Inheriting CGD

CGD is a disorder that affects phagocyte function and that is caused by mutations in any 1 of 5 subunits of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase system.1 There are 2 major types of CGD: X-linked and autosomal recessive.1

X-linked CGD

Males who inherit the mutation will be affected, while females who inherit the mutation will be carriers and may also be at risk as autoimmune events are more common in female CGD carriers than in healthy individuals.1-3

X-linked CGD inheritance pattern chart showing a 50% chance of offspring being unaffected, a 25% chance of carrier female offspring, and a 25% chance of affected boy offspring
  • X = X chromosome with mutation
  • X = normal X chromosome
  • Y = Y chromosome

Autosomal recessive CGD

Autosomal recessive CGD can be passed down when both parents have a gene mutation. Each child has a 25% chance of being affected, 50% chance of being an asymptomatic carrier, and 25% chance of being unaffected and not a carrier.1

Autosomal recessive CGD inheritance pattern chart showing a 25% chance of unaffected offspring, 50% chance of carrier offspring, and a 25% chance of affected offspring
  • G = normal gene
  • g = defective gene

X-linked carriers of CGD may be at risk of serious infection*

Symptomatic mothers of sons with X-linked CGD should be monitored as potential patients as they may present with signs of CGD and experience a wide range of inflammatory and autoimmune symptoms such as3-7:

  • Colitis
  • Joint Pain
  • Weight loss
  • Dermatitis
  • Stomatitis
  • Discoid lupus-like disease
  • Photosensitive rashes

A 2018 study found that 48% of X-linked carriers reported infections, autoimmune symptoms, or both.3 As a result, X-linked carriers of CGD may be at risk of serious infection, should be evaluated, routinely tested, and monitored as patients, especially as they age.

CGD is most commonly inherited in an X-linked mode, with the subunit gp91phox of NADPH oxidase being affected; all other CGD-related subunit deficiencies are inherited in an autosomal recessive mode.1,4,8 CGD can also arise from a de novo mutation.1,8 The vast majority of patients with autosomal recessive CGD have p47phox deficiency.1,4,8

Because of the differences in subunit deficiencies and inheritance of CGD, there is heterogeneity in disease onset and severity.1,4,8

*Serious infection was defined as a clinical event requiring hospitalization and intravenous antibiotics.

NADPH oxidase subunit deficiencies
Subunit (Gene) Mode of Inheritence Frequency Sex Affected
gp91 phox (CYBB) X linked 65-70% 1,4,8 Male/rare in females
p47 phox (NCF1) Autosomal recessive 20-25% 1,4,8 Male/female
p67 phox (NCF2) Autosomal recessive 5-6% 1,4,8 Male/female
p22 phox (CYBA) Autosomal recessive 3-6% 1,4,8 Male/female
p40 phox (NCF4) Autosomal recessive 25 cases 1,9,10
Subunit (Gene): gp91 phox (CYBB) Mode of Inheritence: X linked Frequency: 65-70% 1,4,8 Sex Affected: Male/rare in females
Subunit (Gene): p47 phox (NCF1) Mode of Inheritence: Autosomal recessive Frequency: 20-25% 1,4,8 Sex Affected: Male/female
Subunit (Gene): p67 phox (NCF2) Mode of Inheritence: Autosomal recessive Frequency: 5-6% 1,4,8 Sex Affected: Male/female
Subunit (Gene): p22 phox (CYBA) Mode of Inheritence: Autosomal recessive Frequency: 3-6% 1,4,8 Sex Affected: Male/female
Subunit (Gene): p40 phox (NCF4) Mode of Inheritence: Autosomal recessive Frequency: 25 cases 1,9,10

The data in the above table is from the 1980s and 1990s, which may not fully reflect current distributions based on improved diagnostic tests.

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References: 1. Leiding JW, Holland SM. Chronic granulomatous disease. In: Pagon RA, Adam MP, Ardinger HH, et al, eds. GeneReviews® Seattle (WA): University of Washington, Seattle; 1993-2022. 2. Rider NL, Jameson MB, Creech CB. Chronic granulomatous disease: epidemiology, pathophysiology, and genetic basis of disease. J Pediatric Infect Dis Soc. 2018;7(suppl 1):S2-S5. 3. Marciano BE, Zerbe CS, Falcone EL, et al. X-linked carriers of chronic granulomatous disease: Illness, lyonization, and stability. J Allergy Clin Immunol. 2018;141(1):365-371. 4. Holland SM. Chronic granulomatous disease. Clin Rev Allergy Immunol. 2010;38(1):3-10. 5. Battersby AC, Bruggins H, Pearce MS, et al. Inflammatory and autoimmune manifestations in X-linked carriers of chronic granulomatous disease in the United Kingdom. J Allergy Clin Immunol. 2017;140(2):628-630.e6. 6. Magnani A, Brosselin P, Beauté J, et al. Inflammatory manifestations in a single-center cohort of patients with chronic granulomatous disease. J Allergy Clin Immunol. 2014;134(3):655-662.e8. 7. Song E, Jaishankar GB, 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):10-24. 8. Kuhns DB, Alvord WG, Heller T, et al. Residual NADPH oxidase and survival in chronic granulomatous disease. N Engl J Med. 2010;363(27):2600-2610. 9. Matute JD, Arias AA, Wright NA, et al. A new genetic subgroup of chronic granulomatous disease with autosomal recessive mutations in p40phox and selective defects in neutrophil NADPH oxidase activity. Blood. 2009;114(15):3309-3315. 10. van de Geer A, Nieto-Patlán A, Kuhns DB, et al. Inherited p40phox deficiency differs from classic chronic granulomatous disease. J Clin Invest. 2018;128(9):3957-3975. 

Approved Uses and Important Safety Information

INDICATIONS AND USAGE

ACTIMMUNE® (Interferon gamma-1b) is indicated:

  • For reducing the frequency and severity of serious infections associated with Chronic Granulomatous Disease
  • For delaying time to disease progression in patients with severe, malignant osteopetrosis
IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

  • In patients who develop or have known hypersensitivity to interferon-gamma, E. coli derived products, or any component of the product

WARNINGS AND PRECAUTIONS

  • ACTIMMUNE should be used with caution in patients with:
    • Pre-existing cardiac conditions, including ischemia, congestive heart failure, or arrhythmia
    • Seizure disorders or compromised central nervous system function; reduce dose or discontinue
    • Myelosuppression, or receiving other potentially myelosuppressive agents; consider dose reduction or discontinuation of therapy
    • Severe renal insufficiency
    • Age <1 year
  • Monitoring:
    • Patients begun on ACTIMMUNE before age 1 year should receive monthly assessments of liver function. If severe hepatic enzyme elevations develop, ACTIMMUNE dosage should be modified
    • Monitor renal function regularly when administering ACTIMMUNE in patients with severe renal insufficiency; accumulation of interferon gamma-1b may occur with repeated administration. Renal toxicity has been reported in patients receiving ACTIMMUNE
  • Pregnancy, Lactation, and Fertility:
    • ACTIMMUNE should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus
    • Use of ACTIMMUNE by lactating mothers is not recommended. ACTIMMUNE or nursing should be discontinued dependent on the importance of the drug to the mother
    • Long-term effects of ACTIMMUNE on fertility are not known

DRUG INTERACTIONS

  • Concomitant use of drugs with neurotoxic, hematotoxic, or cardiotoxic effects may increase the toxicity of interferons
  • Avoid simultaneous administration of ACTIMMUNE with other heterologous serum protein or immunological preparations (eg, vaccines)

ADVERSE REACTIONS

  • The most common adverse experiences occurring with ACTIMMUNE therapy are “flu-like” symptoms such as fever, headache, chills, myalgia, or fatigue, which may decrease in severity as treatment continues, and may be minimized by bedtime administration of ACTIMMUNE. Acetaminophen may be used to prevent or partially alleviate the fever and headache
  • Isolated cases of acute serious hypersensitivity reactions have been observed in patients receiving ACTIMMUNE
  • Reversible neutropenia, thrombocytopenia, and elevations of AST and/or ALT have been observed during ACTIMMUNE therapy
  • At doses 10 times greater than the weekly recommended dose, ACTIMMUNE may exacerbate pre-existing cardiac conditions, or may cause reversible neurological effects such as decreased mental status, gait disturbance, and dizziness

Approved Uses and Important Safety Information

INDICATIONS AND USAGE

ACTIMMUNE® (Interferon gamma-1b) is indicated:

  • For reducing the frequency and severity of serious infections associated with Chronic Granulomatous Disease
  • For delaying time to disease progression in patients with severe, malignant osteopetrosis
IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

  • In patients who develop or have known hypersensitivity to interferon-gamma, E. coli derived products, or any component of the product

WARNINGS AND PRECAUTIONS

  • ACTIMMUNE should be used with caution in patients with:
    • Pre-existing cardiac conditions, including ischemia, congestive heart failure, or arrhythmia
    • Seizure disorders or compromised central nervous system function; reduce dose or discontinue
    • Myelosuppression, or receiving other potentially myelosuppressive agents; consider dose reduction or discontinuation of therapy
    • Severe renal insufficiency
    • Age <1 year
  • Monitoring:
    • Patients begun on ACTIMMUNE before age 1 year should receive monthly assessments of liver function. If severe hepatic enzyme elevations develop, ACTIMMUNE dosage should be modified
    • Monitor renal function regularly when administering ACTIMMUNE in patients with severe renal insufficiency; accumulation of interferon gamma-1b may occur with repeated administration. Renal toxicity has been reported in patients receiving ACTIMMUNE
  • Pregnancy, Lactation, and Fertility:
    • ACTIMMUNE should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus
    • Use of ACTIMMUNE by lactating mothers is not recommended. ACTIMMUNE or nursing should be discontinued dependent on the importance of the drug to the mother
    • Long-term effects of ACTIMMUNE on fertility are not known

DRUG INTERACTIONS

  • Concomitant use of drugs with neurotoxic, hematotoxic, or cardiotoxic effects may increase the toxicity of interferons
  • Avoid simultaneous administration of ACTIMMUNE with other heterologous serum protein or immunological preparations (eg, vaccines)

ADVERSE REACTIONS

  • The most common adverse experiences occurring with ACTIMMUNE therapy are “flu-like” symptoms such as fever, headache, chills, myalgia, or fatigue, which may decrease in severity as treatment continues, and may be minimized by bedtime administration of ACTIMMUNE. Acetaminophen may be used to prevent or partially alleviate the fever and headache
  • Isolated cases of acute serious hypersensitivity reactions have been observed in patients receiving ACTIMMUNE
  • Reversible neutropenia, thrombocytopenia, and elevations of AST and/or ALT have been observed during ACTIMMUNE therapy
  • At doses 10 times greater than the weekly recommended dose, ACTIMMUNE may exacerbate pre-existing cardiac conditions, or may cause reversible neurological effects such as decreased mental status, gait disturbance, and dizziness