J Clin Immunol. 2026 Jun 19;46(1):67. doi: 10.1007/s10875-026-02040-y.
ABSTRACT
BACKGROUND: Gain-of-function (GOF) mutations in the STAT1 gene result in heightened interferon signaling and impaired IL-17 immunity. While chronic mucocutaneous candidiasis (CMC) remains the hallmark feature, affected individuals often display a broader phenotype including viral infections, mycobacterial susceptibility, and autoimmune diseases.
CASE PRESENTATION: We describe a 4-year-old girl who initially presented with abdominal pain and was diagnosed with acute appendicitis. During surgery, marked mesenteric lymphadenopathy was discovered, and histopathology revealed acid-fast bacilli. Mycobacterium tuberculosis was confirmed by gastric fluid PCR, prompting initiation of anti-tuberculosis therapy. Her past medical history included hospitalization for herpes zoster and recurrent episodes of oral candidiasis during febrile illnesses. Immunologic evaluation showed normal immunoglobulin levels, vaccine responses, oxidative burst, and lymphocyte proliferation. However, low NK cells, reduced recent thymic emigrants, and decreased class-switched memory B cells were noted. Genetic testing revealed a previously unreported heterozygous STAT1 variant (p.Thr387Arg), classified as likely pathogenic according to ACMG criteria with a CADD score of 23.4. Parental genetic testing was negative, suggesting a de novo mutation. Although STAT1 phosphorylation could not be assessed, the proportion of IL-17-producing CD4⁺ T cells was markedly reduced, supporting impaired Th17 immunity. Based on clinical, immunologic, and genetic findings, a clinical and immunological phenotype consistent with STAT1 GOF was established. One year later, the patient developed arthritis and was diagnosed with systemic lupus erythematosus (SLE) based on autoantibody positivity and low complement levels. During follow-up, she also developed hemophagocytic lymphohistiocytosis (HLH), further reflecting severe immune dysregulation. Ruxolitinib was initiated as bridging therapy, resulting in partial clinical improvement, and hematopoietic stem cell transplantation (HSCT) was planned as definitive therapy.
CONCLUSION: This report describes a novel STAT1 variant consistent with a gain-of-function phenotype associated with disseminated tuberculosis and early-onset SLE, expanding the clinical and molecular spectrum of this disorder. In children presenting with overlapping infectious and autoimmune features, underlying inborn errors of immunity should be considered.
PMID:42319627 | DOI:10.1007/s10875-026-02040-y