A Child with Chronic Mucocutaneous Candidiasis Harbors a Novel Gain-of-Function Mutation in STAT1.

Objective: Germline heterozygous gain-of-function (GOF) mutations in STAT1 impair IL-17-mediated immunity, resulting in carriers' susceptibility to chronic mucocutaneous candidiasis (CMC). JAK inhibitors have shown therapeutic effectiveness in patients with STAT1-GOF mutations.

Methods: The mutation was detected using whole-exome sequencing (WES) and confirmed by Sanger sequencing. The functional impact of the mutation was verified by luciferase reporter assay. The phosphorylation level of STAT1 in patient cells, the phenotyping of leukocyte subtypes, and serum cytokine levels were determined by flow cytometry.

Results: The patient with CMC harbors a heterozygous missense mutation in STAT1 (c.1078G > C, p.V360L). This mutation was functionally validated as a GOF mutation based on functional analysis of the variant and enhanced phosphorylation upon IFN-γ stimulation in the patient's cells. Additionally, the patient demonstrated a decreased proportion of CD4 + T cells, NK cells, and Th17 cells. Flow cytometry analysis revealed a significant decrease in the expression of IL-17 A in CD4 + T cells from the patient. Serological test results showed that the patient's IgM level was decreased, while the levels of IL-2, IL-5, IL-6 and TNF-α were elevated. Topical application of ruxolitinib demonstrated therapeutic efficacy.

Conclusions: The present study reports a pediatric patient with CMC who carries a novel GOF mutation in STAT1. This mutation may impair IL-17 immunity, which could potentially increase the patient's susceptibility to CMC. However, further research is needed to elucidate the underlying mechanism. Although ruxolitinib shows potential as a therapeutic option for CMC, its clinical efficacy requires further validation through experimental studies and long-term patient follow-up.