Gain-of-Function Mutations inSTAT1: A Recently Defined Cause for Chronic Mucocutaneous Candidiasis Disease Mimicking Combined Immunodeficiencies

Abstract

Chronic Mucocutaneous Candidiasis (CMC) is the chronic, recurrent, noninvasive Candida infections of the skin, mucous membranes, and nails. A 26-month-old girl was admitted with the complaints of recurrent oral Candidiasis, diarrhea, and respiratory infections. Candida albicans grew in oral mucosa swab. CMV and EBV DNA titers were elevated. She had hypergammaglobulinemia; IgE level, percentages of lymphocyte subgroups, and in vitro T-cell proliferation responses were normal. She had parenchymal nodules within the lungs and a calcific nodule in the liver. Chronic-recurrent infections with different pathogens leading to significant morbidity suggested combined immunodeficiency, CMC, or Mendelian susceptibility to mycobacterial diseases. Genetic analysis revealed a predefined heterozygous gain-of-function mutation (GOF) (c.1154 C>T, p.Thr385Met) in the gene coding STAT1 molecule. Hematopoietic stem cell transplantation (HSCT) was planned because of severe recurring infections. Patients with STAT1 GOF mutations may exhibit diverse phenotypes including infectious and noninfectious findings. HSCT should be considered as an early treatment option before permanent organ damage leading to morbidity and mortality develops. This case is presented to prompt clinicians to consider STAT1 GOF mutations in the differential diagnosis of patients with chronic Candidiasis and recurrent infections with multiple organisms, since these mutations are responsible for nearly half of CMC cases reported.

Noncanonical STAT3 activity sustains pathogenic Th17 proliferation and cytokine response to antigen

“…STAT3 deletion in murine naive T cells or fibroblasts, and dysfunctional STAT3 in patients with hyper-IgE syndrome, result in enhanced STAT1 activity and gene expression signature ( Costa-Pereira et al, 2002 ; Hirahara et al, 2015 ; Wan et al, 2015 ). Gain-of-function mutations in STAT1 have been shown to inhibit Th17 responses and cause chronic mucocutaneous candidiasis that is clinically similar to Th17 cell–associated immunodeficiency ( Eren Akarcan et al, 2017 ). Thus, these data and our results suggest that negative regulation of STAT1 activation is an important function of STAT3 in maintaining healthy Th17 cell populations at barrier surfaces.…”

The Usefulness of Flow Cytometry for Measuring Phosphorylated Signal Transducer and Activator of Transcription 1 to Diagnose and Manage Chronic Mucocutaneous Candidiasis: A Case Report

“…STAT1 is a key transcription factor that mediates the IFN-α/β signaling and regulates the immune response via factors such as IFN-γ and interleukin-17 [3], and both loss-and gain-of-function STAT1 mutations have been described in PIDs [9]. In the case of the GOF STAT1 mutation, STAT1 hyperphosphorylation causes a defect in Th17 cell differentiation, which is crucial for a mucosal antifungal immunity, and induces clinical characteristics of CMC such as an oral thrush and candida infection of the skin and mucous membranes [17]. Thus, the phosphorylation of STAT1 may be observed with FCM and can be used as a trace marker for the treatment response.…”

Primary immunodeficiency and chronic mucocutaneous candidiasis: pathophysiological, diagnostic, and therapeutic approaches.

“…Herpes simplex virus (HSV), Varicella Zoster virus (VZV), Cytomegalovirus (CMV), Epstein-Barr virus (EBV), and human Papilloma virus (HPV) have also been described. 3,22 Autoimmunity clinical features can develop. Hypo-and hyperthyroidism are the most frequent autoimmune manifestations, followed by type 1 diabetes mellitus (DM), vitiligo, alopecia, psoriasis, lupus erythematosus, pernicious anemia, celiac disease, autoimmune hepatitis, and inflammatory bowel disease.…”