A 4-year-old boy with a history of recurrent Staphylococcal and Aspergillus infections since infancy is found to have a negative dihydrorhodamine (DHR) flow cytometry test. NBT (nitroblue tetrazolium) test is negative. Genetic testing reveals a mutation in the CYBB gene (encoding gp91phox). What is the fundamental mechanism of the immunodeficiency?

• A CYBB mutation impairs myeloperoxidase secretion into phagolysosomes, preventing halide-dependent killing
• B Absent gp91phox prevents neutrophil chemotaxis by disabling integrin signalling via reactive oxygen species
• C CYBB mutation prevents granule fusion with phagolysosomes (degranulation defect) as in Chediak-Higashi syndrome
• D Absent or non-functional gp91phox prevents assembly of the NADPH oxidase complex (NOX2), eliminating the respiratory burst and superoxide production required for intracellular killing of catalase-positive organisms ✓

Explanation

Chronic granulomatous disease (CGD) is caused by mutations in CYBB (X-linked, most common) encoding gp91phox, or in other NOX2 subunits (NCFA/B, p47phox, p67phox). gp91phox is the transmembrane catalytic subunit of the NADPH oxidase (NOX2) complex. Without it, activated phagocytes cannot transfer electrons from NADPH to molecular oxygen, preventing superoxide (O2-) generation and the subsequent formation of hydrogen peroxide, hypochlorous acid (via MPO), and other ROS necessary for killing catalase-positive pathogens (Staph. aureus, Aspergillus spp., Serratia, Nocardia, Burkholderia). Myeloperoxidase is intact; chemotaxis is unaffected; granule fusion (as in Chediak-Higashi) is a separate defect involving LYST gene.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.