SUMMARY
1. Complete homozygous mutations in STAT1 cause a severe immunodeficiency with marked susceptibility to viral, bacterial, and mycobacterial infections, whereas heterozygous STAT1 mutations result in a milder phenotype with susceptibility to only mycobacterial disease.
2. A number of clinical phenotypes have been described with dominant gain of function (GOF) STAT1 mutations which result in enhanced STAT1 phosphorylation.
-Chronic Mucocutaneous Candidiasis (CMC) – Th17 immunity is critical for defense against fungal pathogens. Impaired dephosphorylation of STAT1 results in reduced numbers of Th17 cells.
-Disseminated Coccidiomycosis, Histoplasmosis – The IFN-gamma/IL-12 signaling pathway is critical for defense against intracellular bacteria and mycobacteria as well as certain dimorphic fungi (Histoplasmosis, Coccidiomycosis, Paracoccidiodes). GOF STAT1 mutations result in increased IFN-gamma gene expression but impaired responses to IFN-gamma re-stimulation.
-IPEX-like syndrome – Patients can also present with an IPEX-like disease with normal frequency and function of T regulatory cells. Th17 cells were decreased in patients. However, the exact underlying mechanism of how GOF STAT1 mutations result in autoimmune enteropathy is unclear.
3. Testing should include evaluation for other primary immunodeficiencies which can present with CMC or severe enteropathy.
4. STAT1 gene sequencing confirms the diagnosis
OVERVIEW
1. Complete homozygous mutations in STAT1 cause a severe immunodeficiency with marked susceptibility to viral, bacterial, and mycobacterial infections, whereas heterozygous STAT1 mutations result in a milder phenotype with susceptibility to only mycobacterial disease.
2. A number of clinical phenotypes have been described with dominant gain of function (GOF) STAT1 mutations which result in enhanced STAT1 phosphorylation.
-Chronic Mucocutaneous Candidiasis (CMC) – Th17 immunity is critical for defense against fungal pathogens. Impaired dephosphorylation of STAT1 results in reduced numbers of Th17 cells.
-Disseminated Coccidiomycosis, Histoplasmosis – The IFN-gamma/IL-12 signaling pathway is critical for defense against intracellular bacteria and mycobacteria as well as certain dimorphic fungi (Histoplasmosis, Coccidiomycosis, Paracoccidiodes). GOF STAT1 mutations result in increased IFN-gamma gene expression but impaired responses to IFN-gamma re-stimulation.
-IPEX-like syndrome – Patients can also present with an IPEX-like disease with normal frequency and function of T regulatory cells. Th17 cells were decreased in patients. However, the exact underlying mechanism of how GOF STAT1 mutations result in autoimmune enteropathy is unclear.
EVALUATION
STEP 1: Immune Evaluation
-IgG, IgM, IgA, IgE
-Specific antibody responses to vaccine antigens
-Lymphocyte enumeration by flow cytometry
-Lymphocyte mitogen stimulation
-A general immune screening evaluation should be performed to screen for other T cell or combined immune deficiencies which can present with CMC or enteropathy.
STEP 2: Th17 enumeration
-Patients with gain of function STAT1 mutations have reduced Th17 cell populations.
STEP 3: Gene Sequencing
-STAT1 gene sequencing
-Genetic testing for STAT1 mutations is commercially available and can confirm the diagnosis.
RESOURCES
Diagnostic Resources
1. Th17 enumeration (flow cytometry) and STAT1 Gene Sequencing - Seattle Children Immunology
Literature Resources
1. Liu 2011
STAT1 gain of function mutations and CMCC
2. Sampaio 2013
STAT1 gain of fxn mutations and disseminated histoplasmosis, coccidiomycosis
3. Uzel 2013
STAT1 gain of function mutations and IPEX-like disease