Chronic Granulomatous Disease - CGD

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
• 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
  • Inflammatory bowel disease (IBD)
  • Celiac 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
• 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

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