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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. One of the earliest reports on the pathophysiology of Job syndrome described a chemotactic defect in neutrophils. This defect has since been attributed to defective production of interferon- g (IFN- g ), a major activator of neutrophils when stimulated by interleukin 12 (IL-12). The poor production of IFN- g in response to IL-12 results in the marked elevation of IgE levels
Job syndrome is a rare disorder; about 250 cases have been published.
The syndrome occurs in people of diverse ethnic backgrounds and does not seem to be more common in any specific population.
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.
Other systemic infections may occur. These may include recurrent bacterial arthritis and a staphylococcal osteomyelitis at fracture sites. A history of otitis externa, chronic otitis media, sinusitis, or multiple caries and gingivitis may also exist.
Many patients report retained primary teeth, noneruption of permanent teeth, and double rows of teeth with both primary and permanent intermixed teeth.
Multiple bone fractures are common and often due to unrecognized or minor trauma.
Scoliosis occurs in most teenaged patients.
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. 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.
Causes: Although the described defects in immune response may explain the recurrent infections and chronic dermatitis, the many other congenital abnormalities are not readily explained. A single-locus autosomal dominant model of inheritance with varying expressivity is described, 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.
By definition, hyper-IgE syndrome is characterized by an elevated serum IgE level.
Levels vary, but the vast majority of patients have indices greater than 2000 IU/mL, and many patients have levels as high as 50,000 IU/mL. (Normal values of serum IgE tend to be less than 10 IU/mL in an arithmetic distribution or less than 100 IU/mL after logarithmic conversion, although these values may vary among laboratories.)
Serum IgE values tend to fluctuate to some degree (most often by <50%), and, in some patients, disease activity can significantly decrease over the years.
A normal IgE level should not exclude Job syndrome in an adult.
Serum eosinophil counts are more than 2 SDs above the normal range of values in more than 90% of patients.
Elevated eosinophil counts can be found in secretion samples, including those obtained with abscess drainage and sputum samples in cases of bronchitis or pneumonia.
No correlation is observed between the level of serum IgE and the level of serum eosinophils, and fluctuations in these levels are not associated with infections or flares of the dermatitis.
Imaging Studies:
Pulmonary imaging (eg, x-ray, CT) features typically reveal recurrent alveolar lung infections; pneumatoceles; and, rarely, pneumothorax.
Radiographs of the teeth indicate the dental development age.
Other Tests:
Neutrophil chemotaxis may be assessed by means of in vitro examination of their ability to move toward a chemoattractant. Such chemoattractants include endotoxin-activated serum, sodium caseinate, and formylmethionine-leucine-phenylalanine (fMet-Leu-Phe).
Although results with these tests are most often abnormal when compared with control values, chemotactic responsiveness varies, and the magnitude of the defect is less than that in other disorders (eg, Chediak-Higashi syndrome).
Medical Care: No definitive therapy is available for the treatment of hyper-IgE syndrome. The mainstay of treatment is the control of bacterial infections. Early incision and drainage followed by the intravenous administration of antibiotics are used for cutaneous infections. Coverage is usually aimed at Staphylococcus and Haemophilus species.
Therapy is usually longer than typical treatment because the disease in these patients responds more slowly than that of patients without Job syndrome. Intravenous antibiotic treatment for 2 weeks is typical. Chronic onychomycosis responds well to oral ketoconazole and fluconazole. Eczematous dermatitis has a varied response to high-dose topical steroids.
Chemoprophylaxis in patients with Job syndrome has varied results. Levamisole, an immunopotentiating drug, has been investigated as a therapeutic agent; in one study, it was unhelpful.
Long-term trimethoprim-sulfamethoxazole treatment was used in one patient with recurrent pruritic dermatitis, with resolution of symptoms.
Other patients treated with prophylactic antibiotics had both minor and major infections during therapy, often after several months of being infection free.
Cases in patients with severe hyper-IgE syndrome whose disease was unresponsive to other therapeutic modalities are reported; these cases had a marked clinical response to cyclosporin A. Treatment included low-dose cyclosporin for 6 months or longer. Both cutaneous and pulmonary infections responded to this therapy, and no adverse effects were reported.
In one study, oral disodium cromoglycate (2 g/d) prevented the complications of Job syndrome over a 2-year period.
Two case studies in patients with Job syndrome have shown a dramatic response in preventing infectious and eczematoid complications; patients were treated for as long as 18 months.
In one open-labeled study, high-dose intravenous immunoglobulin had no clear clinical benefit in 9 patients with Job syndrome. Another study showed an improvement in severe eczema along with a decrease in serum IgE levels in 2 patients after they were treated with high-dose intravenous gamma globulin.
Surgical Care:
Surgical excision and drainage of cutaneous infections are often performed. Drainage is usually followed by intravenous antibiotic therapy.
Chronic hidradenitis suppurativa occurs in some patients with Job syndrome. Often, these lesions do not respond to antibiotics, and local excision may be required.
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