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NIAID

STAT3 Gain-of-Function 

Disease

STAT3 gain-of-function disease (also called STAT3 GOF disease) is a rare genetic disorder of the 

immune system. STAT3 GOF disease is named after the gene that causes it, STAT3 (signal transducer 

and activator of transcription 3), and the effect caused by mutations in STAT3—gain-of-function, 

meaning that the gene’s protein becomes overactive.

STAT3 GOF disease is an early-onset autoimmune and lymphoproliferative disease (see Glossary). The 

symptoms of this disease vary and can include swelling of the lymph nodes (lymphadenopathy), reduc

tions in the number of blood cells (autoimmune cytopenias), autoimmunity that affects multiple organs 

and tissues, infections, eczema, and in some cases, short stature. Sarah Flanagan and Mark Russell of 

University of Exeter Medical School and Joshua Milner of NIAID originally described this condition 

in 19 patients in 2014 and 2015. Since then, dozens of additional patients have been identified.

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Genetics and Function

STAT3 GOF disease is caused by gainof-function mutations in the STAT3

gene. This gene provides instructions 

for production of the STAT3 protein, 

part of the STAT family of proteins. 

Various mutations have been identified 

across the length of the STAT3 protein.

STAT proteins play an essential role 

in chemical signaling pathways within 

cells. STAT3 is a transcription fac

tor, a type of protein that regulates 

when other genes are turned on. Once 

activated, STAT3 moves into the 

nucleus of the cell and binds to specific 

areas of DNA. By binding to regula

tory DNA regions near genes, STAT3 

controls the activity of a variety of 

genes. It is necessary for many cellular 

processes, including cell proliferation, 

inflammation, differentiation, and 

cell survival.

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U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health

National Institute of Allergy and Infectious Diseases

Genetics primer: All the cells in the body contain instructions on how to do 

their job. These instructions are packaged into chromosomes, each of which 

contains many genes, which are made up of DNA. Errors, or mutations, in the 

genes can cause diseases such as STAT3 GOF disease. Credit: NIAID

Schematic of the STAT3 protein showing the location of different mutations 

and the resulting amino acid changes. Credit: NIAID 
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Inheritance

STAT3 GOF disease is inherited in an autosomal dominant 

manner, which means that a person needs an abnormal 

gene from only one parent to have the disease. The abnor

mal STAT3 gene dominates the normal STAT3 gene from 

the other parent. Dominant inheritance also means that 

most families with STAT3 GOF disease have affected rela

tives in each generation on the side of the family with the 

mutation. However, researchers have found that, in some 

families, relatives carrying a STAT3 mutation do not 

have symptoms of the disease. This is called incomplete 

penetrance.

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Unlike mutations that run in a family, some STAT3

mutations occur as a result of a mutation in the egg or 

sperm of one of the parents or in the fertilized egg itself. 

These are called de novo, which means “new” mutations. 

In these cases, the patient does not have a family history 

of similar symptoms. De novo mutations can be passed 

on to children.

Children of a parent who carries a STAT3 mutation have a 50 percent chance of inheriting the 

mutation. This means that, within a given family, each child’s risk of inheriting the mutated gene is 

independent of whether or not siblings have the mutation. For example, if the first three children in 

a family have the mutation, the fourth child has the same 50 percent risk of inheriting the mutation. 

Children who do not inherit the abnormal gene will not develop STAT3 GOF disease or pass on 

the mutation.

Clinical Symptoms

Clinically, STAT3 GOF disease is diverse. It is characterized by a buildup of immune cells called 

lymphocytes (lymphoproliferation) and early-onset autoimmunity affecting multiple organs and 

tissues. Exactly when, where, and to what extent these problems will develop in any one person 

cannot be predicted.

Lymphoproliferation: The main signs or symptoms of lymphoproliferation are lymphadenopathy 

(enlarged or swollen lymph nodes that wax and wane over time) and/or splenomegaly (an enlarged 

spleen) and sometimes hepatomegaly (an enlarged liver).

Autoimmunity: Hematologic autoimmunity is the most common type of autoimmunity in STAT3

GOF disease. This includes autoimmune hemolytic anemia (attacks against red blood cells), 

neutropenia (attacks against white blood cells), and/or thrombocytopenia (attacks against platelets). 

Autoimmunity also can develop against other organs and tissues. Examples of such autoimmune 

problems include arthritis (attacks against joints), lung disease (attacks against lungs), hepatitis 

In this example, a man with an autosomal 

dominant disorder has two affected children and 

two unaffected children. Women also can pass 

on the mutation. Credit: U.S. National Library of 

Medicine
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(attacks against liver), eczema (attacks against 

skin), alopecia (attacks against hair follicles), type 

1 diabetes (attacks against part of the pancreas), 

and/or scleroderma (attacks against skin and 

connective tissue).

Some patients also have recurrent, severe infec

tions and fungal infections with low antibody 

levels (hypogammaglobulinemia). Some patients 

have short stature, with some exhibiting profound 

growth failure. In rare cases, patients with STAT3

GOF develop cancers, such as lymphoma.

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Notably, the clinical symptoms of STAT3 GOF 

patients differ distinctly from those associated with 

STAT3 loss-of-function mutations. STAT3 lossof-function mutations are responsible for hyperimmunoglobulin E syndrome, also called Job’s 

syndrome, which is characterized by recurrent skin 

infections, unusual eczema-like skin rashes, and 

susceptibility to severe lung infections.

Laboratory Findings

STAT3 GOF patients have moderately low levels of T cells, hypogammaglobulinemia, and elevated lev

els of immune cells called double negative CD4/CD8 T cells. More studies are required to better under

stand the connection between these laboratory findings and the type and severity of clinical symptoms.

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Treatment

Treatment is based on a person’s clinical condition and may include standard therapies for autoim

mune problems. In one reported case, a patient with severe autoimmune hemolytic anemia responded 

well to the drug rituximab. In another case, use of the drug tocilizumab resulted in a dramatic 

improvement in one patient’s arthritis. Some patients with short stature have responded well to 

growth hormone treatment. Bone marrow transplant is a possible treatment for this condition and 

has been used with mixed results in a small number of patients with severe disease.

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More research with larger numbers of patients is required to further assess these therapeutic 

approaches.

STAT3 GOF Disease and Your Family

Living with STAT3 GOF disease can be difficult not only for the person who has it but also for 

their family members. It is important for families to talk openly about STAT3 GOF disease and 

Clinical features of STAT3 GOF disease. Credit: NIAID
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about how the family is dealing with it so misconceptions can be corrected and children can learn 

to cope with their reactions. Some children with STAT3 GOF disease have to work hard to develop 

their self-confidence and sense of security. Everyone needs to be reminded that they have many 

positive characteristics, especially when their appearance attracts attention (for example, due to 

large lymph nodes).

Some children who have siblings with STAT3 GOF disease worry about their brother or sister being 

in pain or dying from the disease. Some think that they may develop symptoms because they look or 

act like a sibling who has the disease or that the disease is contagious. Some children struggle with 

how much time their parents spend with their sick sibling. Many families benefit from meeting or 

talking to other families affected by the same rare disease. Patient organizations such as the Immune 

Deficiency Foundation (www.primaryimmune.org) also are great resources for providing useful 

information and support. Counseling also can help families cope with the challenges of living with 

a chronic condition.

At the same time, many families say that STAT3 GOF disease has brought them closer together. 

Family members learn about controllable and uncontrollable aspects of life. Although certain aspects 

of the disorder cannot be controlled, how a family responds to the stress of any illness is controllable 

and an important aspect of managing STAT3 GOF disease. Children also learn who they can turn to 

for support and how to solve problems. Acknowledging both the challenges and opportunities that 

STAT3 GOF disease presents helps children develop resilience.
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Glossary

Achalasia—A rare disorder that makes it difficult for food and 

liquid to pass from the esophagus into the stomach.

Autoimmune—Describes a process during which a person’s 

immune system attacks healthy cells, organs, and tissues.

Autosomal dominant—A pattern of inheritance in which an 

affected person has one mutated copy of a gene and one 

normal copy.

Cytopenias—Reductions in the number of blood cells. Cytopenias 

can take several forms: a low red blood cell count results in ane

mia, a low white blood cell count results in leukopenia or neutro

penia, and a low platelet count is called thrombocytopenia.

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De novo mutation—An alteration in a gene that is present for 

the first time in one family member as a result of a mutation 

in the egg or sperm of one of the parents or in the fertilized 

egg itself.

DNA (deoxyribonucleic acid)—A self-replicating material pres

ent in nearly all living organisms. It is the carrier of genetic 

information.

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Double negative CD4/CD8 T cells—Specific type of T cell with

out the markers of a CD4 T cell or a CD8 T cell.

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Eczema—A medical condition in which patches of skin become 

rough and inflamed, with blisters that cause itching and bleeding. 

Sometimes also called atopic dermatitis.

Gain-of-function—The overactivation of a gene or gene product 

caused by a genetic mutation.

Gene—A unit of heredity that is transferred from parent to child. 

Genes are made up of DNA.

Gene expression—The extent to which various genes are 

“turned on,” causing their protein products to be produced.

Heterozygous—For a gene present in two copies (one inherited 

from each parent), heterozygous refers to having a mutation 

or change in only one of the two copies. This is in contrast to 

homozygous, in which both copies have mutations or changes.

Hypogammaglobulinemia—A type of immune deficiency that is 

characterized by a reduction in all types of gamma globulins, 

or infection-fighting antibodies.

Hypothyroidism—A condition in which the thyroid does not 

produce enough thyroid hormone. The thyroid is a small gland 

at the base on the neck, below the Adam’s apple.

Incomplete penetrance—Penetrance refers to the degree to 

which a particular variant of a gene is expressed in a popula

tion. Incomplete penetrance means that not everyone who 

carries the variant expresses the trait.

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Inflammation—A localized physical condition in which part of 

the body becomes reddened, swollen, hot, and often painful, 

typically as a reaction to injury or infection.

Lymphadenopathy—Enlarged lymph nodes.

Lymphoproliferative—Referring to the proliferation or overproliferation of immune cells or lymphocytes.

Nucleus—The control center of a cell, which houses DNA.

Signaling pathways—A set or cascade of chemical reactions 

inside a cell that occurs when a molecule attaches to a receptor 

on the cell membrane to cause a change within the cell.

T-cell lymphopenia—Having too few T cells.

Transcription factor—A protein that binds to specific DNA 

sequences, thereby controlling which genes are “turned on.”

September 2016

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