STAT1 GOF mutations result in enhanced and prolonged interferon signaling, leading to impaired Th17 differentiation and susceptibility to fungal, viral, and mycobacterial infections, as well as autoimmunity [1,2,3]. The clinical spectrum of STAT1-GOF is broad and heterogeneous. While chronic mucocutaneous candidiasis (CMC) is the hallmark feature, patients may also develop viral infections, mycobacterial disease, and autoimmune conditions such as systemic lupus erythematosus, often accompanied by reduced IL-17 responses and abnormalities in lymphocyte subsets [1, 2, 4]. The age of onset and severity of manifestations can vary widely, even among individuals carrying the same variant.

Our patient presented with a combination of disseminated tuberculosis, recurrent mucocutaneous candidiasis, and early-onset systemic lupus erythematosus, suggestive of underlying immune dysregulation. Immunologic evaluation showed preserved global immune function with selective deficits in NK cells, recent thymic emigrants, and class-switched memory B cells, along with a marked reduction in IL-17–producing CD4⁺ T cells.

Genetic analysis identified a heterozygous STAT1 missense variant (p.Thr387Arg) located in the DNA-binding domain. Variants in this region have been associated with both loss- and gain-of-function effects, reflecting the complexity and variability of STAT1-related phenotypes.

Tuberculosis is classically associated with STAT1 loss-of-function mutations; however, disseminated or atypical forms have also been reported in patients with STAT1 GOF [5,6,7]. Although the precise mechanism remains unclear, hyperactive STAT1 signaling has been proposed to impair Th1/Th17-mediated immunity by suppressing interleukin 17 (IL-17) and dysregulating IFN-γ signaling, thereby increasing susceptibility to mycobacterial infections [4, 6].

Systemic lupus erythematosus is an uncommon but recognized autoimmune manifestation of STAT1-GOF, reported in approximately 2–3% of patients in large cohort studies [2, 8].

In our patient, the coexistence of tuberculosis, chronic mucocutaneous candidiasis, and SLE, along with reduced IL-17–producing T cells, supports a STAT1-GOF–like immunophenotype, despite the absence of direct functional validation. The occurrence of HLH further underscores the severity and complexity of immune dysregulation associated with STAT1 variants.

Management of STAT1 GOF remains challenging and may include antifungal prophylaxis, JAK inhibition, and hematopoietic stem cell transplantation [9]. In our patient, ruxolitinib led to partial clinical improvement, and HSCT was pursued as definitive therapy.

This case expands the phenotypic and genotypic spectrum of STAT1-related disease by describing a novel STAT1 variant associated with a complex phenotype of tuberculosis, mucocutaneous candidiasis, and early-onset SLE.