[STAT1 gain-of-function mutation leading to disseminated Talaromyces marneffei infection combined with hemophagocytic syndrome: a case report].

This study reports a 28-year-old HIV-negative male with a STAT1 gain-of-function mutation who presented with a systemically disseminated Talaromyces marneffei (TM) infection, which was complicated by hemophagocytic lymphohistiocytosis (HLH). The patient presented with recurrent fever, weight loss, oral mucosal ulcers, as well as lymphopenia and markedly elevated inflammatory markers during the acute phase of the illness. Imaging revealed scattered ground-glass opacities and nodular shadows in both lungs, as well as localized bronchiectasis, and splenomegaly. Metagenomic next-generation sequencing (mNGS) of bronchoalveolar lavage fluid and bone marrow aspirate specimens revealed TM-specific sequences. Whole-exome sequencing was performed to elucidate the underlying mechanism of recurrent fungal infections. This revealed a de novo heterozygous dominant mutation in the STAT1 gene (c.1151G>A, p.Gly384Asp), localized to the DNA-binding domain at amino acid position 384. This confirmed a STAT1 gain-of-function (STAT1-GOF) variant, which is consistent with the clinical phenotype of impaired antifungal immunity. Over the clinical course, the patient developed HLH. Following a two-week course of intravenous amphotericin B liposome (5 mg/kg per day), followed by oral voriconazole maintenance therapy (200 mg, twice daily), the patient exhibited significant improvements in clinical symptoms and laboratory parameters. Notably, the marked resolution of HLH was closely linked to the successful eradication of the fungal infection. This case highlights three critical clinical implications: (1) Patients with a predisposition to primary immunodeficiency disorders (e.g., STAT1-GOF mutations) should be evaluated for disseminated TM infections, even if they are HIV-negative; (2) mNGS is instrumental in etiological diagnosis and facilitates early intervention for fungal infections; (3) early identification of genetic defects establishes a theoretical basis for precision medicine and guides targeted therapeutic strategies.