SUMMARY
1. STAT3 gain of function mutation patients are characterized by early onset multisystem autoimmune disease. Patients also have recurrent infections and can have a combined immunodeficiency phenotype.
2. Short stature is a key clinical finding.
3. STAT3 over activity results in suppression of other STAT molecules. Impaired STAT5 activation has been described, which may explain the short stature, T cell immunodeficiency and low T regulatory cell numbers. Impaired STAT 1 phosphorylation has also been described, which may explain the susceptibility to mycobacterial infections.
4. The autoimmune manifestations of this condition include autoimmune cytopenia, autoimmune enteropathy, Type I diabetes, and interstitial lung disease.
5. Immune abnormalities include hypogammaglobulinemia with low switched memory B cells. Patients may also have T, B or NK cell lymphopenia. Reduced T regulatory cell numbers have also been described. Patients have a susceptibility to bacterial, viral, fungal, and mycobacterial infections.
6. Patients require uninterrupted immunoglobulin replacement therapy for the antibody deficiency component of their disease.
7. Treatment with Toclizumab (anti IL-6R monoclonal antibody) appears to be effective in treating the autoimmune manifestations of this disease.
8. STAT3 gain of function should be included in the differential diagnosis for patients presenting with clinical symptoms suggestive of CVID + autoimmunity, IPEX-like disease, STAT5b deficiency, and autoimmune lymphoproliferative syndrome (ALPS).
OVERVIEW
STAT3 gain of function mutation patients are characterized by short stature and early onset multisystem autoimmune disease. Patients also have recurrent infections and can have a combined immunodeficiency phenotype.
The autoimmune manifestations of this condition include autoimmune cytopenia, autoimmune enteropathy, Type I diabetes, and interstitial lung disease.
Immune abnormalities include hypogammaglobulinemia with low switched memory B cells. Patients may also have T, B or NK cell lymphopenia. Reduced T regulatory cell numbers have also been described. Patients have a susceptibility to bacterial, viral, fungal, and mycobacterial infections.
STAT3 gain of function should be included in the differential diagnosis for patients presenting with clinical symptoms suggestive of CVID + autoimmunity, IPEX-like disease, STAT5b deficiency, and autoimmune lymphoproliferative syndrome (ALPS).
PATHOGENESIS
STAT3 gain of function mutation patients are characterized by short stature and early onset multisystem autoimmune disease. Patients also have recurrent infectioSTAT3 over activity results in suppression of other STAT molecules. Impaired STAT5 activation has been described, which may explain the short stature, T cell immunodeficiency and low T regulatory cell numbers. Impaired STAT 1 phosphorylation has also been described, which may explain the susceptibility to mycobacterial infections.
DIFFERENTIAL DIAGNOSIS
Other conditions that cause a CVID phenotype with autoimmunity include CTLA-4 deficiency, LRBA deficiency and PIK3CD gain of function mutations. Hyper IgM syndromes, combined immunodeficiencies (Ex. Wiskott-Aldrich, DOCK8) and “leaky” SCID would also be on the differential.
EVALUATION
STEP 1: Quantitative and Functional humoral/cell-mediated Evaluation
- Antibody titers to vaccine antigens
- Flow cytometry for B-cell, T-cell, and NK cell numbers
- Th17 flow cytometry
- Lymphocyte flow cytometry for B-cell subpopulations
- Lymphocyte proliferation to Mitogens/Antigens
- Patients can have have hypogammaglobulinemia and low switched memory B cell numbers. Low T, B and NK cell numbers have also been described.
STEP 2: Gene Sequencing
- STAT3 mutation analysis
- Individual gene sequencing is commercially available. Testing could also be accomplished by whole exome sequencing or whole genome sequencing.
MANAGEMENT
Replacement of serum IgG with monthly IVIG or weekly subcutaneous (SC) Ig is the cornerstone of therapy (400-600 mg/kg per month). Patients who maintain trough IgG levels above 700-900mg/dl have fewer infectious complications. SCIg is ideal for patients who benefit from maintaining steady serum levels of immunoglobulins or who are unable to tolerate IVIG due to adverse side effects (headache, chills, nausea,thrombotic events).
The addition of prophylactic antibiotics can be considered in patients who continue to have bacterial infections despite appropriate immunoglobulin replacement. Patients may also require prophylaxis for fungal and mycobacterial disease.
Tocilizumab (anti IL-6R monoclonal antibody) therapy can be very effective in addressing the autoimmune manifestations of this disease.
RESOURCES
Diagnostic Resources
1. Quantitative Immunoglobulin levels and specific antibody responses to vaccines (readily available at many academic centers and commercial laboratories)
2. Lymphocyte Subsets by Flow Cytometry for T-cell (CD3, CD4, CD8), B-cell (CD19), and NK cell (CD16/56). A CBC with differential needs to be ordered with each test in order to calculate absolute lymphocyte numbers.
- This test is commonly available at many academic centers as well as commercial laboratories
3. Switched Memory B-cells (CD27+IgM-IgD-) by Flow Cytometry
- Children’s Hospital of Philadelphia – Basic Lymphocyte Panel (have pdf of CHOP immunology test requisition and CHOP b cell panel sample requirements)
- Cincinnati Children’s Diagnostic Immunology Laboratory
4. STAT3 gene sequencing
- Cincinnati Childrens molecular genetics