What X-linked recessive disease is characterized by granuloma formation due to the inability of neutrophils, monocytes, and eosinophils to kill microorganisms after normal engulfment?

Chronic Granulomatous Disease is the X-linked Recessive Disease Characterized by Granuloma Formation Due to Defective Microbial Killing

The answer is B. Chronic granulomatous disease. This X-linked recessive disease is characterized by granuloma formation resulting from the inability of neutrophils, monocytes, and eosinophils to kill microorganisms after normal engulfment 1.

Pathophysiology of Chronic Granulomatous Disease (CGD)

CGD is a phagocytic cell defect that presents with:

• Severe pyogenic bacterial and fungal infections affecting the respiratory tract, skin, and viscera
• Granuloma formation in multiple organs
• Gingivostomatitis

The fundamental defect in CGD is in the NADPH oxidase complex, which is responsible for the respiratory burst in phagocytes. This leads to:

1. Normal engulfment of microorganisms by phagocytes
2. Inability to generate reactive oxygen species (ROS) needed to kill the engulfed pathogens
3. Formation of granulomas as the body attempts to contain the unresolved infections

Genetic Basis

• X-linked recessive form (XR-CGD): Most common form (approximately 70% of cases) 2

  • Caused by mutations in the CYBB gene on the X chromosome
  • Encodes the gp91(phox) protein component of NADPH oxidase

• Autosomal recessive forms (AR-CGD): Less common

  • Caused by mutations in CYBA, NCF1, NCF2, or NCF4 genes 2, 3
  • These genes encode other components of the NADPH oxidase complex (p22phox, p47phox, p67phox, and p40phox)

Clinical Manifestations

• Recurrent severe bacterial and fungal infections beginning in early childhood
• Granuloma formation in multiple organs (lungs, liver, GI tract)
• Abscesses in skin, liver, lungs, and bones
• Lymphadenopathy
• Osteomyelitis
• Pneumonia
• Septicemia

Diagnostic Testing

The diagnosis of CGD is based on demonstrating the inability of phagocytes to generate reactive oxygen species:

• Dihydrorhodamine (DHR) flow cytometry test: Shows absent or reduced oxidative burst in neutrophils 4
• Nitroblue tetrazolium (NBT) test: Remains colorless in CGD patients (normally turns blue in activated neutrophils) 4
• Genetic testing to identify the specific mutation

Treatment Approach

1. Prophylactic antimicrobials:

   • Antibacterial (trimethoprim-sulfamethoxazole)
   • Antifungal (itraconazole)

2. Interferon-gamma therapy:

   • Enhances macrophage function and oxidative metabolism 5
   • Does not increase phagocyte superoxide production but improves clinical outcomes

3. Aggressive treatment of acute infections with appropriate antibiotics and antifungals

4. Hematopoietic stem cell transplantation (HSCT):

   • Only curative treatment option 1, 2
   • Can reverse organ dysfunction

5. Gene therapy:

   • Emerging approach for patients without matched donors 2
   • Uses lentiviral vectors targeting gp91(phox) expression

Differential Diagnosis

• Pelger–Huët anomaly: A benign inherited disorder affecting neutrophil nuclear morphology, not associated with granuloma formation
• Chédiak–Higashi disease: Autosomal recessive disorder with partial albinism, recurrent infections, and giant granules in leukocytes
• Alder–Reilly syndrome: Characterized by abnormal granulation of leukocytes, not associated with defective microbial killing

Prognosis

With modern treatment approaches including prophylactic antimicrobials, interferon-gamma, and early aggressive treatment of infections, survival has improved significantly, with many patients reaching adulthood 2. HSCT offers the potential for cure in suitable candidates.