Immune deficiencies, infection, and systemic immune disorders
Diagnostic approach to the hyper-IgE syndromes: Immunologic and clinical key findings to differentiate hyper-IgE syndromes from atopic dermatitis

https://doi.org/10.1016/j.jaci.2010.06.029Get rights and content

Background

Hyper-IgE syndromes (HIES) are primary immunodeficiency disorders characterized by Staphylococcus aureus abscesses, recurrent pneumonia, increased serum IgE levels, and eczema. The association of heterozygous signal transducer and activator of transcription 3 (STAT3) mutations with autosomal dominant (AD)–HIES allows the differentiation of AD-HIES from disorders associated with eczema and increased serum IgE levels, such as other primary immunodeficiencies and atopic dermatitis.

Objective

To facilitate early diagnosis of AD-HIES to initiate appropriate therapy.

Methods

The clinical phenotype (suggested by a National Institutes of Health [NIH] score of ≥40 points), STAT3 genotype, and TH17 cell counts were compared in a cohort of 78 patients suspected of having HIES.

Results

Heterozygous STAT3 missense mutations and in-frame deletions were identified in 48 patients, all but 2 with an NIH score ≥40 points. Patients with STAT3 mutations with HIES showed significantly lower TH17 cell counts compared with patients with wild-type STAT3 and control subjects. Only 1 patient with wild-type STAT3 had both an NIH score ≥40 points and abnormal TH17 cell counts (≤0.2% of CD4+ cells), with this exception being identified with a homozygous dedicator of cytogenesis 8 protein (DOCK8) mutation. Pathologic shedding of primary teeth was present in 3 patients with wild-type STAT3 and 33 patients with STAT3 mutations. Internal abscesses and severe infections were exclusively seen in patients with STAT3 mutations, who also had increased pneumatocele formation and skeletal or connective tissue manifestations compared with patients with wild-type STAT3.

Conclusion

We expanded the number of STAT3 mutations and validated that the NIH score sensitively identifies patients with HIES. Based on our patient cohort, we propose key findings that, when combined with TH17 cell numbers, predict patients with AD-HIES with STAT3 mutations, supporting early diagnosis of AD-HIES.

Section snippets

Subjects

We enrolled 78 patients (50 male and 28 female patients; age range, 8 months to 57 years; median age, 20 years) from 75 unrelated families with diverse ethnic backgrounds. Participants were selected from a group of patients referred to our clinics for possible HIES based on increased serum IgE levels, eczema, staphylococcal infections, no other well-defined PIDD, and NIH scores of greater than 20 points, except for 3 patients with an NIH score as low as 14 points. The original source of

Mutation analysis

All 78 patients enrolled were evaluated for mutations in STAT3. Forty-eight patients from 45 unrelated families were found to have heterozygous STAT3 mutations. The spectrum includes 7 novel and 17 previously reported mutations.8, 9, 10, 11, 12 Six of the 7 novel mutations were missense mutations located in the DNA-binding domain (995 A>T, H332L; 1406 A>G, Q469R), Src homology domain 2 (SH2; 1850 G>A, G617E; 1979 T>C, M660T), and the transactivation domain (2129 T>C, F710C; 2132 T>C, I711T).

Discussion

Some of the most common clinical findings observed in patients with HIES, such as eczema, increased serum IgE levels, and recurrent skin infections, overlap with those associated with other PIDD as well as with severe forms of atopic dermatitis. Because of the discovery that AD-HIES is caused by STAT3 mutations, we correlated the STAT3 genotype with the clinical and laboratory findings of patients suspected of having HIES to determine the most effective screening criteria to predict which

References (34)

  • C. Koga et al.

    Possible pathogenic role of Th17 cells for atopic dermatitis

    J Invest Dermatol

    (2008)
  • K. Eyerich et al.

    Patients with chronic mucocutaneous candidiasis exhibit reduced production of Th17-associated cytokines IL-17 and IL-22

    J Invest Dermatol

    (2008)
  • A.F. Freeman et al.

    Clinical manifestations, etiology, and pathogenesis of the hyper IgE syndromes

    Pediatr Res

    (2009)
  • R.H. Buckley et al.

    Extreme hyperimmunoglobulinemia E and undue susceptibility to infection

    Pediatrics

    (1972)
  • B. Grimbacher et al.

    Hyper-IgE syndrome with recurrent infections—an autosomal dominant multisystem disorder

    N Engl J Med

    (1999)
  • Q. Zhang et al.

    Combined Immunodeficiency Associated with DOCK8 Mutations

    N Engl J Med

    (2009)
  • K.R. Engelhardt et al.

    Large deletions and point mutations involving the dedicator of cytokinesis 8 (DOCK8) in the autosomal-recessive form of hyper-IgE syndrome

    J Allergy Clin Immunol

    (2009)
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    Data included in this publication are part of a medical thesis at the School of Medicine, Ludwig Maximilians University, Munich (L. F. S.). This work was supported by National Institutes of Health grant AI063267-01 and USIDnET grant N01A130070 (T. R. T.), National Institutes of Health grant HD017427-41 and grants from the Jeffrey Modell and Immune Deficiency Foundations (H. D. O.), and the Fritz-Thyssen Foundation (Az. 10.07.1.159) and Ludwig Maximilians University FöFoLe grant (no. 680/658) (E. D. R.).

    Disclosure of potential conflict of interest: A. Wollenberg receives research support from Merck Pharma GMBH. J. Reichenbach receives research support from the Chronic Granulomatous Disorder Research Trust UK. H. D. Ochs receives research support from the National Institutes of Health and the Jeffrey Modell Foundation. T. R. Torgerson is on the scientific advisory board for Baxter Biotherapeutics; receives research support from the National Institutes of Health, CSL Behring, and the Jeffrey Modell Foundation; and is on the medical advisory committee for the Immune Deficiency Foundation. E. D. Renner receives honorarium from the American Academy of Allergy, Asthma & Immunology and receives research support from the Fritz Thyssen Foundation. The rest of the authors have declared that they have no conflict of interest.

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