function assays | Granulomatous colitis | Oculocutaneous albinism, abnormal platelet aggregation with bleeding diathesis, and pulmonary fibrosis |
AICDA, activation-induced cytidine deaminase; AR, autosomal recessive; BLNK, B-cell linker protein; BLOC-3, biogenesis of lysosome-related organelles complex-3; BTK, Bruton tyrosine kinase; CYBA, cytochrome b α subunit; CYBB, cytochrome b β subunit; DHR, dihydrorhodamine; ICOS, inducible costimulator; JAK3, Janus activating kinase 3; NADPH, nicotinamide adenine dinucleotide phosphate; NF-κB, nuclear factor-kB; PHA, phytohemagglutinin; PWM, pokeweed mitogen; RAG, recombinase activating gene; TBX1, T-box 1; TNFRSF, TNF-receptor superfamily; UNG, uracil DNA glycosylase.