Job Syndrome

Autosomal dominant hyperimmunoglobulin E (IgE) syndrome (AD-HIES) was first described as Job syndrome in 1966[1, 2] and included the triad of eosinophilia, eczema, and recurrent skin and pulmonary infections. Elevated IgE level was recognized as a cardinal feature of the syndrome in 1972, and the name HIES was subsequently proposed.[3] The phenotype was later expanded to include many connective tissue and skeletal abnormalities. A scoring system that weighted both the immunologic and somatic features of the syndrome was designed to aid in the clinical diagnosis of these patients (see the table below).[4]

Table. Scoring System for Job Syndrome (Open Table in a new window)

More recently, vascular abnormalities, including coronary aneurysm without atherosclerosis, and brain MRI abnormalities, including focal hyperintensities and Chiari I malformations, have been described. In 2007, autosomal dominant mutations in signal transducer and activator of transcription-3 (STAT3) gene were identified as the molecular cause of this disease.[5, 6, 7] See image below.

Mutations in the STAT3 gene have been identified in almost all cases of clinically verified autosomal dominant hyper-IgE syndrome (AD-HIES).[8, 9] STAT3 is one of 7 human STAT (signal transducer and activator of transcription) proteins, which are critical second messengers for many cytokine, hormone, and growth factor receptors. In general, Janus family tyrosine kinases (JAKs) bind to the intracellular components of cytokine receptors, and are, in turn, bound by STATs upon cytokine signaling. When cytokines bind to their cognate receptor, JAKs phosphorylate the cytokine receptor and subsequently the STATs, which then dissociate from the JAK-receptor complex. Phosphorylated STATs dimerize within the cytosol via their phosphotyrosines and Src-homology 2 (SH2) domains. Dimerized STATs then translocate to the nucleus, where they bind DNA in the promoter sequences of target genes to activate transcription. This activity is typically stopped by STAT dephosphorylation. STAT3 is located on human chromosome17q21.

STAT3 mutations have been found in persons of Asian, African, Caucasian, and Hispanic descent and correlate well with HIES disease. The mutations are predominantly missense and in-frame deletions that lead to production of proteins with dominant negative activity. No null alleles have been identified to date, indicating that haploinsufficiency is not a mechanism for disease causation. Most AD-HIES STAT3 mutations are located in the SH2 and DNA binding regions. Dominant negative mutants antagonize the wild type protein, leading to less than 50% STAT3 activity. This is consistent with the mouse data, which show that heterozygous STAT3 deficiency is not associated with disease, while STAT3 null animals die during embryogenesis. Therefore, HIES patients have less than 50% STAT3 activity, which is enough to sustain life and many aspects of development but inadequate for normal immune function or normal continued tissue remodeling.

AD-HIES is a disease of both too little and too much inflammatory response, which is in part explained by the important role of STAT3 in the induction and signalling of key cytokines, including interleukins IL-6, IL-10, IL-17, IL-22, and IL-23. IL-6 induces acute phase proteins by hepatocytes, neutrophil production in cooperation with colony-stimulating growth factors, stimulation of differentiated B cell growth, stimulation of proinflammatory cytokine production (particularly IL-17), inhibition of the action and production of regulatory T cells, and upregulation of the chemokine MCP-1 (also known as CCL2).

Due to impaired IL-6 and IL-23 signalling through STAT3, the crucial T cell transcription factor retinoid-related orphan receptor gamma (ROR-gt) is diminished, impairing IL-17 expression and Th17 differentiation.[10] Th17 cells are T helper cells that produce IL-17, a cytokine important in neutrophil recruitment and activation and defense against fungal and extracellular bacteria. Th17 cells also produce IL-22, which stimulates epithelial production of b-defensins, small peptides crucial for killing bacteria and fungi. These cytokines, which are inadequately upregulated in HIES, may explain some of the susceptibility to infections of the skin and lung epithelium.

Overexuberant inflammation in AD-HIES is suggested by the frequent development of pneumatoceles following pneumonias, despite adequate therapy of pathogens. Transcriptional array studies and cytokine production studies both show increased proinflammatory cytokines such as tumor necrosis factor alpha (TNFa), interferon gamma (IFNg), and IL-12 in AD-HIES cells compared to normals. Abnormally low IL-10, a cytokine critical for dampening the inflammatory response, may also contribute to the exuberant inflammatory response in HIES. IL-10 signaling is mediated via STAT3. IL-10 has negative feedback regulation of macrophages, which express costimulators that enhance T cell activation and secrete cytokines such as IL-12 and IL-23 to enhance cell-mediated immunity. Therefore, impaired IL-10 production and signaling may be associated with increased proinflammatory cytokines. It may even contribute to the increased IgE and eosinophilia in AD-HIES due to the lack of normal IL-4 suppression.

Frequency

Autosomal dominant hyper-IgE syndrome (AD-HIES) is a rare disease. The exact incidence is unknown. It has no known associations with race, ethnicity, or gender.

Mortality/Morbidity

AD-HIES is associated with a contracted lifespan, with deaths occurring predominantly in adulthood due to the consequences of chronic infections. In a recent review of a large cohort of patients, the average living patient age was 27 years, but ages ranged from 3 to 58 years. Infection-related deaths occurred at an average age of 29 years.

Death in AD-HIES patients is most commonly due to chronic pulmonary infections in the setting of pneumatoceles or bronchiectasis or both. Molds, such as Aspergillus and Scedosporium species, may invade the pulmonary blood vessels, leading to metastatic spread or fatal hemoptysis. These infections are secondary opportunists in regions of destroyed lung caused by the inappropriate healing of previous infections.[11]

AD-HIES patients are at increased risk for Hodgkin and non-Hodgkin lymphoma (relative risk 259), although the number of cases reported is small.[12]

Race

STAT3 mutations have been detected in persons of Caucasian, African, Asian, and Hispanic descent. Although most documented cases are in white patients, this is likely due to referral bias of the population studied.

Sex

No gender-based differences have been described with regard to disease severity or incidence.

Age

In a recent chart review, the average age of diagnosis was 11.5 years. However, the diagnosis can be made in infancy or adulthood. Proband survival has improved over the years along with improved management, allowing patients to have their own children. Given the autosomal dominant nature of HIES, these offspring of known patients receive early diagnosis and therapy.

Eczematoid dermatitis starts in the newborn period and is typically associated with and driven by Staphylococcus aureus infection. Skin abscesses due to S aureus are common and typically not associated with a robust inflammatory response either locally or systemically, hence the term cold abscesses. Mucocutaneous candidiasis, including onychomycosis, occurs frequently. Conversely, severe warts and Molluscum species are not features of autosomal dominant hyper-IgE syndrome (AD-HIES).

Pneumonias start in early childhood, typically due to S aureus, Streptococcus pneumoniae, and Haemophilus influenzae. Similar to the skin abscesses, signs of systemic toxicity are modest. Even when treated aggressively and promptly, the pneumonias often resolve with pneumatocele formation (see image below), presumably due to dysregulated local inflammation and resultant tissue destruction. Later superinfection of the pneumatoceles with Pseudomonas aeruginosa and molds such as Aspergillus and Scedosporium species can be associated with significant morbidity and mortality. Opportunistic infections including Pneumocystis jiroveci pneumonia, disseminated histoplasmosis, cryptococcosis, and coccidioidomycosis also occur, although less frequently. Recurrent bacterial sinusitis and otitis are common, but susceptibility to viral pathogens is not increased.

AD-HIES is also associated with multiple connective tissue and skeletal abnormalities, including scoliosis, hyperextensibility, pathologic fractures, retained primary dentition, craniosynostosis, and vascular abnormalities. Many patients have hyperextensibility of at least one joint. Despite these connective tissue abnormalities, AD-HIES patients typically demonstrate normal wound healing. Most patients report at least one nontraumatic fracture, such as broken ribs with coughing. Osteoporosis is common but does not appear to correlate with frequency of fractures. Retention of primary teeth is due to failure of primary tooth exfoliation;[13] characteristic palatal, tongue, and oral mucosal changes are often present as well. Arterial tortuosity and aneurysm occur, typically of the middle-sized vessels, such as coronary arteries.[14, 15] Brain MRI abnormalities include focal hyperintensities and an increased incidence of Chiari I malformations.[16]

Despite the increased IgE and eosinophilia, patients do not typically have significant atopy with regard to foods or seasonal allergens.

A detailed family history may help identify other cases, but most cases are spontaneously arising mutations or autosomal dominant. The clinical diagnosis of AD-HIES has been based on a composite profile of immunologic and nonimmunologic features, leading to a score that correlates well with identifying STAT3 mutations.

Individuals with autosomal dominant hyper-IgE syndrome (AD-HIES) share a characteristic facial appearance, with a broad nose, deep-set eyes with prominent forehead, and generalized coarsening of the facial features with age. A high arched palate is often present, and double-rowed teeth may be present. Oral thrush may be seen. The tympanic membrane may be scarred from recurrent otitis.

Both pediatric and adult patients may demonstrate an erythematous, scaly pruritic rash, typical of eczematous dermatitis. Scarring from incision and drainage of boils may be present. The nails, vagina, and inguinal region often demonstrate candidiasis.

The pulmonary examination varies depending on previous pulmonary infections and lung parenchymal changes. The examination ranges from normal to decreased tactile fremitus and decreased air exchange associated with large pneumatoceles. Clubbing of the nails is common.

Scoliosis >10 degrees is seen in 60% of patients. Hyperextensibility of at least one joint is present in 70% of patients.

Most, if not all, cases of autosomal dominant hyper-IgE syndrome (AD-HIES) are due to dominant negative mutations in STAT3, a key signaling molecule for immunologic and somatic gene transcription.

CBC with differential is used to assess absolute eosinophil count in patients with autosomal dominant hyper-IgE syndrome (AD-HIES). Eosinophilia usually accompanies the IgE elevation but is not correlated with it. Absolute lymphocyte counts are usually normal, and lymphocyte subsets do not need to be obtained for routine clinical care. Anemia and thrombocytopenia are not typically associated with AD-HIES.

Quantitative serum immunoglobulins IgG, IgA, IgM, IgE: the serum IgE is typically >2000 IU/mL, while other immunoglobulin levels are normal. However, IgE level normalizes in adulthood in about 20% of cases.

Qualitative immunoglobulins to specific antigens may be useful in patients with severe sinopulmonary disease and in those who develop recurrent infections despite effective use of antimicrobial prophylaxis. Some patients with HIES have decreased specific antibody responses to vaccines for Haemophilus influenzae type b (HiB), Streptococcus pneumoniae, tetanus, or diphtheria.

Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are useful if levels are elevated, but normal ESR and CRP levels do not rule out bacterial infection.

Electrolytes, coagulation, renal and hepatic function studies are not affected in HIES.

Skin abscesses should be incised and drained; obtain cultures of drainage.

When lung infection is present, sputum should be obtained through routine collection, sputum induction, or bronchoscopy.

STAT3 mutation analysis should be performed to confirm a high clinical suspicion of AD-HIES.

Chest x-ray, chest CT, or both are necessary to determine the extent of pulmonary parenchymal involvement in autosomal dominant hyper-IgE syndrome (AD-HIES).[18] See image below.

X-rays should be taken of the spine to assess scoliosis.

Complaints of bone or joint paint should be assessed radiologically because of the increased risk of pathologic fractures in these patients.

Vascular abnormalities are usually asymptomatic, including intracranial aneurysms and coronary artery ectasia, tortuosity, and aneurysms. These anomalies are common, as detected by CT and MRI in research studies.

X-ray or MRI studies of the skull often show craniosynostosis.

MRI of the brain usually shows T2-weighted hyperintensities, an increased prevalence of lacunar infarcts, and an increased rate of Chiari type 1 malformations. See image below.

Pulmonary function tests, including diffusing capacity of lung for carbon monoxide (DLCO), provide baseline pulmonary status in patients with autosomal dominant hyper-IgE syndrome (AD-HIES).

Care of patients with autosomal dominant hyper-IgE syndrome (AD-HIES) is primarily directed at treating and preventing recurrent skin and sinopulmonary infections. Prophylactic antimicrobials, such as trimethoprim/sulfamethoxazole, are highly effective. With the increasing prevalence of antibiotic-resistant S aureus and other pathogens, it is important that microbial culture sensitivities be actively obtained to direct antimicrobial therapies. As patients often have minimal signs of systemic toxicity, the threshold for considering active infection requiring aggressive treatment should be low.

The control of dermatitis is essential to decrease the frequency of skin infections and improve the quality of life, particularly for pediatric patients with more severe dermatitis. Exposure to low concentrations of bleach, such as achieved from frequent swimming in a chlorinated pool or taking bleach baths (1/2 cup of bleach to a tub of water for 15 minutes, 3 times a week) are highly effective for controlling staphylococcal skin infections.

Mucocutaneous candidiasis and onychomycosis are treated as needed with antifungals therapy, most commonly fluconazole. Broadening antifungal coverage to include Aspergillus species (itraconazole, voriconazole, posaconazole) should be considered for individuals with pneumatoceles. Annual flu vaccine is recommended.

Intravenous immunoglobulin (IVIG) therapy has been used anecdotally in selected patients with improvement in infections.

Currently, no clear recommendations exist for routine medical therapy of the vascular, musculoskeletal, and connective tissue abnormalities associated with the disorder. Immune reconstitution would theoretically be of benefit for AD-HIES, but the benefit to repairing the immune dysfunction while leaving the somatic abnormalities intact in these patients is unknown. Bone marrow or stem cell transplant has been used in too few cases to be sure of its safety or value in AD-HIES.

Most patients continue as outpatients to monitor for changes in skin disease, pulmonary status, and musculoskeletal complaints. Frequent monitoring is recommended for patients with pneumatoceles or bronchiectasis, as these patients are at increased risk for secondary lung infections. Patients need to be aware that systemic signs of infection are often absent and to seek care if any infection is suspected.

The most common surgical procedure needed in autosomal dominant hyper-IgE syndrome (AD-HIES) is incision and drainage of skin boils, which can often be performed in the office with local anesthesia. Extraction of primary teeth because of delayed deciduation is also common. Some patients with severe scoliosis require bracing and surgical treatment depending upon the degree of curvature. Rarely, patients require lobectomy or pneumonectomy because of pneumatoceles with recurrent infection. However, surgical resection of pneumatoceles should be undertaken only with expert advice, as patients may experience difficulty with residual lung expansion to fill the intrathoracic space with attendant medical complications.

Consultation with dermatology may be useful in management of autosomal dominant hyper-IgE syndrome (AD-HIES)-associated eczematous dermatitis.

Consultation with infectious diseases may be useful in management of extensive pulmonary or cutaneous infection.

Consultation with pulmonology for bronchoscopy with culture may help diagnose the etiology of pneumonia. Bronchoscopy may also help clear thick secretions, as patients tend to have impaired mucociliary clearance.

Consultation with dentistry is often needed for assessment and treatment of retained primary teeth.

Consultation with orthopedics is commonly needed for evaluation and management of scoliosis and fractures.

The goals of pharmacotherapy are to reduce morbidity and prevent complications.

Class Summary

Empiric therapy should be comprehensive in the context of the clinical setting.

Sulfamethoxazole (SMZ) and trimethoprim (TMP) (Bactrim, Bactrim DS)

Inhibits bacterial growth by inhibiting synthesis of dihydrofolic acid.

Antibacterial activity of TMP-SMZ includes common urinary tract pathogens, except Pseudomonas aeruginosa.

Azithromycin (Zithromax, Z-Pak)

Acts by binding to 50S ribosomal subunit of susceptible microorganisms and blocks dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest. Nucleic acid synthesis is not affected.

Concentrates in phagocytes and fibroblasts as demonstrated by in vitro incubation techniques. In vivo studies suggest that concentration in phagocytes may contribute to drug distribution to inflamed tissues.

Treats mild-to-moderate microbial infections.

Amoxicillin and clavulanate (Augmentin)

Amoxicillin inhibits bacterial cell wall synthesis by binding to penicillin-binding proteins. Addition of clavulanate inhibits beta-lactamase producing bacteria.

Good alternative antibiotic for patients allergic or intolerant to the macrolide class. Usually is well tolerated and provides good coverage to most infectious agents. Not effective against Mycoplasma and Legionella species. The half-life of oral dosage form is 1-1.3 h. Has good tissue penetration but does not enter cerebrospinal fluid.

For children >3 months, base dosing protocol on amoxicillin content. Due to different amoxicillin/clavulanic acid ratios in 250-mg tab (250/125) vs 250 mg chewable-tab (250/62.5), do not use 250-mg tab until child weighs >40 kg.

Class Summary

These agents are used to treat bronchospasm refractory to epinephrine.

Albuterol (ProAir HFA, Proventil, Ventolin HFA, AccuNeb)

Beta-agonist for bronchospasm refractory to epinephrine. Stimulates adenyl cyclase to convert ATP to cAMP and causes bronchodilation. Relaxes bronchial smooth muscle by action on beta2-receptors with little effect on cardiac muscle contractility. May decrease mediator release from mast cells and basophils and inhibit airway microvascular leakage.

Frequency may be increased. Institute regular schedule in patients on anticholinergic drugs who remain symptomatic. Available as liquid for nebulizer, MDI, and dry powder inhalers.

Continuous therapy may reduce need for mechanical ventilation.

Class Summary

Calcium supplements are used to strengthen bones.

Calcium carbonate (Oyster Shell Calcium, Cal-Carb Forte)

Calcium supplementation in patients at young ages has been proven to lower the incidence of fractures.

Class Summary

Agents that promote calcium absorption are used.

Cholecalciferol (Vitamin D3)

Promotes absorption of calcium and phosphorus in small intestine. Promotes renal tubule resorption of phosphate. Increases rate of accretion and resorption in bone minerals.

Class Summary

These agents are used to treat mucocutaneous candidiasis and onychomycosis.

Itraconazole (Sporanox)

Fungistatic activity. Synthetic triazole antifungal agent that slows fungal cell growth by inhibiting CYP-450–dependent synthesis of ergosterol, a vital component of fungal cell membranes.

Fluconazole (Diflucan)

Synthetic oral antifungal (broad-spectrum bistriazole) that selectively inhibits fungal cytochrome P-450 and sterol C-14 alpha-demethylation, which prevents conversion of lanosterol to ergosterol, thereby disrupting cellular membranes. Has little affinity for mammalian cytochromes, which is believed to explain its low toxicity. Available as tablets for oral administration, as a powder for oral suspension, and as a sterile solution for IV use. Has fewer adverse effects and better tissue distribution than older systemic imidazoles.

Daily dose varies with indication.

Posaconazole (Noxafil)

Triazole antifungal agent. Blocks ergosterol synthesis by inhibiting the enzyme lanosterol 14-alpha-demethylase and sterol precursor accumulation. This action results in cell membrane disruption. Available as oral susp (200 mg/5 mL). Indicated for prophylaxis of invasive Aspergillus and Candida infections in patients at high risk because of severe immunosuppression.

Voriconazole (Vfend)

Used for primary treatment of invasive aspergillosis and salvage treatment of Fusarium species or Scedosporium apiospermum infections. A triazole antifungal agent that inhibits fungal CYP450-mediated 14 alpha-lanosterol demethylation, which is essential in fungal ergosterol biosynthesis.