What is Job Syndrome?
Hyper-IgE syndrome (HIES) is a rare condition that affects the immune system. It mainly involves eczema (itchy, red, and inflamed skin), frequent skin infections caused by staphylococcal bacteria, and recurring lung infections. Moreover, it features unusually high levels of an immune system protein called IgE, usually seen from an early age.
In 1966, David and his team first mentioned a condition known as “Job syndrome.” The patients affected with this had eczema, recurring lung infections, and lung abscesses, which are pockets of pus. In 1972, a team lead by Buckley connected this condition with increased levels of IgE in the blood and noted a range of physical characteristics that they referred to as HIES.
There are two types of HIES:
1. Type I (Autosomal Dominant Hyper-IgE Syndrome – AD-HIES): People with this type have multiple abnormalities affecting the immune system, connective tissues, bones, blood vessels, and others.
2. Type II (Autosomal Recessive Hyper-IgE Syndrome – AR-HIES): This type still affects the immune system leading to high levels of IgE, regular skin and lung infections, and vulnerability to viral infections. It also involves issues with the central nervous system, but doesn’t present with bone alterations.
Most recently, the International Union of Immunological Societies categorizes primary immunodeficiencies (conditions where the immune system isn’t functioning properly) with specific syndromes as AD-HIES (Job syndrome) and 3 subtypes of AR-HIES that don’t have alterations in the bones or lung cysts. These subtypes are further differentiated into TYK2 deficiency and DOCK8 deficiency, depending on the molecular abnormality present, and one subtype of unknown cause.
What Causes Job Syndrome?
Job syndrome, also known as Hyper IgE syndrome, is a condition that mainly occurs due to a change or ‘mutation’ in a specific gene called STAT3, in about 70% of cases. This gene plays an important role in the immune system. This condition is ‘autosomal dominant’, which means that you only need to inherit the mutated gene from one parent to get the condition. Expressivity is variable, which means the symptoms can vary greatly from one person to another, even within the same family.
Researchers have identified more than 90 different mutations of the STAT3 gene that can result in Job syndrome. In some cases, however, the cause of Job syndrome remains unknown. This means that for about 30% of cases, we don’t understand why Job syndrome develops.
Risk Factors and Frequency for Job Syndrome
Job syndrome, also known as Hyper IgE syndrome, is a very rare health condition, with around 1 in 1,000,000 people affected each year. It was initially discovered in female patients, but it is now known to affect both males and females, and no particular ethnic group is more likely to have it. Although it’s uncommon, there have been occasional cases where more than one member of a family has the syndrome.
Signs and Symptoms of Job Syndrome
Job syndrome is a condition that displays both immune-related and non-immune-related characteristics.
The immune-related symptoms primarily consist of chronic skin irritations, frequent skin and lung bacterial infections, and mucous membrane yeast infections. The skin problems usually start a few weeks after birth and include an itchy rash on the scalp and face, that often becomes infected with a bacterium called Staphylococcus aureus. This leads to wet, crusty, and often infected skin blemishes. Recurring skin abscesses or infections that have little to no inflammation are also common in people with Job syndrome. Yeast infections affecting the skin, mucous membranes and nails are prevalent as well.
People with Job syndrome often experience recurring pneumonia, which can get complicated, leading to lung abscesses, bronchiectasis, and air-filled cysts or “pneumatoceles” in the lung. These cysts can get infected by other types of bacteria and fungi. Other types of infections such as sinusitis, bronchitis, external ear infections, gum inflammation, tooth abscess, inflamed joints, and bone infection can also occur.
Non-immune-related characteristics of Job syndrome become evident in early adolescence or late childhood and include distinctive facial features such as facial asymmetry, prominent forehead, deep-set eyes, wide nasal bridge, wide nasal tip, rough facial skin, wide space between nostrils, protruded jaw, and a high-arched palate. Some people with Job syndrome are born with birth defects like abnormal shaping of the skull and brain malformations.
Musculoskeletal abnormalities are also common. They include hyper-flexibility of the joints, curvature of the spine, and a decrease in bone density. This decreased bone density puts individuals at risk of multiple fractures that occur in about half of the patients, especially in the long bones and ribs. About 60% of patients experience scoliosis of varying severity.
Job syndrome may cause dental abnormalities. Extended retention of baby teeth can hinder the growth of permanent teeth. Approximately 70% of people with Job syndrome retain three or more baby teeth longer than normal.
Vascular anomalies such as irregular blood vessels, heart and brain aneurysms, and heart vessel abnormalities are also observed. Ocular complications can include specific types of eyelid and eyelash conditions, misalignment of the eyes, and even retinal detachment.
Testing for Job Syndrome
The key sign of this condition is a rise in a compound in the blood called Immunoglobulin E (IgE). If your IgE levels are greater than 2000 U/mL, and often over 500 U/mL, it makes it more likely that you have this condition. Doctors sometimes use a scoring system to calculate the likelihood of the condition. Usually, if your IgE is greater than 1000 IU/mL, and your score on the system is greater than 30, it indicates that you potentially have a form of the condition known as AD-HIES due to problems with a protein known as STAT3. The only way for doctors to definitively confirm this diagnosis is by identifying a mutation (a small change) in the STAT3 gene.
Another sign of this condition that doctors look for is a high number of blood cells known as eosinophils. More than 90% of patients will have this sign. However, tests also show that the general white blood cell count can vary among patients – it may be normal, high, or low (a condition known as neutropenia).
Treatment Options for Job Syndrome
The best current treatment for this illness often involves long-term, and sometimes ongoing, use of antibiotics. Various types of antibiotics, such as penicillinase-resistant penicillins, cephalosporins, antifungal agents and others, are used. The specific antibiotics chosen are tailored to the type of infections the patient is experiencing. In some cases, surgical procedures may also be needed, especially when an abscess (a painful, swollen pocket of pus) forms.
Interferon-gamma, a type of protein used in some immune therapies, has not been found to provide any clinical benefit for this condition. However, if the disease is diagnosed early and treated effectively with antibiotics, the chances of survival for the patient can be improved.
In addition to immunological aspects of the condition, there may also be non-immunological issues to manage. This means it’s important to treat complications that may arise from different parts of the body with the help of various health professionals. For instance, if the patient develops scoliosis (a sideways curvature of the spine), bone fractures, or degenerative joint diseases, they may need treatment from an orthopedic surgeon. Similarly, dental abnormalities would require appropriate dental care. Any cardiovascular complications would need to be managed in a specialized care setting.
Bone marrow transplantation is another treatment that has been tried for this condition, with a variety of outcomes reported.
What else can Job Syndrome be?
Based on the symptoms, diagnosing Job syndrome can be challenging because it can be confused with other conditions. These conditions include:
- Other inherent immune system diseases like chronic granulomatous disease
- HIV infection, which is an acquired immune deficiency
- Severe atopic dermatitis, a type of skin inflammation
- Cystic fibrosis, a disease that affects the lungs and digestive system
What to expect with Job Syndrome
While AD-HIES, or Autosomal Dominant Hyper IgE Syndrome, can often present serious risks and health complications, recent advances in medical treatment, consistent check-ups, and patient adherence to their treatment plan have greatly improved the outlook. Now, patients can expect to live up to 50 years or even longer.
Possible Complications When Diagnosed with Job Syndrome
* Common cancers like non-Hodgkin’s lymphoma. Other types of cancers, such as Hodgkin’s lymphoma, vulva cancer, and lung cancer, can occur as well.
* Autoimmune diseases including Systemic Lupus Erythematosus (SLE), a kidney disorder known as membranoproliferative glomerulonephritis, blood vessel inflammation (vasculitis), and a muscle condition known as dermatomyositis.
* High blood pressure associated with abnormalities in the blood vessels.
* Heart attacks due to the rupture of blood vessels in the heart (coronary aneurysms).
* Small strokes due to the rupture of blood vessels in the brain (cerebral aneurysms).
In a simpler format:
- Common cancers such as non-Hodgkin’s and Hodgkin’s lymphoma, and cancers of the vulva and lung
- Autoimmune diseases like Systemic Lupus Erythematosus, a type of kidney disorder, blood vessel inflammation, and a muscle condition
- High blood pressure linked to blood vessel abnormalities
- Heart attacks resulting from ruptured heart blood vessels
- Small strokes due to ruptured blood vessels in the brain
