Bit · Rheum/Immuno
CGD vs Chediak-Higashi vs Job vs LAD
Four phagocyte disorders. Children with recurrent bacterial and fungal infections, but each has a signature defect — kill the bug, get to the bug, hold the immune response together.
Mechanism
The phagocyte's job has three steps: migrate to the site, phagocytose, then kill. Each disorder breaks a different step:
- Chronic Granulomatous Disease (CGD) — defect in NADPH oxidase → neutrophils can't make the respiratory burst (no H₂O₂, no hypochlorite). They engulf bacteria but can't kill them. Recurrent infections by catalase-positive organisms (S. aureus, Aspergillus, Burkholderia, Serratia, Nocardia) — because catalase-negative organisms supply their own H₂O₂ for the host to use, but catalase-positive ones destroy it. Granulomas form because chronic infection drives macrophage activation. Diagnosis: dihydrorhodamine (DHR) flow cytometry test (modern) or nitroblue tetrazolium (older).
- Chédiak-Higashi syndrome — autosomal recessive defect in LYST gene → impaired lysosomal trafficking. Giant abnormal granules in neutrophils (and other cells). Triad: partial albinism, recurrent pyogenic infections, peripheral neuropathy, plus mild coagulation defects. Many patients develop an accelerated lymphoma-like phase.
- Job syndrome (Hyper-IgE / Autosomal Dominant Hyper-IgE Syndrome) — defect in STAT3 → impaired Th17 differentiation → impaired neutrophil recruitment. Classic findings: coarse facies, retained primary teeth, cold skin abscesses (no warmth or redness), chronic eczema, very high IgE, eosinophilia. Recurrent staph infections, especially skin/lung.
- Leukocyte Adhesion Deficiency (LAD) — type 1 is defect in CD18 (β2 integrin) → neutrophils can't adhere to endothelium and exit the vessel. Delayed separation of umbilical cord (>30 days), recurrent skin/mucosal infections without pus, marked neutrophilia in blood (neutrophils stuck in vessels).
Differentiator Table
| CGD | Chédiak-Higashi | Job (Hyper-IgE) | LAD | |
| Defect | NADPH oxidase (no respiratory burst) | LYST gene (lysosomal trafficking) | STAT3 (Th17 defect) | CD18 (β2 integrin) |
| Inheritance | X-linked (most common) or AR | Autosomal recessive | Autosomal dominant | Autosomal recessive |
| Step affected | KILL | Phagolysosome fusion | Recruit (Th17 / neutrophils) | ADHESION / migration |
| Hallmark infections | Catalase-positive (S. aureus, Aspergillus, Serratia, Burkholderia, Nocardia) | Recurrent pyogenic (S. aureus, strep) | S. aureus (cold abscesses), Candida, recurrent pneumonia (pneumatoceles) | Recurrent bacterial without pus |
| Distinctive features | Granulomas (chronic infection), DHR-flow positive, abnormal NBT | Partial albinism, peripheral neuropathy, giant granules in PMNs, accelerated phase | Coarse 'leonine' facies, retained baby teeth, ↑ IgE, eczema, eosinophilia, scoliosis, fractures | Delayed umbilical cord separation (>30 days), no pus, marked neutrophilia in blood |
| Lab clue | DHR / NBT test abnormal | Giant granules on smear | Serum IgE > 2000 IU/mL, eosinophilia | Marked peripheral neutrophilia |
| Treatment | TMP-SMX + itraconazole prophylaxis, IFN-γ; HSCT | HSCT | TMP-SMX prophylaxis; treat infections | HSCT |
The Pivot
Three questions usually decide it:
- Catalase-positive infections + granulomas + abnormal DHR test? → CGD.
- Partial albinism + peripheral neuropathy + giant granules? → Chédiak-Higashi.
- Coarse facies + retained teeth + high IgE + cold abscesses? → Job.
- Delayed cord separation + no pus + high blood neutrophils? → LAD.
NBME-Style Stem
A 4-year-old boy presents with recurrent staphylococcal abscesses, pneumonia (with pneumatocele formation), and severe eczema. Examination shows a broad nose, prominent forehead, and retention of his primary teeth. Serum IgE is 4,800 IU/mL. Eosinophil count is elevated. Which of the following is the most likely diagnosis?
Concept Anchor
Three steps in phagocyte work, three different breakdowns. CGD can't kill (NADPH oxidase); Chédiak can't traffic lysosomes (giant granules); LAD can't get out of the vessel (no adhesion); Job can't recruit neutrophils (Th17 defect). The clinical signature on each disorder gives away which step is broken.