Continuing Education Activity

Job Syndrome (Hyper-IgE syndrome) is a rare, primary immunodeficiency distinguished by the clinical triad of atopic dermatitis, recurrent skin staphylococcal infections, and recurrent pulmonary infections. The disease is characterized by elevated IgE levels with an early onset in primary childhood. This activity reviews the evaluation and management of Job syndrome and highlights the role of the interprofessional team in educating patients about their prognosis.

Objectives:

• Explain the differential diagnosis of Job syndrome.
• Outline the risk factors of developing Job syndrome.
• Describe the pathophysiology of Job syndrome.
• Summarize the interprofessional team's strategies for improving care coordination and communication regarding the management of patients with Job syndrome.

Introduction

Hyper-IgE syndrome (HIES) is a rare, primary immunodeficiency distinguished by the clinical triad of atopic dermatitis, recurrent skin staphylococcal infections, and recurrent pulmonary infections. Furthermore, there are elevated IgE levels of early-onset in primary childhood.

David et al. first described reported "Job syndrome" in 1966 in two patients with eczema, recurrent pulmonary infections, and cold lung abscesses. Later, in 1972, Buckley et al. reported the association of this condition with increased serum immunoglobulin E (hyper-IgE) levels and a series of phenotypic features called HIES.

The HIES is classified into 2 types. 

• Type I: Autosomal dominant hyper-IgE syndrome (AD-HIES), in which patients have abnormalities in different systems, including the immune system, connective tissue, skeletal and vascular among others
• Type II: Autosomal recessive hyper-IgE syndrome (AR-HIES), which also affects the immune system, manifesting in high IgE, recurrent skin and lung infections, sensitivity to viral infections such as molluscum contagiosum, and central nervous system (CNS) involvement, but does not have musculoskeletal alterations

Most recently, the International Union of Immunology Societies describes primary immunodeficiencies (PID) with well-defined syndromes as AD-HIES (Job syndrome) and 3 subtypes of AR-HIES that do not present skeletal or pneumatoceles alterations. These are further subdivided into TYK2 deficiency, DOCK8 deficiency, according to a molecular abnormality, and one of unknown origin.[1][2][3]

Etiology

Job syndrome is due to a mutation in the STAT3 gene in more than two-thirds of cases (70%). The transmission of this syndrome is autosomal dominant and variable expressivity. More than 90 different mutations have been reported. In the rest of the cases, the etiology of Job syndrome remains unclear.[1][4]

Epidemiology

The annual incidence of Job syndrome is estimated at around 1: 1,000,000. Although initially described in female subjects, both genders are affected, with no ethnic factor. A family character has only rarely been described.[1]

Pathophysiology

Job syndrome is due to a specific genetic mutation of autosomal dominant inheritance in the STAT3. STAT3 is involved in healing mechanisms and immune mechanisms. The mutation of this gene will lead to an intensification of the production of immunoglobulin E by B lymphocytes, the loss of the modulation capacity of their production by IL-6, IL-10, and IFN-gamma, and a defect chemotaxis of neutrophils. The lack of anti-inflammatory effects of IL-10 is probably the cause of the inappropriate inflammatory response observed in patients with Job syndrome. IL-6 plays an essential role in the genesis of Th17 cells; therefore, the lack of this cytokine leads to a deficiency of Th17 cells in Job syndrome. The CD4 + Th17 cells play an important role in the defense against infections mainly bacteria and extracellular fungi.

In addition, aside from its immunological role, this molecule has the role of pleiotropic signaling, which explains other non-immunological findings observed in the Job syndrome, such as long bone fractures and a late rash. Secondary teeth with primary teeth retained among immunodeficiencies.[1][4]

History and Physical

Job syndrome is characterized by clinical signs of immunological and non-immunological order.

Immunological Features

These mainly include chronic eczematoid eruptions, recurrent skin and pulmonary bacterial infections, and mucocutaneous candidiasis. The skin manifestations usually appear very early, a few weeks after birth. They include a pruriginous eczematoid rash affecting the scalp and face, that is rapidly superinfected with Staphylococcus aureus, resulting in weeping, crusty, and follicular infectious lesions. Recurrent cold staphylococcal skin abscesses that are associated with little or no inflammation are seen in these patients. Candida infections are common; they affect the skin, mucous membranes, and nails.

Recurrent pneumonia is typical, predominately due to S. aureus, and less frequently due to Streptococcus pneumoniae, and Haemophilus. It can get complicated with the development of recurrent lung abscesses, bronchiectasis, and pneumatoceles. These pneumatoceles can get colonized with Aspergillus and Pseudomonas. Superinfection with Pneumocystis carinii[5] was also reported.

Cryptococcosis and histoplasmosis can manifest outside the lung. Other infectious manifestations such as sinusitis, bronchitis, otitis externa, gingivitis, dental abscess, septic arthritis, and osteomyelitis can be seen.[6][7][8][9][10][11][12][13][14][15][16][17][18][17][16][14][19][14]

Non-immunological Features

Patients with Job syndrome have characteristic facial features that appear in early adolescence or earlier in late childhood, for example, facial asymmetry, prominent forehead, deep-set eyes, broad nasal bridge, wide fleshy nasal tip[20], rough fascial skin, increased inter-alar distance, prognathism, and high-arched palate. Birth defects like craniosynostosis and Arnold Chiari type 1 malformation have been documented.

Musculoskeletal abnormalities are common. They include hyperextensibility of the joints, scoliosis, and osteopenia. Hyperextensibility(noted in about 68% of the patients) may result in the early onset of degenerative joints disease. Bone density is decreased and is the source of multiple pathological fractures that occur in approximately 50% of patients (long bones and ribs). Scoliosis of variable severity is observed in approximately 60% of patients.

Anomalies of dentinogenesis are possible manifestations. Decreased resorption of the roots of the deciduous teeth may result in prolonged retention of the deciduous teeth, preventing the appearance of definitive teeth. About 70% of the patients with Job syndrome have been reported to retain three or more primary teeth.

Vascular manifestations include tortuosity or dilatation, coronary, cerebral and aortic aneurysms, and congenital coronary artery abnormalities.

Ocular complications include xanthelasmas, chalazions, strabismus and retinal detachment.[6][7][8][9][10][11][12][13][14][15][21][15][14][19][14]

Evaluation

The main diagnostic feature is an increase in serum IgE levels of more than 2000 U/mL, and often 500 U/mL. A clinical score has been developed to define the probability of diagnosis. A total IgE concentration greater than 1000 IU/mL and a weighted score of greater than 30 indicate an AD-HIES of the defect in STAT3, and a dominant-negative heterozygote mutation in STAT3 confirms the diagnosis.[1][6]

Eosinophilia is observed in more than 90% of the patients. The WBC count can be normal, elevated, or reduced in number(neutropenia).[15]

Treatment / Management

The most effective treatment, for now, for this condition is the long-term, sometimes continuous, use of antibiotics (penicillinase-resistant penicillins, cephalosporins, antifungal agents, and others) by adapting the treatment to the infections occurring in these patients and sometimes using surgical procedures during abscess development.

Interferon-gamma has shown no clinical benefit in this condition. Thanks to the antibiotics, and if the diagnosis is made early, patient survival can be increased. The management of non-immunological manifestations must be interprofessional. It aims to treat complications. Thus, scoliosis, depending on its severity, as well as bone fractures and degenerative joints diseases may require orthopedic surgery. Dental abnormalities require adequate stomatological treatment. Cardiovascular complications are managed in a specialized environment.[1][6][7][9]

Bone-marrow transplantation has been associated with mixed results in these patients.[15]

Differential Diagnosis

According to the clinical presentation, the diagnosis of Job syndrome could be difficult and arise with other diagnoses including in particular other types of primitive (chronic granulomatous disease) or acquired (HIV infection) immunodeficiency, severe atopic dermatitis, or cystic fibrosis.[1][11]

Prognosis

Although AD-HIES is associated with high morbidity and mortality, advances in medical care, close monitoring and patient compliance have led to improved prognosis, with survival up to 50 years or more.[1][22]

Complications

• Malignancies especially non-Hodgkin's lymphoma. Other cancers have also been reported such as Hodgkin's lymphoma, cancers of the vulva, and the lung.
• Autoimmune diseases like SLE, membranoproliferative glomerulonephritis, vasculitis, and dermatomyositis.
• Hypertension associated with vascular abnormalities.
• Myocardial infarction due to the rupture of coronary aneurysms.
• Lacunar infarcts due to the rupture of cerebral aneurysms.[15][19][15]

Pearls and Other Issues

Job syndrome is a rare, primary immunodeficiency due to mutations in STAT3 and characterized by defects in immunity with eczematous and non-immunologic system disorders. Antenatal diagnosis is theoretically possible. However, the very low incidence and the sporadic nature in the majority of cases make this method without much interest. The treatment at the moment is purely symptomatic. A biological or gene therapy in the future could change the prognosis of this syndrome.

Enhancing Healthcare Team Outcomes

Job syndrome is a rare immunological disorder characterized by recurrent infections. The disorder is primarily managed by the hematologist and infectious disease expert but the outpatient follow-up is done by the primary caregiver and nurse practitioner as part of interprofessional team management. Most of these patients require long term antibiotic therapy combined with drainage of an abscess, so a pharmaceutical consult is in order to appropriately target antimicrobial therapy.

The management of non-immunological manifestations must be interprofessional. It aims to treat complications. Thus, scoliosis, depending on its severity, as well as bone fractures and degenerative joints diseases may require orthopedic surgery. Dental abnormalities require adequate stomatological treatment. Cardiovascular complications are managed in a specialized environment.[1][6][7][9] An outpatient nurse should make regular home visits to ensure that the patient's health is stable, and report back to the healthcare team regarding their findings. These interprofessional activities can improve patient care significantly. [Level 5] While the outlook has improved with better care over the past 3 decades, many of these patients do have a shortened life span.