Sex: affects mostly males (as most mutations are X-linked)
Age of Presentation: most cases present in pediatric population
Approximately 76% of Cases are Diagnosed Before Age 5
Approximately 10% of Cases are Diagnosed in Second Decade of Life (Teens)
However, the Clinical Presentation Can Vary Considerably and the Age of First Severe Infection May Occur in Adulthood
Age of Onset Varies with Genetics: for unclear reasons, autosomal recessive variants have later age of onset than X-linked variants
Disease Associations
In Contrast to Many Other Immunodeficiency States, Chronic Granulomatous Disease is Not Believed to Be Associated with an Increased Risk of Neoplasia
Genetics and Etiology
X-Linked Recessive
Frequency: accounts for 65% of cases
Defects
Defect in NADPH Oxidase 91-kDa Plasma Membrane Subunit
Involved in Forming the b-558 Heterodimeric Cytochrome Plasma Membrane Protein
Clinical Manifestations
X-Linked Pattern of Inheritance Has Earlier Onset of Disease, More Severe Clinical Manifestations, and Higher Mortality Rate Than the Autosomal Recessive Pattern of Inheritance: for unclear reasons
Autosomal Recessive
General Comments
Frequency: accounts for 35% of cases
Defects
Defect in NADPH Oxidase 22-kDa Plasma Membrane Subunit
Accounts for <5% of All CGD Cases
Involved in Forming the b-558 Heterodimeric Cytochrome Plasma Membrane Protein
Defect in NADPH Oxidase 40-kDa Cytoplasmic Subunit
Defect in this Gene Has Been Associated with Severe Inflammatory Bowel Disease in a Single Child with Impaired Respiratory Burst Activity
Defect in NADPH Oxidase 47-kDa Cytoplasmic Subunit
Accounts for 25% of All CGD Cases
Involved in Forming a Cytoplasmic Protein, Which Interacts with the Cytochrome Following Cell Activation
Defect in NADPH Oxidase 67-kDa Cytoplasmic Subunit
Accounts for <5% of All CGD Cases
Involved in Forming a Cytoplasmic Protein, Which Interacts with the Cytochrome Following Cell Activation
Clinical Manifestations
Autosomal Recessive Pattern of Inheritance Has Later Onset of Disease, Less Severe Clinical Manifestations, and Lower Mortality Rate Than the X-Linked Recessive Pattern of Inheritance: for unclear reasons
Physiology
Defective NADPH Oxidase in Neutrophil and Mononuclear Phagocytes
Impaired Respiratory Burst Oxidase Activity, Resulting in Impaired Hydrogen Peroxide (H2O2) Synthesis (Hydrogen Peroxide and Chloride are Substrates for Neutrophil and Mononuclear Phagocyte Myeloperoxidase, Resulting in the Synthesis of Hypochlorite, Which Has a Bactericidal Effect)
Inability to Defend Against a Specific Subset of Catalase-Positive Organisms: catalase allows organisms to degrade their own hydrogen peroxide
Intact Defense Against Streptococcus: as this organism produces hydrogen peroxide, providing the phagocyte with the oxidant which it is unable to synthesize
Excessive Inflammatory Reaction: due to abnormal inability to degrade antigens and chemoattractants -> inability to turn off local inflammatory process
Granuloma Formation: due to impaired killing of intracellular organisms by macrophages
Diagnosis
Nitroblue Tetrazolium Test (NBT)
Older Test: no longer used in many labs
Nitroblue Tetrazolium Test: abnormal
Failure of the patient’s activated neutrophils to reduce NBT is virtually pathognomonic of CGD
False-Positive Test
Positive NBT test can also be seen in very severe glucose-6-phosphate dehydrogenase deficiency (these patients will also have severe hemolytic anemia) (see Glucose-6-Phosphate Dehydrogenase Deficiency)
Technique: patient’s neutrophils are incubated with catalase + dihydrorhodamine 123 (DHR), then stmulated with the mitogen, phorbol 12-myristate 13-acetate (PMA) -> DHR oxidation to rhodamine is assessed using flow cytometry, giving a stimulation index (index of stimulated vs unstimulated cells)
Immunoblot (Western Blot) of Neutrophil Proteins
Confirmatory Test: elucidates the specific missing subunit
Unresolved Issues Related to Stem Cell Transplantation
Proper Degree of Immune Ablation Prior to Stem Cell Transplant
Proper Degree of T-cell Depletion of the Allograft
Appropriate Prophylaxis to Prevent Graft vs Host Disease (see Graft vs Host Disease)
Gene Therapy
Experimental
Prognosis
Mortality Rate: with current prophylaxis, mortality has decreased to 2 deaths per 100 patients per year, with life expectancy extended well into adulthood
Insurability
In California, Children with Pre-Existing Conditions Cannot Be Denied Coverage
Children Can Currently Remain on Their Parents Insurance Coverage Until Age 26
California Children’s Services (CCS): children up to age 21 can get health care (provided that their parents meet the financial criteria of income <$40k per year, medical expenses >20% of family’s adjusted gross income, or qualifications for Medi-Cal with full benefits or Healthy Families Insurance)
References
Invasive pulmonary infection due to Scedosporium apiospermum in two children with chronic granulomatous disease. Clin Infect Dis. 1998;27(6):1437 [MEDLINE]
