eMedicine Specialties > Dermatology > Allergy & Immunology

Job Syndrome

Author: Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
Coauthor(s): Mordechai M Tarlow, MD, Physician, Department of Medicine, Section of Dermatology, Kimball Medical Center
Contributor Information and Disclosures

Updated: Jul 17, 2009

Introduction

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.

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

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

Pathophysiology

The pathophysiology of Job syndrome (HIE syndrome, or hyper-IgE 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.⁴ One of the earliest reports on the pathophysiology of Job syndrome described a chemotactic defect in neutrophils.⁵ 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).⁶

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.⁷ 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.⁸

Although the cytokine dysregulation seems to play a role in its pathophysiology, the causative gene has not yet been identified.⁹ In one study, no unique polymorphisms or mutations were found in candidate genes from the toll-like receptor pathway.¹⁰ 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.

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

Clinical

History

Although the diagnosis of Job syndrome (HIE syndrome, or hyper-IgE syndrome) is usually delayed until the patient reaches childhood or early adulthood, symptoms may begin in infancy.

• Dermatologic features
  • Nearly all patients have a history of moderate-to-severe, pruritic, eczematous skin eruptions in early life. The eruption does not have a seasonal variation and is present, to some degree, at all times.
  • Intermittent episodes of staphylococcal abscesses are common. These abscesses are often referred to as cold abscesses because they do not cause pain, heat, or redness.
  • Chronic mucocutaneous candidiasis and onychomycosis are common and usually caused by Candida species.
• Systemic features
  • Recurrent bronchitis is common, and a history of Staphylococcus aureus or Haemophilus influenzae pneumonia is usually associated with pneumatocele development. These pneumatoceles may become superinfected with Pseudomonas aeruginosa and Aspergillus fumigatus. Also see Pneumonia, Bacterial.
  • Other systemic infections may occur. These may include recurrent bacterial arthritis and a staphylococcal osteomyelitis at fracture sites. Patients also may have a history of otitis externa, chronic otitis media, sinusitis, multiple caries and gingivitis, or cervicofacial infection.¹¹
  • Many patients report retained primary teeth, noneruption of permanent teeth, and double rows of teeth with both primary and permanent intermixed teeth.¹²
  • Multiple bone fractures are common and often due to unrecognized or minor trauma.
  • Scoliosis occurs in most teenaged patients.
  • Peripheral T-cell lymphoma has been described as a rare association with Job syndrome.¹³
  • Coronary artery aneurysms have been described in patients with HIE recurrent infection syndrome.¹⁴
  • Sarmento et al report an association with Dubowitz syndrome, HIE syndrome, and nasal polyposis.¹⁵

Physical

• Dermatologic findings
  • Moderate-to-severe, papular, pruritic eczematous lesions are typical; they may also be pustular and may become impetiginized. The areas of involvement predominately include the flexural areas, the area behind the ears, and the area around the hairline.
  • Cold staphylococcal abscesses that lack the typical signs of infection appear as fluctuant masses. These abscesses may be mistaken for cysts or benign tumors. They vary in size and can occur on any part of the body.
  • Furunculosis and cellulitis may also be present.
  • Chronic mucocutaneous candidiasis and onychomycosis are common.
  • A vesicular eruption similar to herpetic lesions may occur in newborns, with the more typical eczematous component developing over the next several months.
• Systemic findings
  • Fever is rare. Recurrent productive cough is associated with bronchitis. Pneumonia with complicating pneumatocele development and empyema may be present, although these are less common in children who are receiving prophylactic antibiotics.
  • Recurrent bacterial arthritis and staphylococcal osteomyelitis may occur at fracture sites. Culture results in suspected osteomyelitis are often negative, but the findings on diagnostic images are usually consistent with this diagnosis. This osteomyelitis responds well to antibiotic treatment.
  • Frequent bone fractures are a feature of Job syndrome and occur in persons of all ages. The fractures usually occur in the long bones, ribs, and pelvic bones. They are often associated with an absence of pain.
  • Scoliosis is common. Approximately one third of patients have a spinal curvature greater than 20°.
  • Hyperextensible joints are also common.
  • A characteristic coarse facies is associated with Job syndrome.¹⁶ The most striking features are a greater interalar width and a longer outer canthal distance. A prominent brow and supraorbital ridge with the impression of deep-set eyes is observed. These features tend to become more pronounced with age.
  • Oral manifestations include retained primary dentition, a high arched palate, variations of the oral mucosa and gingiva, and recurrent oral candidiasis.¹⁷

Causes

Although the described defects in immune response may explain the recurrent infections and chronic dermatitis associated with Job syndrome (HIE syndrome, or hyper-IgE syndrome), the many other congenital abnormalities are not readily explained. A single-locus autosomal dominant model of inheritance with varying expressivity is described,¹⁸ and the greater severity of cases in younger generations of patients may suggest genetic anticipation. Findings from a multipoint analysis confirm that the proximal 4q region contains the disease locus for Job syndrome.¹⁹

• Search for CME/CE on This Topic »

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