Dermatologic Manifestations of Job Syndrome

Updated: Jun 09, 2016
  • Author: Robert A Schwartz, MD, MPH; Chief Editor: Dirk M Elston, MD  more...
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Overview

Background

First described in 1966, the hyperimmunoglobulin E (hyper-IgE or HIE) syndrome is a rare immunodeficiency disorder that has an autosomal dominant inheritance pattern. HIE syndrome has variable expressivity and is associated with multiple abnormalities. The most common findings are recurrent skin abscesses (hence, the name Job syndrome), pneumonia with pneumatocele development, and high serum levels of IgE. Facial, dental, and skeletal features are also associated with this syndrome. See the image below.

Father and daughter with autosomal dominant Job sy Father and daughter with autosomal dominant Job syndrome (hyperimmunoglobulin E syndrome). Note the father's distinctive facies with prominent forehead, deep-set eyes, broad nasal bridge, and wide interalar distance.

Although most cases are sporadic, multiplex families displaying autosomal dominant and autosomal recessive inheritance have been described. [1] Autosomal recessive patients tend to have severe molluscum contagiosum and other viral infections and may develop severe neurological complications. These patients also lack skeletal or dental involvement and do not develop lung cysts. Some authorities believe 2 separate syndromes exist, not one.

Type 1 HIE syndrome displays abnormalities in multiple systems, including the skeletal, dental, and immune systems, whereas type 2 HIE syndrome shows abnormalities confined to the immune system. [2] Hypomorphic mutations have been found in the signal transducer and activator of transcription 3 (STAT3) gene in type 1 HIE syndrome and a null mutation in the tyrosine kinase 2 (Tyk2) gene. Cytokine responses in both types of HIE syndrome revealed severe defects leading to impaired T-helper type 17 function. Another study credited deficiency of Th17 cells in HIE syndrome to mutations in STAT3 in a majority of evaluated patients. [3] However, defective Th17 responses may be seen in classic disease without STAT3 mutations, with the extent of the defective Th17 response postulated to determine the clinical phenotype. [4]

Also see the pediatrics article Hyperimmunoglobulinemia E (Job) Syndrome.

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Pathophysiology

The pathophysiology of Job syndrome (HIE syndrome, or hyper-IgE syndrome) is not completely understood. [5] Patients consistently have a poor, delayed hypersensitivity response to antigens. This delayed response is associated with alterations in T-lymphocyte populations and various interleukin and cytokine abnormalities. [6] One of the earliest reports on the pathophysiology of Job syndrome described a chemotactic defect in neutrophils. [7] This defect has since been attributed to defective production of interferon-gamma, a major activator of neutrophils when stimulated by interleukin (IL)–12. The poor production of interferon-gamma in response to IL-12 results in the marked elevation of IgE levels (by means of unopposed IL-4 action). [8]

Other factors in the abnormal immunologic response are described. Patients with HIE syndrome have elevated levels of granulocyte-macrophage colony-stimulating factor, which may also explain the decreased chemotaxis and increased oxygen radical production and tissue damage. [9] Deficient suppressor T-cell numbers and activity and an imbalance in helper T cell type 1 (TH1) and helper T cell type 2 (TH2) also may play a role in an abnormal response. [10]

Although the cytokine dysregulation seems to play a role in its pathophysiology, the causative gene has not yet been identified. [11] In one study, no unique polymorphisms or mutations were found in candidate genes from the toll-like receptor pathway. [12] A significantly large number of immunoglobulin-related genes were found to be up-regulated in this syndrome. Perhaps the distinct patterns may facilitate understanding of its pathophysiology and, possibly, its diagnosis.

The hyper-IgE syndromes have multiple genetic bases. The majority of patients have dominant mutations in the signal transducer and activator of transcription 3 (STAT3) gene STAT3. [13] Autosomal recessive mutations in DOCK8 are linked with the autosomal recessive hyper-IgE syndrome in combination with severe atopic dermatitis, food allergies, and recurrent pneumonias. [14, 15] Dominant-negative mutations in the STAT3 gene have been associated with the classic multisystem form of hyper-IgE syndrome. [16] A novel STK4 mutation has been described in patients with autoimmune cytopenias having features overlapping with those of DOCK-8 deficiency hyper-IgE syndrome. [17]

Hyper-IgE syndrome may be associated with defective salivary activity, which accounts for the enhanced susceptibility of these patients to oral candidiasis. [18]

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Epidemiology

Frequency

Job syndrome (HIE syndrome, or hyper-IgE syndrome) is a rare disorder; about 250 cases have been published.

Race

Job syndrome (HIE syndrome, or hyper-IgE syndrome) occurs in people of diverse ethnic backgrounds and does not seem to be more common in any specific population.

Sex

No sex predilection is reported for Job syndrome (HIE syndrome, or hyper-IgE syndrome).

Age

Job syndrome (HIE syndrome, or hyper-IgE syndrome) usually commences in infancy, but diagnosis is often delayed until childhood or even adulthood.

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Prognosis

Few data are available on the prognosis of patients with Job syndrome (HIE syndrome, or hyper-IgE syndrome). Many Job syndrome patients who are undergoing regular monitoring and receiving appropriate treatment will live beyond the age of 50 years. Death is often due to infectious complications.  The mortality rate is elevated because of systemic infections.

Significant morbidity is associated with Job syndrome (HIE syndrome, or hyper-IgE syndrome). The vast majority of patients have severe cutaneous and pulmonary disease, and most patients have multiple bone fractures and scoliosis.

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Patient Education

Educate patients with Job syndrome (HIE syndrome, or hyper-IgE syndrome) about the importance of recognizing the early signs of infection so that treatment can be initiated as soon as possible.

Mild local pain should be considered a sign of possible infection, and Job syndrome patients should be taught that the typical inflammatory response does not necessarily occur.

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