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Review
. 2009 May;65(5 Pt 2):32R-37R.
doi: 10.1203/PDR.0b013e31819dc8c5.

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

Alexandra F Freeman  1 , Steven M Holland
Affiliations
Review

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

Alexandra F Freeman et al. Pediatr Res. 2009 May.

Abstract

Autosomal dominant Hyper-IgE syndrome (AD-HIES) is a rare primary immunodeficiency characterized by eczema, recurrent skin and lung infections, elevated serum IgE, and various connective tissue, skeletal, and vascular abnormalities. Mutations in signal transducer and activator of transcription 3 (STAT3) have recently been found to account for most cases; however, the pathogenesis of the varied features remains poorly defined. A distinct syndrome, known as autosomal recessive HIES (AR-HIES) manifests as severe eczema, recurrent bacterial and viral skin infections, and sinopulmonary infections. As opposed to STAT3 deficient HIES, AR-HIES lacks the connective tissue and skeletal manifestations but has an increase in neurologic abnormalities. In this review, we discuss the clinical presentations, genetic etiologies, and immunologic abnormalities of these two syndromes. In addition, we discuss animal models of STAT3 deficiency that provide insight into the pathogenesis of HIES. Further understanding of how STAT3 results in the diverse manifestations of HIES will allow us to develop more specific therapies for HIES as well as for many of the manifestations, such as scoliosis, recurrent staphylococcal infections, and eczema, which are common in the general population.

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Figures

Figure 1
Figure 1
Chest CT of an individual with AD-HIES showing pneumatocoeles complicated by aspergilloma.
Figure 2
Figure 2
Cervical spine X-ray of a 48 year old with AD-HIES showing severe degenerative spine disease.
Figure 3
Figure 3
Brain MRI of a 21 year old with AD-HIES showing multiple focal hyperintensities.
Figure 4
Figure 4
STAT3 signaling pathway. Multiple cytokines, including Il-6, IL-10, IL-21, IL-22, and IL-23 activate STAT3 phosphorylation. Dimerized STAT3 enters the nucleus to affect transcription of various genes. STAT3 can also dimerize with other STATs. Normal STAT3 signaling leads to the upregulation and down regulation of the cytokines shown in the right lower corner. IL-10 and SOCS (suppressors of cytokine signaling) can downregulate STAT3 activity.
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