Job Syndrome · What It Is, Causes, Signs and Symptoms, Treatment, and More

Job syndrome is a rare immune deficiency disorder characterized by recurrent skin and lung infections and severe eczema. One of its main features is that individuals present extremely high serum levels of immunoglobulin E, an antibody that’s primarily associated with allergic responses.  

Job syndrome belongs to a group of primary immune deficiencies that are collectively known as hyperimmunoglobulin IgE syndromes (HIES). These conditions share elevated IgE levels and overlapping clinical features and are classified according to their inheritance pattern and underlying genetic changes.  

Job syndrome is caused by mutations in the signal transducer and activator of the transcription 3 (STAT3) gene, which encodes for a variety of cell signaling molecules (e.g., cytokines, hormones, and growth factors) that are involved in pathways responsible for regulating the body’s immune response. Specifically, mutations in the STAT3 gene result in defective Th17 cell differentiation and function. Th17 cells are a subset of helper T cells that defend against extracellular pathogens such as bacteria and fungi. They are also involved in the recruitment of neutrophils by the release of interferon-gamma, thereby regulating the body’s autoimmune response (i.e., downregulating the activation of self-reactive cells) and maintaining the integrity of mucosal barrier surfaces (e.g., gastrointestinal tract). Th17 cellular impairments result in an increase in susceptibility to infections.  

STAT3 gene defects also lead to impaired Th9 cell differentiation and function. Th9 cells are another subset of helper T cells that produce IL-9, a cytokine  that plays a role in allergy, asthma, and autoimmune inflammation. It does so by recruiting eosinophils a white blood cell that protects the body from allergens, parasites, and foreign bacteria, which are important mediators in the pathophysiology of allergic asthma.  

Mutations in STAT3 gene are inherited in an autosomal dominant pattern, which means that a person only needs to inherit one altered copy of the gene to develop the condition. So, if a parent has the mutation, each child has a 50% chance of inheriting it, and the condition can affect both males and females equally. 

The most characteristic features of Job syndrome are recurrent skin and lung infections, particularly caused by commensal skin flora like Staphylococcus aureus. Patients commonly develop “cold” skin abscesses, so called because they lack the usual signs of redness, warmth, and pain due to the impaired inflammatory response. Recurrent pneumonias are frequent and may lead to structural lung damage, including bronchiectasis, which refers to dilations of the lower airways. These infections typically begin in early childhood and tend to recur in adulthood despite treatment. 

Another manifestation is severe eczema, often resembling atopic dermatitis. The skin is chronically inflamed, itchy, and prone to secondary infections. 

Generalized physical findings seen in Job syndrome include deep-set eyes, broad nasal bridge, prominent forehead, and chin. There may also be skeletal and connective tissue disorders, such as joint hyperextensibility, retained primary teeth, scoliosis, osteopenia, and recurrent fractures after minimal trauma. Less common but clinically relevant manifestations include mucocutaneous candidiasis, chronic sinusitis or otitis, and an increased risk of vascular abnormalities, such as coronary or cerebral aneurysms. 

Diagnosis of Job syndrome begins with a thorough review of symptoms and medical history, followed by confirmation via laboratory and molecular testing. Job syndrome is suspected in older children or adults with typical facial features, recurrent sinopulmonary infections, skin abscesses, and chronic eczema. A focused physical exam can help assess for any musculoskeletal abnormalities like scoliosis or hyperextensibility of joints.  

Laboratory testing typically reveals high serum levels of IgE (i.e., ranging from 1,000 to greater than 50,000 IU/mL), elevated eosinophil counts (i.e., 40 to 50 percent of total white blood cell count), and low or absent levels of Th17 cells. Molecular testing typically reveals a pathogenic variant of the STAT3 gene. While imaging is not required for the diagnosis, it may be helpful in the management of vascular disease like aneurysms, if present.