STAT3 Gain-of-Function Disease (STAT3 GOF) is an extremely rare genetic disorder that strongly affects the immune system, causing severe autoimmunity (when your white blood cells attack your own body tissues) that starts at an early age. The STAT3 gene controls the activity of some T cells – a type of white blood cell – and when a particular gain-of-function mutation occurs in them, these T-cells become overactive. Gain-of-function mutations usually lead to the overproduction or overactivity of whatever cell they occur in. In STAT3 GOF, the overactive T-cells cause abnormalities in chemical signalling pathways, leading to autoimmunity.
The autoimmunity in STAT3 GOF usually demonstrates itself in the form of very swollen lymph nodes (lymphadenopathy), abnormally low blood cells (cytopenia), and damage to several organs like the liver, the skin, the lungs, and more. STAT3 GOF is often very difficult to treat because the medicines that reduce autoimmunity can also be toxic, as well as predispose people to severe infections.
The symptoms of STAT3 GOF can range widely from person to person, and almost every part of the body can be affected by it.
Important symptoms of STAT3 GOF include:
Autoimmune Lymphoproliferative Syndrome (ALPS)
Caspase Eight Deficiency State (CEDS)
CARD9 Deficiency And Other Syndromes Of Susceptibility To Candidiasis
Chronic Granulomatous Disease (CGD)
Common Variable Immunodeficiency (CVID)
Congenital Neutropenia Syndromes
Hyper-Immunoglobulin E Syndromes
Hyper-Immunoglobulin M Syndromes
Interferon Gamma, Interleukin 12 And Interleukin 23 Deficiencies
Leukocyte Adhesion Deficiency (LAD)
PLCG2-Associated Antibody Deficiency And Immune Dysregulation (PLAID)
Severe Combined Immunodeficiency (SCID)
STAT3 Dominant Negative Disease (STAT3DN)
Warts, Hypogammaglobulinemia, Infections, And Myelokathexis (WHIM) Syndrome
Wiskott-Aldrich Syndrome (WAS)
X-Linked Agammaglobulinemia (XLA)
X-Linked Lymphoproliferative Disease (XLP)
Immunodeficiency Disease Medications
STAT3 GOF is caused by a gain-of-function mutation at the STAT3 gene. This means that the STAT3 gene overproduces certain proteins, which leads to the feature of STAT3 GOF disease.
Sometimes STAT3 GOF is a familial, inherited disorder and people get it from their parents. Other times, STAT3 GOF arises from de novo mutations, which are mutations that occurs spontaneously in a person during their conception.
There are no known risk factors for STAT3 GOF other than family history. This is because STAT3 GOF is inherited in an autosomal dominant manner, which means the abnormal, mutated copy of the STAT3 gene dominates the normal, non-mutated copy. In a family where one parent has STAT3 GOF and the other parent does not, each child of theirs will have a 50% chance of having STAT3 GOF.
Because STAT3 GOF is so rare (it has been diagnosed in less than 100 people worldwide) the exact methods for diagnosing it haven’t been outlined yet.
So far, the specialists who treat STAT3 GOF recommend that T cells are counted and differentiated into types. A low T cell count is one of the signs leading to a diagnosis of immunodeficiency disorders in general, and of STAT3 GOF in particular.
Genetic testing may also be important in diagnosing STAT3 GOF, especially if it is STAT3 GOF that is heritable and passed down in a family.
Unfortunately, STAT3 GOF cannot be cured. Instead, STAT3 GOF is managed supportively, which means it is treated with interventions that help improve the day-to-day lives of people that live with the disorder.
Treatment for STAT3 GOF is often individualized, to suit the symptoms that arise in each affected person. Most patients may require strong immunosuppressant drugs, like rituximab or tocilizumab, which can be helpful to treat symptoms like arthritis or autoimmune anaemia. Still, these drugs may cause significant problems. Immunosuppressants are often toxic to certain cells in our bodies, and they also dramatically increase the risk of infection, so it is important to take them only under the close supervision of your doctor.
Bone marrow transplants may be used as a treatment for STAT3 GOF and may improve the immune function of people with severe disease.
Ultimately, the exact treatment of STAT3 GOF is decided often by a team of specialist doctors, taking into consideration the goals of each patient to deliver the best possible outcome.