Immunology · Year 2 · from Immunology
Case 2: Job Syndrome (Hyper-IgE Syndrome - STAT3 Deficiency)
Patient Demographics
- Age: 12 years old
- Sex: Female
- Ethnicity: Caucasian
Chief Complaint
Recurrent skin abscesses and pneumonia
History of Present Illness
A 12-year-old girl is referred for evaluation of recurrent Staphylococcus aureus skin abscesses and two episodes of pneumonia. Her mother notes that the skin abscesses are unusual - they are large but do not seem very red or painful ("cold abscesses"). She has had eczema since infancy. Her first pneumonia at age 8 resulted in a residual lung cyst that is still present.
Past Medical History
- Eczema since infancy (severe, requiring topical steroids)
- Recurrent skin abscesses since age 2 (Staph aureus cultured multiple times)
- Pneumonia at ages 8 and 11 (first caused pneumatocele formation)
- Chronic mucocutaneous candidiasis (oral thrush, onychomycosis)
- Retained primary teeth (required extraction of 6 baby teeth)
- Multiple fractures from minimal trauma (arm age 7, leg age 10)
Family History
- No family history of similar symptoms
- Parents are healthy
Physical Examination
- General: Girl with coarse facial features
- Vital Signs: Normal
- HEENT: Coarse facies with broad nasal bridge, wide-set eyes, prominent forehead; oral thrush present
- Skin: Multiple hyperpigmented scars from healed abscesses; one large "cold" abscess on thigh - fluctuant but minimal erythema or warmth
- Lungs: Clear, but imaging shows right lower lobe pneumatocele
- MSK: Hyperextensible joints, mild scoliosis
- Teeth: Several retained primary teeth
Laboratory Workup
| Test | Result | Reference Range |
|---|---|---|
| WBC | 10,500/uL | 4,500-13,500/uL |
| Eosinophils | 18% | 0-4% |
| IgE | 8,500 IU/mL | <100 IU/mL |
| IgG | Normal | -- |
| IgA | Normal | -- |
| IgM | Normal | -- |
| Th17 cells (% of CD4) | 0.2% | 1-2% |
| STAT3 gene | Dominant negative mutation | Wild type |
Clinical Image
Image showing pneumatocele (lung cyst) formation, a characteristic complication of pneumonia in Hyper-IgE syndrome. Image source: Wikimedia Commons (https://commons.wikimedia.org/wiki/File:Pneumatocele1.PNG). Licensed under CC BY-SA 3.0.
Diagnosis
Autosomal Dominant Hyper-IgE Syndrome (Job Syndrome) due to STAT3 dominant negative mutation.
Discussion
Job syndrome (AD-HIES) results from dominant negative mutations in STAT3, causing a multisystem disorder with both immunological and connective tissue manifestations:
Immunological features:
- Markedly elevated IgE (often >2000 IU/mL)
- "Cold" staphylococcal abscesses: Lack the typical inflammatory signs due to impaired neutrophil chemotaxis
- Recurrent pneumonia with pneumatocele formation: Characteristic; cysts persist and can become superinfected with Aspergillus or Pseudomonas
- Chronic mucocutaneous candidiasis: Due to impaired Th17 responses
Why is Th17 important here?
- STAT3 is required for Th17 differentiation
- Th17 cells produce IL-17, which recruits neutrophils and induces epithelial antimicrobial peptides
- Impaired Th17 function leads to susceptibility to Staph aureus and Candida at mucocutaneous surfaces
Non-immunological features (distinguish from other causes of elevated IgE):
- Coarse facies
- Retained primary teeth (failure to resorb roots)
- Hyperextensible joints
- Pathological fractures (osteopenia)
- Scoliosis
- Coronary artery aneurysms (rare)
Treatment
- Prophylactic antibiotics: TMP-SMX for Staph aureus prevention
- Antifungal prophylaxis: For mucocutaneous candidiasis
- Aggressive treatment of infections: Including drainage of abscesses
- Pneumatocele management: Surveillance for superinfection; may require surgical resection
- Skin care: Aggressive eczema management
- Bone health: Calcium, vitamin D supplementation
- Dental care: Monitor for and extract retained primary teeth
- No established definitive therapy: HSCT has been attempted but results are mixed