Definition/General
Introduction:
Chronic granulomatous disease (CGD) is a rare primary immunodeficiency disorder characterized by defective neutrophil and macrophage function
It results from mutations in NADPH oxidase complex genes leading to inability to generate reactive oxygen species
The disease predisposes to recurrent infections and granuloma formation.
Origin:
Results from mutations in NADPH oxidase components: gp91phox (CYBB gene, X-linked), p22phox (CYBA gene), p47phox (NCF1 gene), p67phox (NCF2 gene), and p40phox (NCF4 gene)
The defect prevents respiratory burst in phagocytes
Leads to inability to kill catalase-positive organisms.
Classification:
Classified by genetic subtype: X-linked CGD (gp91phox deficiency, 65% cases)
Autosomal recessive CGD: p47phox deficiency (25% cases), p22phox deficiency (5% cases), p67phox deficiency (5% cases)
Classical vs variant forms based on residual oxidase activity.
Epidemiology:
Incidence approximately 1 in 200,000-250,000 births
X-linked form most common (65%)
Male predominance in X-linked form
Equal gender distribution in autosomal recessive forms
Earlier diagnosis improving outcomes.
Clinical Features
Presentation:
Recurrent bacterial and fungal infections
Granulomatous inflammation
Lymphadenopathy and hepatosplenomegaly
Pulmonary infections (Aspergillus)
Skin and soft tissue abscesses
Gastrointestinal granulomas.
Symptoms:
Recurrent pneumonia and abscesses
Staphylococcal and Aspergillus infections
Granulomatous colitis
Osteomyelitis
Lymphadenitis
Growth retardation
Chronic diarrhea.
Risk Factors:
Family history of recurrent infections
Male gender (X-linked form)
Consanguineous parents
Early onset pneumonia
Granulomatous inflammation
Catalase-positive organism infections.
Screening:
Dihydrorhodamine (DHR) test (gold standard)
Nitroblue tetrazolium (NBT) test
Complete blood count (normal neutrophil count)
Genetic testing
Superoxide production assay
Family screening.
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Gross Description
Appearance:
Bone marrow aspirate shows normal cellularity
Normal neutrophil numbers and morphology
Possible reactive changes
No granulomas in bone marrow typically
Normal other lineages.
Characteristics:
Normocellular bone marrow
Morphologically normal neutrophils
Functional defect not morphologically apparent
Reactive lymphoid elements may be present
No specific gross abnormalities.
Size Location:
Lymph nodes enlarged (granulomatous)
Hepatosplenomegaly common
Pulmonary granulomas
Gastrointestinal involvement
Bone marrow architecture normal.
Multifocality:
Systemic granulomatous disease
Multi-organ involvement
Recurrent infections various sites
Chronic inflammatory changes
Progressive organ dysfunction.
Microscopic Description
Histological Features:
Normal bone marrow cellularity and morphology
Normal neutrophil count and appearance
Functional defect requires special testing
Possible reactive lymphoid aggregates
No granulomas in bone marrow.
Cellular Characteristics:
Morphologically normal neutrophils
Normal nuclear segmentation
Normal cytoplasmic granules
Defective respiratory burst (not morphologically evident)
Normal other cell types.
Architectural Patterns:
Preserved bone marrow architecture
Normal cellular distribution
Appropriate maturation patterns
No inflammatory infiltrates
No fibrosis or granulomas.
Grading Criteria:
Severity by DHR test results: Severe (<5% normal activity)
Moderate (5-20% activity)
X-linked form typically severe
Autosomal forms variable severity
Clinical severity correlates with oxidase activity.
Immunohistochemistry
Positive Markers:
MPO highlights normal neutrophils
CD15 marks neutrophils
Elastase shows neutrophil granules
CD68 marks macrophages
Lysozyme in myeloid cells.
Negative Markers:
NADPH oxidase components may be reduced/absent (special staining)
Viral markers typically negative
Abnormal infiltrates not present in bone marrow
Granulomatous markers absent in marrow.
Diagnostic Utility:
Confirms normal neutrophil morphology
Demonstrates adequate neutrophil numbers
Shows normal maturation
Requires functional testing for diagnosis
Excludes morphological neutrophil defects
Guides further testing.
Molecular Subtypes:
X-linked CGD (gp91phox deficient)
p47phox-deficient CGD
p22phox-deficient CGD
p67phox-deficient CGD
p40phox-deficient CGD (rare).
Molecular/Genetic
Genetic Mutations:
CYBB mutations (X-linked, gp91phox)
NCF1 mutations (p47phox deficiency)
CYBA mutations (p22phox deficiency)
NCF2 mutations (p67phox deficiency)
NCF4 mutations (p40phox deficiency)
Large deletions common in NCF1.
Molecular Markers:
Absent or reduced NADPH oxidase activity
Defective superoxide production
Abnormal DHR/NBT tests
Normal neutrophil count
Normal morphology
Specific protein deficiencies.
Prognostic Significance:
X-linked form more severe
p47phox deficiency milder course
Early diagnosis improves outcomes
Prophylactic treatment prevents infections
Gene therapy successful in trials
Bone marrow transplant curative.
Therapeutic Targets:
Antimicrobial prophylaxis (TMP-SMX, itraconazole)
Interferon-gamma (immunomodulatory)
Bone marrow transplantation (curative)
Gene therapy (experimental success)
Aggressive infection treatment.
Differential Diagnosis
Similar Entities:
Leukocyte adhesion deficiency
Myeloperoxidase deficiency
Specific granule deficiency
Hyper-IgE syndrome
Other phagocyte defects
Secondary immunodeficiency.
Distinguishing Features:
CGD: Defective respiratory burst
CGD: Normal neutrophil morphology
CGD: Granulomatous inflammation
LAD: Adhesion defects
LAD: High neutrophil counts
MPO deficiency: Absent peroxidase
MPO deficiency: Usually asymptomatic
HIES: Elevated IgE.
Diagnostic Challenges:
Confirming functional defect
Identifying genetic subtype
Distinguishing from other phagocyte defects
Carrier detection
Prenatal diagnosis
Treatment optimization.
Rare Variants:
Variant CGD with residual activity
Late-onset CGD
McLeod phenotype (associated)
Inflammatory bowel disease predominant
Autoimmune manifestations.
Sample Pathology Report
Template Format
Sample Pathology Report
Complete Report: This is an example of how the final pathology report should be structured for this condition.
Specimen Information
Bone marrow aspirate and biopsy from [site], adequate for evaluation
Diagnosis
Chronic Granulomatous Disease (Suspected)
Classification
Classification: Primary immunodeficiency with neutrophil dysfunction
Bone Marrow Cellularity
Cellularity: [X]% for age (normal), with morphologically normal neutrophils
Lineage Assessment
Granulopoiesis: normal count and morphology. Erythropoiesis: normal. Megakaryopoiesis: normal
Morphological Features
Shows normal bone marrow with adequate, morphologically normal neutrophils
Special Studies
Functional testing: recommend DHR/NBT test
Genetic testing: recommend CGD gene panel
Clinical correlation: recurrent infections, granulomas
Clinical Correlation
Normal bone marrow morphology. Functional testing required for CGD diagnosis
Final Diagnosis
Bone marrow morphology normal. Clinical suspicion of chronic granulomatous disease requires functional confirmation