Dermatologic Manifestations of Job Syndrome 

Updated: Mar 30, 2020
Author: Robert A Schwartz, MD, MPH; Chief Editor: Dirk M Elston, MD 

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. A few phenotypic descriptions in the Bible from the Book of Job are said to resemble some of these patients, beyond the boils.[1, 2] 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.[3] 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.[4, 5] 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.[6] 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.[7]

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

Pathophysiology

The pathophysiology of Job syndrome (HIE syndrome, or hyper-IgE syndrome) is not completely understood.[8] 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.[9] One of the earliest reports on the pathophysiology of Job syndrome described a chemotactic defect in neutrophils.[10] 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).[11]

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.[12] 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.[13]

Although the cytokine dysregulation seems to play a role in its pathophysiology, the causative gene has not yet been identified.[14] In one study, no unique polymorphisms or mutations were found in candidate genes from the toll-like receptor pathway.[15] 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.[16] They do not seem to have a propensity to develop food allergies and anaphylaxis.[17] 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.[18, 19, 20] Dominant-negative mutations in the STAT3 gene have been associated with the classic multisystem form of hyper-IgE syndrome.[21] A novel STK4 mutation has been described in patients with autoimmune cytopenias having features overlapping with those of DOCK-8 deficiency hyper-IgE syndrome.[22]

Hyper-IgE syndrome may be associated with defective salivary activity, which accounts for the enhanced susceptibility of these patients to oral candidiasis.[23]

Etiology

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,[24] ; 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.[25]

Most patients have HIE syndrome caused by dominant negative mutations in the STAT3 gene.[26] Impaired Th17 cell development may account for the cutaneous pathology.

STAT3 mosaicism may produce a milder phenotype.[27]

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.

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.

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.

 

Presentation

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 of Job syndrome

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 of Job syndrome

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.[28]

Many patients report retained primary teeth, noneruption of permanent teeth, and double rows of teeth with both primary and permanent intermixed teeth.[29]

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.[30]

Coronary artery aneurysms have been described in patients with HIE recurrent infection syndrome.[31]

Sarmento et al report an association with Dubowitz syndrome, HIE syndrome, and nasal polyposis.[32]

Physical Examination

Dermatologic findings in Job syndrome

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.

Disseminated molluscum contagiosum may also be evident.[33, 34]

Systemic findings in Job syndrome

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.[35] 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, missing permanent teeth buds, fissured tongue, variations of the oral mucosa and gingiva, and recurrent oral candidiasis.[36, 37]

Rectal histoplasmosis has been described in a patient with Job syndrome.[38]

Complications

Fournier gangrene due to infectious multiple atheromas of scrotal skin that progressed to the groin and thigh has been described in a patient with Job syndrome (HIE syndrome, or hyper-IgE syndrome).[39]

Job (hyperimmunoglobulinemia E) syndrome may predispose to the development of malignancies, especially lymphomas, mainly mature B-cell lymphomas, and classic Hodgkin lymphoma.[40]

 

DDx

Diagnostic Considerations

Differentiation from other disorders associated with eczema and increased serum IgE levels, such as other primary immunodeficiencies and atopic dermatitis, can be challenging.[41, 42, 19]

Chronic granulomatous disease with markedly elevated IgE levels may mimic hyperimmunoglobulin E syndrome.[43] However, tuberculosis may be associated with Job syndrome and may be first evident as miliary tuberculosis.[44]

The relevance of eosinophilia and hyper-IgE in immigrant children from Africa and Latin America has been explored. The prevalence and causes of eosinophilia and hyper-IgE in 362 immigrant children in Spain was prospectively evaluated, with the most frequent causes of absolute eosinophilia being filariasis (52.6%), strongyloidiasis (46.8%), and schistosomiasis (28.9%) and the most frequent causes of increased levels of IgE being filariasis (41.9%), strongyloidiasis (29.6%), and schistosomiasis (22.2%).[45] Thus, eosinophilia and hyper-IgE are important biomarkers of helminthiasis in children coming from tropical and subtropical areas.

Differential Diagnoses

 

Workup

Laboratory Studies

By definition, hyper-IgE syndrome (HIE syndrome, Job 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 standard deviations 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, radiography, CT scanning) features of Job syndrome (HIE syndrome, or hyper-IgE syndrome) typically reveal recurrent alveolar lung infections; pneumatoceles; and, rarely, pneumothorax.

Radiographs of the teeth indicate the dental development age.

Other Tests

In Job syndrome (HIE syndrome, or hyper-IgE syndrome), 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).

A polymerase chain reaction (PCR)–based high-resolution DNA-melting assay scanning selected exons of the STAT3 gene may establish a rapid molecular diagnosis in many patients.[46]

Histologic Findings

In Job syndrome (HIE syndrome, or hyper-IgE syndrome), histologic examination of vesicopapules may reveal an eosinophil-rich infiltration around the hair follicles, similar to that of eosinophilic pustular folliculitis.

 

Treatment

Medical Care

No definitive therapy is available for the treatment of hyper-IgE syndrome (HIE syndrome or Job 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. The second-generation cephalosporin cefaclor has also been recommended.[5]

Acupuncture treatment has been reported to be of value for symptom management of patients with hyper-IgE syndrome, although further studies are required for confirmation.[47]

Job syndrome 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.[48] 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.[49] 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.[50]

The autosomal recessive variant may benefit from bone marrow transplantation and hematopoietic stem cell graft.[51, 52]

Acupuncture treatments may decrease the severity of symptoms.[53]

Surgical Care

Surgical excision and drainage of cutaneous infections are often performed in patients with Job syndrome (HIE syndrome, or hyper-IgE syndrome). 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.

Special care is required for surgical procedures in these patients.[54]

Consultations

An allergist and immunologist may help in establishing the diagnosis of Job syndrome (HIE syndrome, or hyper-IgE syndrome). An infectious disease specialist may help in cases with infectious complications. An orthopedist should be involved in the care of those with scoliosis and fractures.

Prevention

Initiate treatment at the first signs of infection to prevent long-term complications from Job syndrome (HIE syndrome, or hyper-IgE syndrome). Regularly screen Job syndrome patients for scoliosis so that early noninvasive treatment can be used.

Long-Term Monitoring

Extra vigilance may be required in routine screening of Job syndrome (HIE syndrome, or hyper-IgE syndrome) patients for scoliosis. If a school-based program exists, healthcare providers should be made aware of the Job syndrome patient's greater-than-typical risk of scoliosis. Early detection with proper care can prevent progression of Job syndrome.

 

Medication

Medication Summary

The goals of pharmacotherapy for Job syndrome (HIE syndrome, or hyper-IgE syndrome) are to eradicate infections, reduce the morbidity rate, and prevent complications.

Antimicrobials

Class Summary

Therapy must be comprehensive and cover all likely pathogens in the context of the clinical setting.

Nafcillin (Nafcil, Unipen, Nallpen)

Nafcillin is initial therapy for suspected penicillin G-resistant streptococcal or staphylococcal infections. Because of thrombophlebitis, particularly in elderly patients, administer nafcillin parenterally for only a short term (1-2 d); change to the oral route as clinically indicated. Use for the treatment of pulmonary and cutaneous infections.

Oxacillin (Bactocill, Prostaphlin)

Oxacillin is a bactericidal antibiotic that inhibits cell wall synthesis. It is used in the treatment of infections caused by penicillinase-producing staphylococci. It may be used to initiate therapy in suspected staphylococcal infection. Use this agent for the treatment of pulmonary and cutaneous infections.

Ampicillin (Marcillin, Omnipen, Polycillin, Principen, Totacillin)

Ampicillin has bactericidal activity against susceptible organisms. Use it to treat pulmonary and cutaneous infections.

Vancomycin (Lyphocin, Vancocin, Vancoled)

Vancomycin is a potent antibiotic directed against gram-positive organisms and active against Enterococcus species. It is useful in the treatment of septicemia and skin structure infections. Vancomycin is indicated for use in patients who cannot receive penicillins and cephalosporins, those whose disease did not respond to these drugs, and those who have infections with resistant staphylococci. To avoid toxicity, the current recommendation is to assay vancomycin trough levels after the third dose, with sample drawn 0.5 hour prior to the next dose. Use creatinine clearance to adjust the dose in renal impairment. Use it for the treatment of pulmonary and cutaneous infections.

Cefazolin (Ancef, Kefzol, Zolicef)

Cefazolin is a first-generation semisynthetic cephalosporin that arrests bacterial cell wall synthesis, inhibiting bacterial growth. It is primarily active against skin flora, including S aureus. Cefazolin is typically used alone for skin and skin-structure coverage. Intravenous and intramuscular dosing regimens are similar. Use it for the treatment of pulmonary and cutaneous infections.

Sulfamethoxazole and trimethoprim (Bactrim, Bactrim DS)

This combination inhibits bacterial growth by inhibiting the synthesis of dihydrofolic acid. It is used for the prevention and/or suppression of inflammatory symptoms of Job syndrome.

Cyclosporine (Sandimmune, Neoral)

Cyclosporine is helpful in a variety of skin disorders. It is used for the prevention and/or suppression of inflammatory symptoms of Job syndrome.

Antifungals

Class Summary

Their mechanism of action may involve an alteration of RNA and DNA metabolism or an intracellular accumulation of peroxide that is toxic to the fungal cell.

Fluconazole (Diflucan)

Fluconazole has fungistatic activity. It is a synthetic oral antifungal (broad-spectrum bistriazole) that selectively inhibits fungal cytochrome P-450 and sterol C-14 alpha-demethylation, preventing the conversion of lanosterol to ergosterol and thereby disrupting cellular membranes. It is used for the treatment of fungal infections in Job syndrome, including onychomycosis.

Ketoconazole (Nizoral)

Ketoconazole has fungistatic activity. It is an imidazole broad-spectrum antifungal agent; it inhibits the synthesis of ergosterol, causing cellular components to leak and resulting in fungal cell death. Ketoconazole is used for the treatment of fungal infections in Job syndrome, including onychomycosis.