Hyper-IgE Syndrome (Job's Syndrome)

Hyper-IgE syndrome is a rare primary immunodeficiency characterized by recurrent infections, eczema, and markedly elevated serum IgE levels.

Key Points:

• Two main types:
  • Autosomal Dominant (AD-HIES, STAT3 deficiency)
  • Autosomal Recessive (AR-HIES, DOCK8 deficiency)
• Classic triad:
  • Recurrent staphylococcal abscesses
  • Pneumonia with pneumatocele formation
  • Elevated serum IgE (>2000 IU/mL)

Clinical Manifestations

Immunologic Features:

• Skin Manifestations:
  • Newborn rash (often first sign)
  • Eczema (severe and chronic)
  • "Cold" abscesses (minimal inflammation)
  • Mucocutaneous candidiasis
• Respiratory Tract:
  • Recurrent pneumonia
  • Pneumatocele formation
  • Bronchiectasis
  • Aspergillus infections
• Other Infections:
  • Sinusitis
  • Otitis media
  • Oral/esophageal candidiasis

Non-Immunologic Features (AD-HIES):

• Facial Features:
  • Coarse facies
  • Broad nasal bridge
  • Deep-set eyes
  • Asymmetric facial features
• Skeletal Abnormalities:
  • Retained primary teeth
  • Pathologic fractures
  • Scoliosis
  • Joint hyperextensibility
• Vascular Abnormalities:
  • Coronary artery aneurysms
  • Arterial tortuosity

Diagnostic Approach

Laboratory Studies:

• Immunologic Testing:
  • Serum IgE (>2000 IU/mL)
  • Eosinophilia
  • Specific antibody responses
  • Lymphocyte subsets
• Genetic Testing:
  • STAT3 sequencing (AD-HIES)
  • DOCK8 sequencing (AR-HIES)

NIH Scoring System:

• Clinical features scored:
  • Pneumonia
  • Newborn rash
  • Pathologic fractures
  • Characteristic face
  • High palate
  • Retained primary teeth
  • Scoliosis
  • Infections
  • Eczema
• Laboratory features scored:
  • High serum IgE
  • Eosinophilia

Imaging Studies:

• Chest imaging (pneumatoceles)
• Skeletal surveys
• Brain MRI (if needed)
• Dental X-rays

Treatment and Management

Infection Prevention and Control:

• Prophylactic Antibiotics:
  • Anti-staphylococcal coverage
  • Antifungal prophylaxis
• Immunoglobulin Replacement:
  • IVIG if indicated
  • Monitor trough levels
• Skin Care:
  • Regular bleach baths
  • Topical antimicrobials
  • Moisturizers

Management of Complications:

• Respiratory:
  • Aggressive treatment of infections
  • Pulmonary rehabilitation
  • Surgery for pneumatoceles if needed
• Musculoskeletal:
  • Fracture prevention
  • Physical therapy
  • Vitamin D supplementation
• Dental:
  • Regular dental care
  • Timely extraction of primary teeth

Genetics and Pathophysiology

Genetic Basis:

• AD-HIES:
  • STAT3 mutations
  • Role in multiple cytokine pathways
  • Impact on Th17 cell development
• AR-HIES:
  • DOCK8 mutations
  • Affects T cell function
  • Impairs immune synapse formation

Pathophysiologic Mechanisms:

• Immune Dysfunction:
  • Impaired neutrophil chemotaxis
  • Defective antimicrobial responses
  • Abnormal inflammatory responses
• Tissue Effects:
  • Connective tissue abnormalities
  • Bone remodeling defects
  • Delayed wound healing