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Davari F, Mehdizadeh S, Hoseini-Aghdam M, Dabbaghzadeh A. Immune Dysregulation and Chronic Mucocutaneous Candidiasis in a Child With STAT1 Gain-of-function Mutation: A Case Report and Literature Review. J. Pediatr. Rev 2026; 14 (2) :197-206
URL: http://jpr.mazums.ac.ir/article-1-802-fa.html

Background: Chronic mucocutaneous candidiasis (CMC) is most commonly associated with gain-of-function (GOF) mutations in STAT1, which impair immune regulation and predispose to recurrent fungal infections, autoimmunity, and lymphoproliferative disorders. The clinical spectrum of STAT1 GOF is broad, ranging from severe multisystem involvement to milder phenotypes. Here, we present a case of a child carrying the STAT1 GOF mutation A267V, who exhibited an attenuated phenotype limited to mucocutaneous candidiasis. 
Case Presentation: A 10-year-old girl presented with recurrent episodes of oral thrush and chronic onychomycosis, consistent with isolated mucocutaneous candidiasis. She had no history of systemic infections, autoimmune disease, or lymphoproliferative manifestations. Family history was notable for early-onset esophageal cancer in her father. Immunological evaluation revealed a preserved CD4/CD8 ratio (2.05), normal immunoglobulin levels, and absence of autoantibodies. Despite normal B-cell counts, her vaccine response was impaired, with non-protective diphtheria-specific IgG levels, suggesting a defect in STAT1-mediated follicular helper T cell function. Genetic analysis confirmed a heterozygous STAT1 GOF mutation (A267V), consistent with autosomal dominant inheritance of CMC. The patient was treated with fluconazole for fungal infection control and the Janus kinase (JAK) inhibitor baricitinib to modulate hyperactive JAK-signal transducer and activator of transcription (JAK–STAT) signaling. This therapeutic approach resulted in resolution of infections and improvement in inflammatory activity. This case illustrates an attenuated phenotype of STAT1 GOF disease, in which the A267V variant was associated with susceptibility to candidiasis but preservation of broader immune homeostasis. Unlike the typical presentation of STAT1 GOF, the patient demonstrated normal immune parameters, including immunoglobulin levels and CD4/CD8 ratio, and no autoimmunity or systemic fungal disease. The clinical response to baricitinib highlights the therapeutic potential of JAK–STAT pathway inhibition in STAT1 GOF syndromes.             
Conclusions: This case expands the clinical spectrum of STAT1 GOF mutations by demonstrating that the A267V variant can present as an isolated mucocutaneous phenotype without systemic immune dysregulation. It also emphasizes the potential of JAK inhibition as a targeted therapeutic strategy and the importance of long-term cancer surveillance in these patients.