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Novel STAT3 gain-of-function variant with hypogammaglobulinemia and recurrent infection phenotype
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  • Melinda Erdös,
  • Masumoto Tsumura,
  • Julia Kallai,
  • Arpad Lanyi,
  • Zoltan Nyul,
  • Gyorgy Balazs,
  • Satoshi Okada,
  • Laszlo Marodi
Melinda Erdös
University of Debrecen
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Masumoto Tsumura
Hiroshima University
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Julia Kallai
University of Debrecen
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Arpad Lanyi
University of Debrecen
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Zoltan Nyul
Pecs University
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Gyorgy Balazs
Heim Pal Korhaz
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Satoshi Okada
Hiroshima University
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Laszlo Marodi
Semmelweis University
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Abstract

Signal transducer and activator of transcription 3 (STAT3) gain-of-function (GOF) syndrome is an early-onset monogenic inborn error of immunity characterized by multi-organ autoimmune disorders, growth failure and lymphoproliferation. We describe that STAT3 GOF syndrome may be presented with hypogammaglobulinemia and recurrent severe upper and lower respiratory tract infections. The patient we present here did not have multi-organ autoimmunity and lacked early-onset autoimmune manifestations. Chest CT examinations showed mild bronchiectasis with areas of non-fibrosing alveolar-interstitial disease and maldevelopment of bilateral first ribs. By using Sanger sequencing, we revealed a novel c.508G>C, p.D170H STAT3 variant affecting the coiled coil domain (CCD) of STAT3. Functional studies confirmed that p.D170H was a GOF variant as showed by increased pSTAT3 and STAT3 transcriptional activity. Our observation suggests that STAT3 GOF syndrome can manifest in early childhood with hypogammaglobulinemia and recurrent severe respiratory tract infections and may lack autoimmune manifestations. We suggest that patients with hypogammaglobulinemia and severe, recurrent infections should be screened for STAT3 variants even if autoimmune manifestations are missing.

Peer review status:ACCEPTED

05 Mar 2021Submitted to Clinical & Experimental Immunology
08 Mar 2021Submission Checks Completed
08 Mar 2021Assigned to Editor
09 Mar 2021Reviewer(s) Assigned
05 Apr 2021Review(s) Completed, Editorial Evaluation Pending
08 Apr 2021Editorial Decision: Revise Major
22 Apr 20211st Revision Received
23 Apr 2021Reviewer(s) Assigned
10 May 2021Review(s) Completed, Editorial Evaluation Pending
10 May 2021Editorial Decision: Revise Minor
10 May 20212nd Revision Received
11 May 2021Review(s) Completed, Editorial Evaluation Pending
12 May 2021Editorial Decision: Accept