Excerpt from Job Syndrome

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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 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.

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.

The eMedicine pediatrics article Hyperimmunoglobulinemia E (Job) Syndrome may be of interest.

Pathophysiology

The pathophysiology of Job syndrome is not completely understood. 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.² One of the earliest reports on the pathophysiology of Job syndrome described a chemotactic defect in neutrophils.³ 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).⁴

Other factors in the abnormal immunologic response are described. Patients with HIE have elevated levels of granulocyte-macrophage colony-stimulating factor, which may also explain the decreased chemotaxis and increased oxygen radical production and tissue damage.⁵ 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.⁶

Although the cytokine dysregulation seems to play a role in its pathophysiology, the causative gene has not yet been identified.⁷ 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.

A news article from 2007, STAT3 Mutations Linked to Hyper-IgE Syndrome, may be of interest.

Frequency

International

Job syndrome is a rare disorder; about 250 cases have been published.

Mortality/Morbidity

• Significant morbidity is associated with Job syndrome.
• The vast majority of patients have severe cutaneous and pulmonary disease, and most patients have multiple bone fractures and scoliosis.
• The mortality rate is elevated because of systemic infections.

Race

The 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.

Age

HIE usually commences in infancy, but diagnosis is often delayed until childhood or even adulthood.

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