Table 1.

Immunodeficiency and Associated GI Disorders

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.