Chronic granulomatous disease (CGD) is an inherited primary immunodeficiency disorder characterized by severe, recurring infections with formation of granulomas. Phagocytic cells ingest but cannot digest bacteria or fungi due to a malfunction of the nicotinamide adenosine dinucleotide phosphate (NADPH) oxidase system.
Diagnosis
Indications for Testing
Severe and recurrent bacterial and fungal infections, presence of granulomas, colitis, pneumonias, osteomyelitis, lymphadenitis
Laboratory Testing
- Nonspecific testing to rule out other disorders
- Serum quantitative immunoglobulins – rule out disorders associated with immunoglobulin deficiency
- Complement activity enzyme immunoassay – rule out complement deficiency
- CBC with differential – rule out other causes of chronic infection (eg, neutropenic disorders)
- Leukocyte adhesion deficiency panel – rule out leukocyte adhesion deficiency
- Specific testing
- Neutrophil oxidative burst assay (dihydrorhodamine [DHR]) via flow cytometry
- Preferred screening test
- Disease is indicated by absence or significant alteration of activity
- Other, less reliable tests
- Measurement of superoxide production, ferricytochrome C reduction, nitroblue tetrazolium test
- Neutrophil oxidative burst assay (dihydrorhodamine [DHR]) via flow cytometry
- Genetic testing
- X-linked chronic granulomatous disease (CGD) – CYBB gene
- Autosomal recessive CGD – CYBA, NCF1, NCF2, NCF4 genes
Differential Diagnosis
- Chronic recurrent infections
- Hypogammaglobulinemia
- Complement deficiency
- Leukocyte adhesion deficiency type 1
- Hyper IgE syndrome (Job syndrome)
- Kostmann agranulocytosis
- Autoimmune neutropenia
- Myeloperoxidase deficiency
- Innate immune deficiency
- Wiskott-Aldrich syndrome
- Severe combined immunodeficiency
- HIV/AIDS
- Bowel disease
- Granulomatous disease
- Sarcoidosis
- Infection
- Mycobacterium tuberculosis
- Fungal disease
Background
Epidemiology
- Incidence – 1/250,000 births
- X-linked CGD
- CYBB – 60-70% of cases
- Autosomal recessive CGD
- NCF1 – 25% of cases
- CYBA – <5% of cases
- NCF2 – <5% of cases
- NCF4 – very rare
- Age – dependent on type of CGD
- Classic X-linked in males – typically <3 years
- Carrier females of X-linked – usually >3 years
- Females with skewed X-chromosome inactivation – similar to males
- Sex – M>F by 85%
Inheritance
- X-linked form – 60-70% of cases
- Involves CYBB gene mutations in the 13 exons encoding the 91-kD heavy chain of cytochrome b558
- Typically earlier onset and more severe disease than autosomal recessive CGD
- Involves CYBB gene mutations in the 13 exons encoding the 91-kD heavy chain of cytochrome b558
- Autosomal recessive forms
- NCF1 – encodes p47phox
- GT deletion in exon 2 (c.75_76delGT) accounts for ~85% of causative variants in NCF1 (Vázquez, 2001)
- CYBA – encodes p22phox
- NCF2 – encodes p67phox
- NCF4 – encodes p40phox
- NCF1 – encodes p47phox
Pathophysiology
- Function of phagocytes (neutrophils and macrophages)
- First line of defense against bacterial and fungal infections
- Migrate to the site of infection – phagocytosis occurs, which generates microbicidal reactive oxygen products
- Neutrophils and macrophages are ingested by the phagosome
- Other nonoxidative factors are added that assist in killing pathogenic microorganisms
- CGD – abnormalities of neutrophils and macrophages
- Gene mutations cause defective microbicidal oxidant production secondary to a defect in the neutrophil respiratory burst
- Results in decreased production of superoxide, hydrogen peroxide, hydroxyl radical, and hypochlorite ions within neutrophils and macrophages
- Defective production causes susceptibility to infections from organisms that may be nonpathogenic in an immunocompetent individual
- Most common infections – bacterial (eg, catalase-positive microorganisms) and fungal organisms
Clinical Presentation
- Signs and symptoms usually appear very early in childhood for X-linked male cases
- May not present until later in life, especially with mild cases or autosomal recessive/variant forms of X-linked CGD
- Ophthalmic – chorioretinitis
- Oral – periodontitis, gingivitis, stomatitis, aphthous ulcerations
- Gastrointestinal – nausea, diarrhea, vomiting, colitis/enteritis with inflammatory bowel disease (IBD)-like manifestations (blood in stool, granulomas in gastrointestinal tract), splenomegaly, hepatitis
- Genitourinary – urethral/ureteral strictures, bladder granulomas, urinary tract infections
- Pulmonary – pneumonia, obliterative bronchiolitis, bronchiectasis
- Skin and musculoskeletal – lymphadenitis, skin and visceral abscesses, osteomyelitis
- Infections
- Chronic obstructive granulomas form at sites of infection
- Characterized by bacterial and fungal infections, with most common agents including
- Staphylococcus aureus
- Burkholderia cepacia
- Serratia marcescens
- Nocardia spp
- Aspergillus spp
- Concomitant autoimmune disorders
- Systemic lupus erythematosus
- Immune thrombocytopenia
- Juvenile idiopathic arthritis
ARUP Laboratory Tests
Aid in screening for chronic granulomatous disease (CGD)
Results are not intended to be used as the sole means for clinical diagnosis or patient management decisions
Specimen must remain ambient and be tested within 48 hours of collection
Semi-Quantitative Flow Cytometry
Initial test in workup of immunoglobulin disorders
Order in conjunction with serum protein electrophoresis and immunofixation to rule out plasma cell dyscrasia in adults and older children (>15 years) with suspected hypogammaglobulinemia
Quantitative Immunoturbidimetry
Initial screening for suspected deficiency in the classical complement pathway
Quantitative Immunoturbidimetry
Aids in the diagnosis of type 1 and 2 leukocyte adhesion deficiency
Panel measures CD11a, CD11b, CD15, and CD18 on neutrophils
Semi-Quantitative Flow Cytometry
Useful when a pathogenic familial variant identifiable by sequencing is known
Consultation with a genetics counselor is advised
Massively Parallel Sequencing
References
IDF - Chronic Granulomatous Disease
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Emmanuele V, López LC, Berardo A, et al. Genetics and immunopathology of chronic granulomatous disease. Semin Immunopathol. 2008;30(3):209-235.
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Köker MY. Novel human pathological mutations. Gene symbol: NCF2. Disease: chronic granulomatous disease. Hum Genet. 2010;127(1):113.
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Picard C, Al-Herz W, Bousfiha A, et al. Primary immunodeficiency diseases: an update on the classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency 2015. J Clin Immunol. 2015;35(8):696-726.
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Roos D, Kuhns DB, Maddalena A, et al. Hematologically important mutations: X-linked chronic granulomatous disease (third update). Blood Cells Mol Dis. 2010;45(3):246-265.
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Song E, Jaishankar GB, Saleh H, et al. Chronic granulomatous disease: a review of the infectious and inflammatory complications. Clin Mol Allergy. 2011;9(1):10.
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Hill HR, Augustine NH, Pryor RJ, et al. Rapid genetic analysis of x-linked chronic granulomatous disease by high-resolution melting. J Mol Diagn. 2010;12(3):368-376.
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Locke BA, Dasu T, Verbsky JW. Laboratory diagnosis of primary immunodeficiencies. Clin Rev Allergy Immunol. 2014;46(2):154-168.
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Vázquez N, Lehrnbecher T, Chen R, et al. Mutational analysis of patients with p47-phox-deficient chronic granulomatous disease: the significance of recombination events between the p47-phox gene (NCF1) and its highly homologous pseudogenes. Exp Hematol. 2001;29(2):234-243.
Medical Experts
Hill

Krautscheid

Panel includes IgA, IgG, and IgM