STAT3 dominant-negative disease (STAT3DN)—also known as autosomal dominant hyper-IgE syndrome (AD-HIES) or Job’s Syndrome—results from mutations in the gene that encodes a signaling protein called STAT3. People with this disease tend to have very high levels of an antibody called immunoglobulin E (IgE), recurrent infections of the skin and lungs, recurrent bone fractures, unusually flexible joints, and inflamed skin.
STAT3 dominant-negative disease has widespread deleterious effects on patients’ health, so NIAID scientists aim to develop and enhance treatments to improve patients’ quality of life. In addition, NIAID scientists hope that studying this disease will help them better understand the physiological processes associated with the genetic tendency to develop certain types of infections and allergic diseases.
NIAID investigators identified the role of STAT3 in this disease in 2007. Since then, NIAID-supported researchers have made multiple discoveries about how the loss-of-function mutation in the STAT3 gene leads to patients’ symptoms. NIAID-supported clinical research seeks to determine the effect of STAT3 dominant-negative disease on the immune system, including which immune cells and responses are affected and how these abnormalities translate into patients’ symptoms.
Causes
STAT3 dominant-negative disease results from mutations in the gene that encodes a signaling protein called STAT3. This protein is involved in many different activities of the body, explaining why the disease affects not only the immune system but also facial appearance, bones, lungs, skin, and arteries.
Signs and Symptoms
People with STAT3 dominant-negative disease (STAT3DN) have very high levels of IgE and may have recurrent infections of the skin and lungs. These infections are often caused by the bacterium Staphylococcus aureus but also may be caused by other bacteria and fungi. Patients also tend to have recurrent bone fractures, unusually flexible joints, and inflamed skin, and may have a rash similar to eczema. Baby teeth in people with this disease often do not fall out on their own. People with STAT3DN also often have distinctive facial characteristics, such as uneven facial features, prominent forehead, deep-set eyes, broad nasal bridge, wide, fleshy nose tip, and protruding lower jaw.
In 2008, NIAID scientists discovered that important immune cells called Th17 cells are missing in people with STAT3DN. NIAID researchers also found in 2011 that an unusually low number of immune memory cells may cause people with the disease to be more susceptible to some viral infections. In 2013 and 2016, NIAID researchers showed that the STAT3 mutation protects people from more severe allergic disease by interfering with the process that causes typical allergic reactions.
Diagnosis
A doctor will suspect STAT3DN in a person with eczema, very high IgE, recurrent boils, and pneumonias. Blood tests diagnosing the disease will show normal levels of IgG, IgA, and IgM antibodies but very high levels of IgE antibodies. People with the disease also may show a high number of white blood cells called eosinophils and a poor response to immunizations. Sequencing of the patient’s DNA can confirm the presence of the STAT3 mutation.
Treatment
The most effective treatments for STAT3 dominant-negative disease are continuous antibiotics and antifungals as needed, as well as careful monitoring for infections, which can be severe even when symptoms do not appear so. Some patients receive antibody replacement therapy. Antiseptic approaches, such as dilute bleach baths, often help prevent skin infections and improve eczema.