Chronic Granulomatous Disease - CGD

  • Diagnosis
  • Algorithms
  • Background
  • Lab Tests
  • References
  • Related Topics

Indications for Testing

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 (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
  • Genetic testing
    •  X-linked chronic granulomatous disease (CGD) – CYBB gene
    • Autosomal recessive CGD – CYBA, NCF1, NCF2, NCF4 genes

Differential Diagnosis

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.

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
  • Autosomal recessive forms
    • NCF1 – encodes p47-phox
      • GT deletion in exon 2 accounts for majority of mutations
    • CYBA – encodes p22-phox
    • NCF2 – encodes p67-phox
    • NCF4 – encodes p40-phox

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

Tests generally appear in the order most useful for common clinical situations. Click on number for test-specific information in the ARUP Laboratory Test Directory.

Neutrophil Oxidative Burst Assay (DHR) 0096657
Method: Semi-Quantitative Flow Cytometry

Limitations

Results alone are not diagnostic

Specimen must remain ambient and be tested within 48 hours of collection

Follow Up

With abnormal result, consider genetic testing

Chronic Granulomatous Disease (CYBB Gene Scanning and NCF1 Exon 2 GT Deletion) with Reflex to CYBB Sequencing 2006356
Method: Polymerase Chain Reaction/High Resolution Melt Analysis

Limitations

Diagnostic errors can occur due to rare sequence variations

Deep intronic mutations in CYBB, mutations in NCF1 other than the GT deletion in exon 2, and mutations in additional genes associated with CGD are not evaluated

Large CYBB gene deletions/duplications will not be detected in females

Breakpoints of large CYBB deletions/duplications will not be determined in males

Lack of GT deletion in exon 2 does not rule out carrier status due to potential recombination between NCF1 and its pseudogenes

Chronic Granulomatous Disease (NCF1) Exon 2 GT Deletion 2006366
Method: Polymerase Chain Reaction/High Resolution Melt Analysis

Limitations

Diagnostic errors can occur due to rare sequence variations

Mutations in NCF1 other than the GT deletion in exon 2, and mutations in additional genes associated with CGD are not evaluated

Lack of GT deletion in exon 2 does not rule out carrier status due to potential recombination between NCF1 and its pseudogenes

Chronic Granulomatous Disease, X-Linked (CYBB) Gene Scanning with Reflex to Sequencing 2006361
Method: Polymerase Chain Reaction/High Resolution Melt Analysis

Limitations

Diagnostic errors can occur due to rare sequence variations

Deep intronic mutations in CYBB and mutations in additional genes associated with CGD are not evaluated

Large CYBB gene deletions/duplications will not be detected in females

Breakpoints of large CYBB deletions/duplications will not be determined in males

Related Tests

Guidelines

Al-Herz W, Bousfiha A, Casanova J, Chatila T, Conley MEllen, Cunningham-Rundles C, Etzioni A, Franco JLuis, Gaspar B, Holland SM, Klein C, Nonoyama S, Ochs HD, Oksenhendler E, Picard C, Puck JM, Sullivan K, Tang ML K. Primary immunodeficiency diseases: an update on the classification from the international union of immunological societies expert committee for primary immunodeficiency. Front Immunol. 2014; 5: 162. PubMed

General References

Hill HR, Augustine NH, Pryor RJ, Reed GH, Bagnato JD, Tebo AE, Bender JM, Pasi BM, Chinen J, Hanson C, de Boer M, Roos D, Wittwer CT. Rapid genetic analysis of x-linked chronic granulomatous disease by high-resolution melting. J Mol Diagn. 2010; 12(3): 368-76. PubMed

Immune Deficiency Foundation. Towson, MD [Accessed: Nov 2015]

Köker Y. Novel human pathological mutations. Gene symbol: NCF2. Disease: Chronic granulomatous disease. Hum Genet. 2010; 127(1): 113. PubMed

Leiding JW, Holland SM. Chronic Granulomatous Disease. 2012 Aug 9 [updated 2016 Feb 11]. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, Bird TD, Fong CT, Mefford HC, Smith RJH, Stephens K, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016. PubMed 

Locke BA, Dasu T, Verbsky JW. Laboratory diagnosis of primary immunodeficiencies. Clin Rev Allergy Immunol. 2014; 46(2): 154-68. PubMed

Roos D, Kuhns DB, Maddalena A, Roesler J, Lopez JAlvaro, Ariga T, Avcin T, de Boer M, Bustamante J, Condino-Neto A, Di Matteo G, He J, Hill HR, Holland SM, Kannengiesser C, Köker Y, Kondratenko I, van Leeuwen K, Malech HL, Marodi L, Nunoi H, Stasia M, Ventura AMaria, Witwer CT, Wolach B, Gallin JI. Hematologically important mutations: X-linked chronic granulomatous disease (third update). Blood Cells Mol Dis. 2010; 45(3): 246-65. PubMed

Song E, Jaishankar GBala, Saleh H, Jithpratuck W, Sahni R, Krishnaswamy G. Chronic granulomatous disease: a review of the infectious and inflammatory complications. Clin Mol Allergy. 2011; 9(1): 10. PubMed

Stasia MJosé, Li XJun. Genetics and immunopathology of chronic granulomatous disease. Semin Immunopathol. 2008; 30(3): 209-35. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

Bender JM, Rand TH, Ampofo K, Pavia AT, Schober M, Tebo A, Pasi B, Augustine NH, Pryor RJ, Wittwer CT, Hill HR. Family clusters of variant X-linked chronic granulomatous disease. Pediatr Infect Dis J. 2009; 28(6): 529-33. PubMed

Hill HR, Augustine NH, Pryor RJ, Reed GH, Bagnato JD, Tebo AE, Bender JM, Pasi BM, Chinen J, Hanson C, de Boer M, Roos D, Wittwer CT. Rapid genetic analysis of x-linked chronic granulomatous disease by high-resolution melting. J Mol Diagn. 2010; 12(3): 368-76. PubMed

Hill HR. Hyperinflammatory pulmonary disease in chronic granulomatous disease. Pediatr Infect Dis J. 2011; 30(9): 808-10. PubMed

Madden JL, Schober ME, Meyers RL, Bratton SL, Holland SM, Hill HR, Rollins MD. Successful use of extracorporeal membrane oxygenation for acute respiratory failure in a patient with chronic granulomatous disease. J Pediatr Surg. 2012; 47(5): E21-3. PubMed

Stasia MJosé, van Leeuwen K, de Boer M, Martel C, Mollin M, Thuret I, Michel G, Hanson C, Augustine NH, Coutton C, Satre V, Wittwer CT, Hill H, Roos D. Rare duplication or deletion of exons 6, 7 and 8 in CYBB leading to X-linked chronic granulomatous disease in two patients from different families. J Clin Immunol. 2012; 32(4): 653-62. PubMed

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Last Update: June 2016