Version June 2024
| Disease | Gastrointestinal presentation | Epidemiology and common extraintestinal features | Key diagnostic tests |
| Predominantly antibody deficiencies | |||
| Common variable immunodeficiency | Chronic diarrhea, malabsorption, weight loss, giardiasis, atrophic gastritis, pernicious anemia, NLH, IBD-like disease, sprue-like disease, hepatitis, hepatomegaly, liver dysfunction, primary biliary cirrhosis, granulomatous liver disease, and gastric carcinoma | Patients of any age, both males and females. Sinopulmonary bacterial infections, autoimmune hematologic disorders (eg, autoimmune hemolytic anemia, ITP), splenomegaly. | IgG and either IgA or IgM below the lower limit of normal for age, poor or absent responses to protein and polysaccharide vaccines. |
| X-linked agammaglobulinemia | Chronic diarrhea, malabsorption, viral and bacterial gastrointestinal infections, enteropathy resembling Crohn disease, gastric adenocarcinoma, and colorectal cancer | Boys, usually 6 months to 5 years of age. Sinopulmonary bacterial infections, chronic enteroviral infections (echovirus, coxsackie) presenting as meningoencephalitis or chronic hepatitis. Vaccine-related polio after live vaccination. Hypoplastic tonsils, adenoids. | Low to absent IgG, IgA, IgM. Low to absent CD19+ B cells. Absent antibody responses to vaccines and microbial antigens. |
| X-linked hyperimmunoglobulin M syndrome | Protracted and recurrent infectious diarrhea, FTT, oral ulcers, gingivitis, rectal ulcer, progressive liver disease, sclerosing cholangitis, carcinomas of the liver, pancreas, biliary tract | Boys, usually during first years of age. Recurrent sinopulmonary bacterial infections, opportunistic infections. Hypoplastic tonsils. | Normal or elevated IgM with low IgG, IgA, and IgE. Lack of response to polysaccharide and protein vaccines. |
| Selective IgA deficiency | Diarrhea, celiac disease, IBD, NLH, and giardiasis | Patients of any age, both males and females. Often are asymptomatic. Symptomatic patients may have sinopulmonary infections, autoimmune disorders, and/or allergic disorders. | Serum IgA low or absent, with normal IgG and IgM. Occasional impaired responses to polysaccharide vaccines and less commonly, protein vaccines. Some have associated IgG subclass deficiency. |
| Combined immunodeficiencies | |||
| Severe combined immunodeficiency | Diarrhea, FTT, bacterial and viral gastrointestinal infections, candidiasis of oral cavity, esophagus and anus, villous atrophy in small intestine, GVHD and GVHD-like process in small intestine and colon | Both males and females, usually presents within the first 3 months of life, early-onset severe and/or recurrent bacterial, viral, and fungal infections, and FTT. | Absent or decreased circulatory T cells. Normal, increased, or decreased B cells. Normal, absent, or decreased NK cells. Lack of functional antibodies. Low or absent TRECs on newborn screening. |
| MHC class II deficiency or bare-lymphocyte syndrome | Diarrhea and FTT | Similar to SCID even though milder forms also exist. | Normal number of T cells, decreased number of CD4+ T cells. Normal number of B cells. Lack of functional antibodies. Normal in vitro response of T cell to PHA. Absence of MHC class II expression and slight decrease in MHC class I expression on B cells. |
| Lipopolysaccharides responsive beige-like anchor (LRBA) deficiency and cytotoxic T lymphocyte-associated protein 4 (CLTA4) deficiency | IBD, recurrent gastrointestinal infections and FTT | Both males and females, severe and early-onset humoral immune deficiency, recurrent infections, autoimmunity, and EBV infections. | Low IgG and IgA in most cases. Normal or low number of B cells. Normal or decreased CD4 numbers. Low or normal numbers of B cells. Reduced IgG and IgA in most cases. |
| Adenosine deaminase deficiency | Autoimmune hepatitis and chronic diarrhea | Both males and females, often with costochondral junction flaring, neurologic features, and hearing impairment. Partial deficiency may lead to delayed or milder presentation. | Absent of T cells at birth or progressive decrease. Progressive B cell and immunoglobulin levels decrease. Decreased NK cells. |
| Well-defined syndromes with immunodeficiency | |||
| DiGeorge syndrome | Diarrhea, feeding difficulties, FTT, and candidiasis | Both males and females. Structural abnormalities may present at birth. Recurrent infections present in those older than 3 to 6 months. Conotruncal cardiac anomalies, hypoplastic thymus, hypocalcemia, and abnormal facies, slow cognitive development. | Normal or decreased T cells. Normal B cells. Normal or decreased NK cells. |
| Wiskott-Aldrich syndrome | Early-onset gastrointestinal bleeding and early-onset IBD-like colitis | Young males within the first 2 years of life, thrombocytopenia with small platelets, eczema, autoimmunity, lymphoma, and recurrent bacterial and viral infections. | Decreased number and function of T cells, normal number of B cells, normal or increased number of NK cells, but their function may be impaired. Impaired response to polysaccharide vaccines. Decreased IgM, normal or decreased IgG, increased IgA, and IgE. Decreased function of regulatory T (Treg) cells. Impaired chemotaxis of phagocytic cells. |
| Hyperimmunoglobulin E syndrome | Disseminated gastrointestinal infection caused by Cryptococcus and Histoplasma, colon diverticulitis and perforation, and severe food allergy | Patients of any age. Both male and females. Facial abnormalities, eczema, skeletal abnormalities, delay of shedding primary teeth, recurrent and/ or severe cutaneous and pulmonary bacterial infections mainly due to Staphylococcus aureus and Candidiasis. | Markedly increased IgE. Impaired specific antibody production. Decreased memory B cells. Increased B cell-activating factor. Decreased T helper type 17 (Th17) and T follicular helper cells. |
| Ataxia-telangiectasia | Adenocarcinomas and lymphoreticular malignancies of gastrointestinal tract | Both males and females. Commonly presents in early childhood. Ataxic gait, telangiectasia, recurrent sinopulmonary infections, and tendency to malignancies. | Decreased or normal IgG, IgA, and IgE subclasses. Increased or normal IgM. Progressive decrease of T cells. Elevated levels of alpha-1-fetoprotein, radiosensitivity. |
| Immunodeficiency with multiple intestinal atresias | Multiple intestinal atresias involving stomach to rectum, gastrointestinal obstruction, and gastrointestinal infections | Both boys and girls. Presents early after birth. Multiple intestinal atresias, which is frequently accompanied by intrauterine polyhydramnios and death at an early age and SCID-like phenotype in some cases. | Hypogammaglobulinemia. T cells may be absent. |
| Nuclear factor kappa B essential modulator (NEMO) deficiency | Diarrhea, abdominal pain, malabsorption, mycobacterial and CMV infection, bloody stool, weight loss, atypical enterocolitis, vomiting, and giardiasis | Almost all patients are male. Presents in the first year of life in most cases. Recurrent and/or severe infections by bacteria, mycobacteria, viruses and fungal organisms, ectodermal dysplasia, and colitis. | Hypogammaglobulinemia with impaired response to polysaccharide vaccines. Normal or increased IgM and IgA. Impaired function of NK cells and lymphocytosis. |
| Hepatic veno-occlusive disease with immunodeficiency | Early-onset hepatic veno-occlusion, liver CMV, Candida infections, and hepatosplenomegaly | Both males and females. Susceptibility to Pneumocystis jiroveci pneumonia, thrombocytopenia; cerebrospinal leukodystrophy. | Normal or decreased T cells. Normal or decreased B cells. Decreased immunoglobulins. Absent of tissue plasma cells. |
| Disease | Gastrointestinal presentation | Epidemiology and common extraintestinal features | Key diagnostic tests |
| Phagocytic defects | |||
| Chronic granulomatous disease | Diarrhea with or without blood, steatorrhea, malabsorption, FTT, abdominal pain, constipation, gastrointestinal infections, hepatic abscess, perirectal abscess, cholecystitis noncaseating granulomatous colitis resembling Crohn disease, granulomata formation, dysphagia, esophageal dysmotility, and gastrointestinal obstruction | Majority of patients are males. At any age but most commonly before 5 years of age. Granuloma formation, and severe and/or recurrent bacterial and fungal infections. | Hypogammaglobulinemia. Anemia of chronic disease. Impaired neutrophil function tests. |
| Severe congenital neutropenia | Oral and gastrointestinal tract ulcers, development of Clostridium bacteremia, abdominal pain episodes | Both males and females. Deep seated infection due to bacteria and/or fungi, omphalitis. Susceptibility to myelodysplastic syndromes. | Neutropenia below 0.5 g/L measured on at least three occasions. Myeloid differentiation arrest in bone marrow aspiration. |
| Defects in innate immunity | |||
| Chronic mucocutaneous candidiasis | Chronic and recurrent candidiasis in oral cavity, esophagus and gastrointestinal tract, dental abnormalities, chronic diarrhea, and constipation | Both males and females. Usually presents before 5 years of age. Candidiasis of skin, mucous membranes, and nails, autoimmunity. | Impaired in vivo and in vitro response to Candida. Some have impaired response to polysaccharide vaccines. Hypogammaglobulinemia is rare. Anemia of iron deficiency or vitamin B12 deficiency. Impaired thyroid, liver, and blood sugar tests due to an underlying autoimmune cause. |
| Mendelian susceptibility to mycobacterial disease | Salmonellosis and gastrointestinal candidiasis | Both males and females. Infections caused by weakly virulent mycobacteria, such as Bacillus Calmette-Guérin vaccines and environmental mycobacteria. Tuberculosis and other intramacrophagic bacteria, fungi, or parasites. | Reduced IFN-gamma-mediated immunity tests. Reduced IL-12-mediated immunity tests. |
| Autoinflammatory disorders | |||
| Familial Mediterranean fever | Recurrent abdominal pain, peritoneal lining, diarrhea mechanical bowel obstruction, volvulus, strangulation, IBD, nonalcoholic steatohepatitis, and cryptogenic cirrhosis | Both males and females. Recurrent fever, serositis, and inflammation responsive to colchicine. Predisposes to vasculitis. | Mature granulocytes, cytokine-activated. Monocytes. Decreased production of pyrin. Induced IL-1 and decreased macrophage apoptosis. |
| Periodic fever, aphthous stomatitis, pharyngitis, and adenitis | Aphthous stomatitis | Both males and females. Recurring fevers with an early age of onset. Constitutional symptoms. Cervical lymphadenitis and pharyngitis. | Leukocytosis. Increased C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). |
| Diseases of immune dysregulation | |||
| Immune dysfunction, polyendocrinopathy, enteropathy, X-linked (IPEX) | Watery diarrhea, which can also be mucoid or bloody, malabsorption, FTT, and severe enteropathy resembling food allergy | Typically a male infant. Autoimmune endocrinopathy, such as type 1 diabetes mellitus and thyroiditis. Dermatitis most commonly in the form of eczema. | Typically eosinophilia. Neutropenia, anemia, or thrombocytopenia are also present. Increased total and antigen-specific IgE. Increased IgA in one-half of patients. IgG and IgM may be normal or low. Impaired thyroid and blood sugar tests. |
| CD25 deficiency | Similar to IPEX | Severe infections. Other features similar to IPEX. | Similar to IPEX. Impaired response to antigen specific vaccines. |
| STAT5b deficiency | Similar to IPEX | Growth hormone resistance. Other features similar to IPEX. | Similar to IPEX. |
| Hermansky-Pudlak syndrome | Granulomatous colitis which may resemble IBD, enamel hypoplasia, lactase deficiency, and bacterial overgrowth | Both males and females. Presents in infancy or early childhood. Recurrent infections, partial albinism, pulmonary fibrosis, and bleeding tendency. | Normal number but with absent function of cytotoxic T and NK cells. |
| Chediak-Higashi syndrome | Gingivitis, periodontal disease, oral ulcers, and enterocolitis | Both males and females. Presents in infancy or early childhood. Recurrent pyogenic infections, partial oculocutaneous albinism, progressive neurologic dysfunction, bleeding tendency, and a lymphoma-like accelerated phase. | Neutropenia. Decreased chemotactic response of neutrophils and monocytes. Normal number but with absent function of NK cells. Increased number of activated T cells but absent functional cytotoxic T cell cells. Hypergammaglobulinemia. Abnormal coagulation tests. |
| IL-10, IL-10 receptor 1 deficiency, and IL-10 receptor 2 deficiency | Early-onset IBD accompanied by folliculitis and arthritis | Both males and females. Usually presents before 3 months of age. Folliculitis and arthritis. | Absence of functional IL-10 secretion and signaling pathway. |
| Complement deficiencies | |||
| Hereditary angioedema | Severe abdominal pain, diarrhea, rectal bleeding, acute surgical abdomen and ascites, intestinal edema, colitis, and intussusception | Both males and females. Recurrent angioedema without urticaria. Laryngeal edema. | Absent or dysfunction of C1 esterase inhibitor. Low complement C4 and normal C1q level. |
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