Signal transducer and activator of transcription 3 (STAT3) plays a crucial role in immune system differentiation and regulation. Gain-of-function mutations in STAT3 have been linked to early-onset autoimmunity and lymphoproliferation, leading to dysregulated and hyperactive immune responses [1]. Here, we describe a previously unreported variant in the STAT3 gene in a pediatric patient with Evans syndrome.
The patient, a 13-year-old male, was diagnosed with Evans syndrome at age 3 after experiencing recurrent episodes of autoimmune anemia, neutropenia, and thrombocytopenia, which were poorly responsive to intravenous immunoglobulin (IVIG), frequently requiring corticosteroids, and he was transitioned to sirolimus. Evaluation for autoimmune lymphoproliferative syndrome at the time of initial diagnosis was significant for normal B and T cells, no mention of double-negative T cells, and hypocellular bone marrow. A variant of uncertain significance in FADD, (c.66G>A (p.Glu22=)) was reported, which has since been reclassified as likely benign. The patient continued to have thrombocytopenia and developed intermittent splenomegaly, and lymphadenopathy, and diffuse eczematous dermatitis. He has had multiple hospital admissions for refractory thrombocytopenia and viral and bacterial pneumonias. He also has extensive pansinusitis, mastoiditis, and recurrent otitis with hearing impairment. The family history is significant for liver failure of unknown etiology, necessitating a liver transplant, and a sister with inflammatory bowel disease. Genetic testing for inborn errors of immunity and cytopenias revealed a variant of uncertain significance: a missense mutation in exon 21 of the STAT3 gene, STAT3 (c.1987_1988delinsCT (p.Thr663Leu)).
The patient's clinical presentation is consistent with STAT3 gain-of-function syndrome, characterized by autoimmune cytopenias, lymphoproliferation, dermatitis, and frequent infections. Although this exact variant has not been previously documented, a similar missense mutation, p.Thr663Ile, has been implicated in STAT3 gain-of-function syndrome. Functional studies are ongoing to further assess the pathogenicity of this variant and familial variant testing is pending. We propose that this novel STAT3 variant may contribute to a phenotype consistent with STAT3 gain-of-function syndrome, leading to immune dysregulation in our patient.
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