FOXI3 is a transcription factor essential for pharyngeal arch development, with certain variants linked to autosomal dominant craniofacial microsomia. Emerging evidence implicates specific FOXI3 mutations in thymic hypoplasia and lymphopenia, akin to 2p11.2 deletions involving the FOXI3 locus.
We describe a full-term female infant identified through newborn screening with low TREC levels, subsequently referred for immunologic evaluation. She demonstrated a low absolute number of TREC copies, moderately decreased CD4 (∼600 cells/μL), and CD8 (∼200 cells/μL) T cell counts with preserved functional responses. Additional findings included mild hypogammaglobulinemia and mild B cell lymphopenia age-appropriate class-switched memory B cells. Genetic analysis revealed a missense variant of uncertain significance in FOXI3 (c.512T>C and p.Ile171Thr) within the DNA-binding domain, alongside variants in DNAAF4 (heterozygous frameshift) and G6PD (pathogenic). Cytogenomic studies were unremarkable.
We propose FOXI3 haploinsufficiency as a potential mechanism underlying her T cell lymphopenia. At 20 months of age, she remains clinically stable on trimethoprim-sulfamethoxazole prophylaxis without significant infections, and live viral vaccines have been withheld.
This case highlights the potential role of FOXI3 in thymic function and T cell development. The long-term prognosis remains uncertain, underscoring the need for further biochemical and functional studies to clarify the pathogenicity of FOXI3 variants and optimize clinical management strategies.
