Autosomal dominant hyper-IgE syndrome (AD-HIES), formerly known as Job syndrome, is a condition that affects several body systems, particularly the immune system. Recurrent infections are common in people with this condition. Affected individuals tend to have frequent bouts of pneumonia, which are caused by certain kinds of bacteria that infect the lungs and cause inflammation. Inflammation is a normal immune system response to injury and foreign invaders (such as bacteria). However, excessive inflammation can damage body tissues. Recurring pneumonia often results in the formation of air-filled cysts (pneumatoceles) in the lungs. Frequent skin infections and an inflammatory skin disorder called eczema are also very common in AD-HIES. These skin problems cause rashes, blisters, accumulations of pus (abscesses), open sores, and scaling.

For unknown reasons, people with AD-HIES have abnormally high levels of an immune system protein called immunoglobulin E (IgE) in the blood. IgE normally triggers an immune response against foreign invaders in the body, particularly parasitic worms, and is involved in allergies. However, IgE is not needed for these roles in people with AD-HIES, and it is unclear why affected individuals have such high levels of the protein without having allergies.

AD-HIES also affects other parts of the body, including the bones and teeth. Many people with AD-HIES have skeletal abnormalities such as an unusually large range of joint movement (hyperextensibility), an abnormal curvature of the spine (scoliosis), reduced bone density (osteopenia), and a tendency for bones to fracture easily. A common dental abnormality in this condition is that the primary (baby) teeth do not fall out at the usual time during childhood but are retained as the adult teeth grow in. Other signs and symptoms of AD-HIES can include abnormalities of the arteries that supply blood to the heart muscle (coronary arteries), distinctive facial features, and structural abnormalities of the brain, which do not affect a person's intelligence.

Mutations in the STAT3 gene cause most cases of AD-HIES. This gene provides instructions for making a protein that plays important roles in several body systems. To carry out its roles, the STAT3 protein attaches to DNA and helps control the activity of particular genes. In the immune system, the STAT3 protein regulates genes that are involved in the maturation of immune system cells, especially certain types of T cells. T cells and other immune system cells help control the body's response to foreign invaders such as bacteria and fungi.

Changes in the STAT3 gene alter the structure and function of the STAT3 protein, impairing its ability to control the activity of other genes. A shortage of functional STAT3 blocks the maturation of T cells (specifically a subset known as Th17 cells) and other immune cells. The resulting immune system abnormalities make people with AD-HIES highly susceptible to infections, particularly bacterial and fungal infections of the lungs and skin. The STAT3 protein is also involved in the formation of cells that build and break down bone tissue, which could help explain why STAT3 gene mutations lead to the skeletal and dental abnormalities characteristic of this condition. It is unclear how STAT3 gene mutations lead to increased IgE levels.

Mutations in the ZNF341 gene cause a disorder similar to AD-HIES but with a different pattern of inheritance. When the STAT3 gene is involved, one altered copy of the gene is sufficient to cause the disorder (which is known as autosomal dominant inheritance). In contrast, when the ZNF341 gene is involved, both copies of the gene are altered (which is known as autosomal recessive inheritance).

The ZNF341 gene provides instructions for making a protein that appears to control the activity of the STAT3 gene. ZNF341 gene mutations, which prevent production of functional ZNF341 protein, result in a shortage of STAT3 protein, leading to immune system problems similar to those caused by STAT3 gene mutations.

AD-HIES is thought to be caused by mutations in other genes that have not been definitively linked to the condition.

Normal Function

The STAT3 gene is part of a family known as the STAT genes. These genes provide instructions for making proteins that are part of essential chemical signaling pathways within cells. When STAT proteins are turned on (activated) by certain chemical signals, they move into the cell's nucleus and attach (bind) to particular areas of DNA. The STAT proteins bind to regulatory regions near genes, which allows the proteins to control whether these genes are turned on or off. STAT proteins are called transcription factors on the basis of this action.

Through its regulation of gene activity, the STAT3 protein is involved in many cellular functions. It helps control cell growth and division (proliferation), cell movement (migration), and the self-destruction of cells (apoptosis).

The STAT3 protein is active in tissues throughout the body. It plays an important role in the development and function of several body systems and is essential for life. In the immune system, the STAT3 protein transmits signals for the maturation of immune system cells, especially T cells and B cells. These cells help control the body's response to foreign invaders such as bacteria and fungi.

In addition, the protein is involved in the regulation of inflammation, which is one way the immune system responds to infection or injury, and it plays a role in cellular processes that promote allergic reactions.

In the skeletal system, the STAT3 protein is involved in the formation of specialized cells that build and break down bone tissue. These cells are necessary for the normal development and maintenance of bones.

Health Conditions Related to Genetic Changes

Autosomal dominant hyper-IgE syndrome

More than 100 germline mutations in the STAT3 gene have been identified in people with autosomal dominant hyper-IgE syndrome (AD-HIES), a disorder of the immune system that leads to recurrent skin and lung infections as well as abnormalities of the bones, teeth, and blood vessels. The condition is characterized by high levels of an immune system protein called immunoglobulin E (IgE), which is involved in allergic reactions. Most of the mutations involved in this condition change single amino acids in the STAT3 protein.

Changes in the STAT3 gene that cause AD-HIES alter the structure and function of the STAT3 protein, impairing its ability to control the activity of other genes. Most of these mutations have a dominant-negative effect, which means that the altered protein produced from one copy of the STAT3 gene interferes with the function of the normal protein produced from the other copy of the gene.

The lack of STAT3's signaling function disrupts the normal maturation of T cells (specifically a subset known as Th17 cells) and other immune system cells. The resulting immune system abnormalities make people with AD-HIES highly susceptible to infections, particularly bacterial and fungal infections affecting the lungs and skin.

A shortage of functioning STAT3 protein prevents cells from reacting to signals that trigger allergic reactions, which explains why people with AD-HIES do not have an increased risk of allergies, despite having high levels of IgE. It is unclear why levels of this protein are elevated in affected individuals.

The role of STAT3 protein in the formation and maintenance of bone tissue may help explain why STAT3 gene mutations lead to the skeletal and dental abnormalities characteristic of this condition, but it is unclear what causes blood vessel abnormalities in AD-HIES.

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Autoimmune disorders

At least 20 STAT3 gene mutations have been found to cause an autoimmune disorder that affects many body systems. Autoimmune disorders are a group of immune system abnormalities in which the immune system malfunctions and attacks the body's own cells and tissues.

In people with these STAT3 gene mutations, autoimmunity typically begins in infancy or early childhood and involves more than one body system. In these individuals, signs and symptoms commonly result from immune system attacks on insulin-producing cells in the pancreas (type 1 diabetes), red blood cells (autoimmune hemolytic anemia), platelets (autoimmune thrombocytopenia), or tissues in the digestive tract (autoimmune enteropathy).

The mutations involved in these conditions are typically inherited and are found in every cell of the body (known as germline mutations). They change single protein building blocks (amino acids) in the STAT3 protein, resulting in an altered protein that is abnormally active. Due to this effect, the mutations are classified as "gain-of-function."

Normally, the STAT3 protein is switched on and off in response to signals that control cell growth and development. A continuously active version of this protein relays messages to the nucleus even in the absence of these chemical signals. Abnormal STAT3 activity prevents normal control of the immune system, leading to autoimmunity.

Cancers

STAT3 gene mutations are found in approximately one-third of cases of a blood cancer called large granular lymphocytic leukemia (LGL), which is characterized by the accumulation of white blood cells (lymphocytes) that are abnormally large and contain structures called granules.

Individuals with LGL may also have an autoimmune disorder, primarily rheumatoid arthritis or autoimmune hemolytic anemia, and other blood cell abnormalities, such as pure red cell aplasia. There are two forms of the condition, based on the type of white blood cell involved: T-cell large granular lymphocytic leukemia (T-LGL) and chronic lymphoproliferative disorders of NK cells (CLPD-NKs). Both forms have the same signs and symptoms.

Unlike mutations that cause the autoimmunity (described above), LGL-associated STAT3 gene mutations are not inherited and are found only in the abnormal lymphocytes. (Such mutations are known as somatic mutations.) The mutations involved in LGL are classified as "gain-of-function," leading to an overactive STAT3 protein.

Researchers believe that the overactive STAT3 protein instructs cells to continue growing and dividing, and prevents damaged cells from self-destructing (undergoing apoptosis). Excess STAT3 protein may contribute to the growth of cancers by allowing abnormal cells to grow and divide uncontrollably.

Other Names for This Gene

• acute-phase response factor
• APRF
• APRF Transcription Factor
• DNA-binding protein APRF
• FLJ20882
• hypothetical protein MGC16063
• IL6-Response Factor
• LIF(leukemia inhibitory factor)-Response Factor
• LIF-Response Factor
• signal transducer and activator of transcription 3 (acute-phase response factor)
• STAT3_HUMAN

Genomic Location

AD-HIES has an autosomal dominant pattern of inheritance, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In about half of cases caused by STAT3 gene mutations an affected person inherits the mutation from one affected parent. The other half result from new mutations in the gene and occur in people with no history of the disorder in their family.

A similar condition caused by mutations in the ZNF341 gene has an autosomal recessive pattern of inheritance, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

The diagnosis of autosomal dominant hyper IgE syndrome (AD-HIES) is most often made based on a combination of clinical and laboratory findings. Diagnostic guidelines have been developed that include both immunologic /infectious manifestations and skeletal/connective tissue abnormalities. Molecular genetic testing of the STAT3 gene confirms the diagnosis.

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.

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.