Clinical Presentation

Hyper-IgE Syndrome with STAT3 Mutation

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Note:
  • Clinical features have been observed to accumulate over time as affected children get older, hence, any diagnostic algorithm is likely to underdiagnose young patients

Hyper-IgE Syndrome with DOCK8 Mutation

  • DOCK8 encodes a protein implicated in the regulation of the actin cytoskeleton; most of the patients with DOCK8 deficiency lack DOCK8 protein expression
  • Atopy, immunologic basis remains to be defined
    • Atopic dermatitis (~90%)
    • Asthma (~45%)
    • Allergies (~65%) including food allergy
  • Viral Infections (~90%), extremely difficult to treat and often are disfiguring
    • HPV-associated flat and verrucous warts (~30%)
    • Orolabial, anogenital, corneal HSV (~50%)
    • Molluscum contagiosum virus (~40%)
    • Severe varicella or herpes zoster (~20%)
  • Other infections
    • Respiratory tract infections (>90%)
    • Bacterial skin infections (~80%)
    • Mucosal or nail candidiasis (~70%)
  • Represents a combined immune deficiency
    • High IgE, IgG, IgA
    • Low IgM, IgA
    • Eosinophilia
    • Lymphopenia (CD4>CD8>NK cell>B cell)
  • High incidence of malignancy: squamous cell CA (~15%) and lymphoma (~10%)
  • Immune reconstitution may be the most appropriate therapeutic approach but the data are premature in terms of outcome


Elevated IgE Differential Diagnosis


Hyper-IgE Syndromes vs AD

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  • The profile of low percentages of CD3+, CD4+, and naïve CD8+ T cells (CD45RA+/CCR7+) along with a normal total B cell percentage but low percentages of memory B cells (CD27+/IgD- and CD27+/IgD+) is strongly associated with DOCK8 deficiency (vs. severe AD)


Diagnosis

Hyper-IgE Syndrome with STAT3 Mutation

  • Transmitted as an autosomal-dominant trait, thus, a positive family history contributes to the risk of having HIES
  • Diagnostic guidelines for STAT3-mutant HIES
Possible
IgE ≥1000 IU/mL plus a weighted score of clinical features >30 (see STAT3-Score worksheet below) based on recurrent pneumonia, newborn rash, pathologic bone fractures, characteristic face, and high palate
Probable
These characteristics plus lack of TH17 cells or a family history for definitive HIES
Definitive-------
These characteristics plus a dominant-negative heterozygous mutation in STAT3

STAT3-Score
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IL-17 from T helper
  • STAT3 is required to induce CD4+ T cells to produce IL-17, a cytokine that is important for the elicitation of an effective immune response to several bacteria and fungi.
  • T helper IL-17 functional assay measures the ability of CD4+ T cells to make IL-17 (which is defective in patients with HIES)


Hyper-IgE Syndrome with DOCK8 Mutation

  • Lymphocyte subset profile is suggestive (see above)
  • Since most of the patients with DOCK8 deficiency lack DOCK8 protein expression the diagnostic approach is immunoblotting for DOCK8 in cell lysates followed by confirmatory sequencing of the DOCK8 gene
  • Analysis for gross DNA deletions by an exon-level microarray complete genome hybridization (CGH) test
  • Flow cytometry assay for DOCK8 expression using a commercially available mAb to DOCK8
    • Caveats: may not be useful for testing shipped blood samples in which extensive degradation of normal DOCK8 protein can occur, and may not be useful in the few DOCK8 deficient patients with a missense mutation in DOCK8 and near normal expression of the mutant DOCK8 protein



References