STAT1 and STAT3 gain of function

Individuals with STAT1 GOF will present to a healthcare provider because of chronic or unusual infections or severe autoimmune disease that is not easily controlled with standard immune-suppressing medications.

One of the most common manifestations in individuals with STAT1 GOF is chronic infections with a fungus that are mostly limited to mucosal surfaces, skin, and nails, also known as chronic mucocutaneous candidiasis (CMC). This occurs in more than 90% of individuals with STAT1 GOF. CMC is an infection of the mucus membranes of the mouth (called thrush), gastrointestinal tract, skin, and nails with Candida or other common skin fungus. Presentation of CMC is usually in childhood, with some as young as 1 at the time the infections start. CMC can often be difficult to treat, requiring oral antifungal medication, and likely will return when antifungal medications are stopped.

More rarely, individuals with STAT1 GOF can be susceptible to severe invasive fungal infections. These infections include Aspergilllus, Histoplasma, Coccidiomycosis, and Cryptococcus. Pneumonia, an infection of the lungs, is the most common site of invasive fungal infection.

Bacterial infections with common, community-acquired bacterial organisms also occur in individuals with STAT1 GOF. The infections have a tendency to occur in the lungs as lower respiratory tract infections, bronchitis, or pneumonia. Bacterial infections of the eye, skin, and nail beds are also common. Individuals with STAT1 GOF are also susceptible to mycobacterial infections. Mycobacterium is a class of bacteria that typically only infect individuals with immunodeficiency or those that are immune suppressed.

Viral infections are also a source of concern in these individuals. The most common viruses causing infection are herpes family viruses such as herpes simplex virus, the cause of cold sores; varicella-zoster virus, the virus that causes chickenpox and shingles; Epstein-Barr virus (EBV), the cause of mononucleosis; human papillomavirus (HPV), the cause of warts; and cytomegalovirus (CMV), a virus that typically goes unnoticed but causes severe disease in individuals with immune deficiency. These viruses can cause skin infection, pneumonia, or enter the bloodstream where they cause widespread infection and dysfunction of different organ systems.

Most individuals develop some form of autoimmunity by the third decade of life. The autoimmunity that occurs in STAT1 GOF often affects the endocrine and hematologic systems. Hypothyroidism and early onset diabetes are common. Autoimmune hemolytic anemia and autoimmune thrombocytopenia (autoimmune destruction of red blood cells or platelets, respectively) can be life-threatening and may require blood or platelet transfusions.

A subset of individuals with STAT1 GOF have symptoms very similar to immunodysregulation-polyendocrinopathy-enteropathy-X-linked (IPEX). These individuals have early onset autoimmunity, such as diabetes mellitus and hypothyroidism as well. In addition, individuals with STAT1 GOF with similar symptoms to IPEX can have severe enteropathy. Enteropathy is destruction of the small and large intestine's absorptive surface. Individuals with enteropathy have substantial difficulty in absorbing nutrients and have very frequent diarrhea with weight loss and malnutrition. Because of poor nutrition, individuals will have growth failure.

Other clinical features include a susceptibility to the development of aneurysms in the brain. An aneurysm is an abnormal out-pouching of a blood vessel that causes the blood vessel wall to become weak. Small numbers of individuals have learning disabilities. Some individuals also demonstrate susceptibility to skin, gastrointestinal tract, and throat cancer.

The immune features in individuals with STAT1 GOF can be very variable. Individuals may have low lymphocyte counts and function, including low T cells, B cells, and NK cells. Some individuals may also have hypogammaglobulinemia (low IgG, low IgA, or low IgM). Susceptibility to infections, particularly viruses and Mycobacterium, occurs when there are abnormal lymphocyte counts and/or function.

Individuals with STAT3 GOF most commonly present with severe, early-onset autoimmunity. Individuals often have more than one autoimmune disease and the symptoms of autoimmunity are severe and hard to control. The most common types of autoimmunity involve the endocrine (hormone) system, the hematologic system (blood cells and platelets), gastrointestinal tract, lungs, and liver.

Thyroid disease is the most common autoimmune endocrine disorder, treated with thyroid replacement. Hematologic autoimmune disorders include autoimmune destruction of the blood cells and platelets that can be life-threatening and require transfusions of blood or platelets. Enteropathy, due to autoimmune destruction of the lining of the intestinal tract, presents as chronic diarrhea and can cause severe malabsorption of nutrients and failure to thrive. In addition, some individuals may have inflammation of the intestine or colon, termed colitis, that can also lead to poor weight gain, abdominal pain, chronic diarrhea, and blood in the stool. Autoimmune destruction of the liver or lung can lead to organ dysfunction or failure respectively. Other autoimmune disorders, including eczema, rheumatoid arthritis, and eye disease, can also occur.

A major feature of individuals with STAT3 GOF is the presence of lymphoproliferative disease. In lymphoproliferative disease, immune cells in lymphoid organs grow at an abnormal rate (lymphoproliferation). Lymphoid organs include the spleen, liver, and lymph nodes. When this growth occurs, these organs expand causing abnormally large lymph nodes, liver, and/or spleen. Lymphoproliferation can ultimately impact the function of the affected organ and can prevent the lymph cells from responding appropriately when there is an infection.

Acute short stature is another common feature in individuals with STAT3 GOF. The height of individuals is often substantially lower than expected for their age, and this persists to adulthood. Individuals often are treated with growth hormone replacement, but it is controversial as to whether there is any benefit.

Immune abnormalities also are variable in individuals with STAT3 GOF. Low T cell and B cell numbers can occur, as can hypogammaglobulinemia (low IgG, low IgA, or low IgM). It is often hard to differentiate if the immune abnormalities are secondary to the treatment of the autoimmune features. Infections can occur in STAT3 GOF, but the autoimmune features are the more common presentation. Infections, including bacterial, viral, mycobacterial, and fungal, can be severe, invasive, and life-threatening. Prophylaxis against infections is often used, especially if a substantial number of immune-suppressing medications are used for treatment of autoimmunity.