Somatic STAT3 Gain-of-Function (GOF) syndrome underlying susceptibility to Parvovirus B19, Pseudomonas aeruginosa, and Histoplasma capsulatum infections

Abstract

Infections in overtly immunocompromised persons (e.g. those living with advanced HIV, receiving malignancy-targeting chemotherapy, or recipients of transplants), may present with severe disease. In the absence of overt immunosuppression, unexplained severe disease due to prevalent microbes may reflect an underlying “inborn error of immunity” (IEI). IEI are monogenic penetrant defects of immunity: Classically, the genetic mutation is germline, that is, derived from germ cells, vertically transmitted to offspring in Mendelian fashion (autosomal dominant, autosomal recessive, or X-linked), and present in all cells of the affected individual. IEI may also be caused by naturally-occurring autoantibodies directed to immunologic components (such as cytokines) (Casanova et al., 2024) or by somatic mutations (Aluri and Cooper, 2023). Somatic mutations occur when a deleterious genetic variant occurs in the post-zygotic stage of development and can affect any body cell, other than germ cells; they are well-known causes of solid and hematologic malignancies. Somatic IEI syndromes are emerging, typically associated with lymphoproliferative diseases or autoinflammatory disorders. We report the case of a young woman with unexplained severe infections in whom a somatic gain-of-function (GOF) mutation in Signal transducer and activator of transcription 3 (STAT3) was found.