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Hyper-IgE syndrome

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aliasesJob syndrome, hyperimmunoglobulin E syndrome

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  • Definition: defect in neutrophil chemotaxis
  • Etiology
    • Autosomal Dominant mutation in STAT3 gene.
    • Defect leads to deficiency in Th17 cells and impaired production of IL-17.
    • Consequence: Impaired neutrophil recruitment (chemotaxis) to sites of infection.
    • Th17/Th2 Imbalance:
      • Th17 cells normally help regulate and suppress excessive Th2 immune responses.
      • STAT3 deficiency prevents Th17 differentiation loss of inhibition on Th2 cells.
      • Result is a compensatory skew towards a Th2-dominant response.
    • Cytokine Dysregulation:
      • Excess Th2 activity leads to overexpression of specific cytokines:
        • ↑ IL-4: Drives B-cells to class switch to IgE.
        • ↑ IL-5: Stimulates growth, differentiation, and activation of Eosinophils.
        • ↑ IL-13: Contributes to IgE production and allergic inflammation (eczema).
  • Clinical features
    • Mnemonic: FATED
      • Facies: Coarse features (broad nose, deep-set eyes, prominent forehead, doughy skin).
      • Abscesses: Recurrent “cold” staphylococcal abscesses (lack heat/warmth due to poor neutrophil influx). c
        • Failure to recruit neutrophils lack of inflammatory inflammation (heat/redness).
      • Teeth: Retained primary teeth (failure to exfoliate), leading to double rows of teeth.
        • STAT3 defect impaired osteoclast function inability to resorb primary tooth roots.
      • Elevated IgE.
      • Dermatologic: Severe eczema (atopic dermatitis). c
        • Th2 cytokines + ↓ antimicrobial peptides (defensins) barrier breakdown and chronic S. aureus colonization.
    • Recurrent Infections: Sinopulmonary infections (pneumonia) often leading to pneumatocele formation.
    • Skeletal: Bone fragility, recurrent fractures, scoliosis/hyperextensibility.
  • Diagnosis
    • Initial / Key Labs:
      • Serum IgE: Markedly elevated (typically > 2,000 IU/mL, frequently > 10,000 IU/mL).
      • CBC: Prominent eosinophilia (peripheral blood and tissue). c
      • Other Igs (IgG, IgA, IgM): Usually normal (mild variations possible).
    • Imaging:
      • CXR / Chest CT: Detects lung consolidation, abscesses, and characteristic pneumatoceles.
      • Skeletal X-rays: Evaluates scoliosis, osteopenia, and cortical bone thinning/fractures.
    • Confirmatory / Gold Standard:
      • Genetic testing: Mutation analysis identifying STAT3 (AD) or DOCK8 (AR) mutations.
  • Differential diagnostics
    • Wiskott-Aldrich Syndrome (WAS):
      • Diff by: X-linked recessive (WAS mutation), presentation with microthrombocytopenia (small platelets, low MPV, petechiae/bleeding), and atopic dermatitis. Serum IgE can be elevated, but platelet abnormalities are absent in Hyper-IgE.

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