Novel germline STAT3 gain-of-function mutation causes autoimmune diseases and severe growth failure

Koji Saito, MD; Minoru Fujimoto, MD, PhD; Eiji Funajima, MSc; Satoshi Serada, PhD; Tomoharu Ohkawara, MD; Masayuki Ishihara, MD, PhD; Mamiko Yamada, MD, PhD; Hisato Suzuki, MD, PhD; Fuyuki Miya, PhD; Kenjiro Kosaki, MD, PhD; Mikiya Fujieda, MD, PhD; Tetsuji Naka, MD, PhD

Journal of Allergy and Clinical Immunology: Global (Nov 2024)

Novel germline STAT3 gain-of-function mutation causes autoimmune diseases and severe growth failure

Koji Saito, MD,
Minoru Fujimoto, MD, PhD,
Eiji Funajima, MSc,
Satoshi Serada, PhD,
Tomoharu Ohkawara, MD,
Masayuki Ishihara, MD, PhD,
Mamiko Yamada, MD, PhD,
Hisato Suzuki, MD, PhD,
Fuyuki Miya, PhD,
Kenjiro Kosaki, MD, PhD,
Mikiya Fujieda, MD, PhD,
Tetsuji Naka, MD, PhD

Affiliations

Koji Saito, MD: Department of Pediatrics, Kochi Medical School, Kochi University, Nankoku, Japan; Department of Pediatrics, National Hospital Organization Kochi National Hospital, Kochi, Japan; Department of Clinical Immunology, Kochi Medical School, Kochi University, Nankoku, Japan
Minoru Fujimoto, MD, PhD: Department of Clinical Immunology, Kochi Medical School, Kochi University, Nankoku, Japan; Division of Allergy and Rheumatology, Department of Internal Medicine, Iwate Medical University School of Medicine, Yahaba, Japan; Corresponding author: Minoru Fujimoto, MD, PhD, Division of Allergy and Rheumatology, Department of Internal Medicine, Iwate Medical University School of Medicine, 2-1-1 Idaidori, Yahaba-cho, Shiwa-gun, Iwate 028-3695, Japan.
Eiji Funajima, MSc: Institute for Biomedical Sciences Molecular Pathophysiology, Iwate Medical University, Yahaba, Japan
Satoshi Serada, PhD: Department of Clinical Immunology, Kochi Medical School, Kochi University, Nankoku, Japan; Institute for Biomedical Sciences Molecular Pathophysiology, Iwate Medical University, Yahaba, Japan
Tomoharu Ohkawara, MD: Department of Clinical Immunology, Kochi Medical School, Kochi University, Nankoku, Japan; Division of Allergy and Rheumatology, Department of Internal Medicine, Iwate Medical University School of Medicine, Yahaba, Japan
Masayuki Ishihara, MD, PhD: Department of Pediatrics, Kochi Medical School, Kochi University, Nankoku, Japan
Mamiko Yamada, MD, PhD: Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan
Hisato Suzuki, MD, PhD: Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan
Fuyuki Miya, PhD: Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan
Kenjiro Kosaki, MD, PhD: Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan
Mikiya Fujieda, MD, PhD: Department of Pediatrics, Kochi Medical School, Kochi University, Nankoku, Japan
Tetsuji Naka, MD, PhD: Department of Clinical Immunology, Kochi Medical School, Kochi University, Nankoku, Japan; Division of Allergy and Rheumatology, Department of Internal Medicine, Iwate Medical University School of Medicine, Yahaba, Japan; Institute for Biomedical Sciences Molecular Pathophysiology, Iwate Medical University, Yahaba, Japan

Journal volume & issue: Vol. 3, no. 4
p. 100312

Abstract

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Background: In recent years, germline gain-of-function (GOF) mutations in signal transducer and activator of transcription 3 (STAT3) have been identified as a cause of early-onset multiorgan autoimmune diseases with the widespread use of next-generation sequencing, and targeted therapies such as tocilizumab have been reported to be effective. Objective: We sought to assess whether a novel STAT3 mutation detected by whole-exome sequencing is pathogenic and examine the efficacy of targeted therapy. Methods: A pediatric patient with idiopathic pulmonary hemosiderosis, autoimmune thyroiditis, inflammatory bowel disease unclassified, leukocytosis, thrombocytosis, and severe growth failure was examined. Results: This 7-year-old boy had idiopathic pulmonary hemosiderosis at the age of 6 months. Despite high-dose steroid therapy, pulmonary fibrosis progressed. Furthermore, he presented with severe growth failure, autoimmune thyroiditis, leukocytosis, thrombocytosis, and inflammation bowel disease unclassified. Given the presence of multiple autoimmune diseases, whole-exome sequencing was performed, which detected germline de novo heterozygous STAT3 mutation (NM_139276.2; c.2144C>A, p.(P715Q)). Dual-luciferase reporter assay revealed this novel STAT3 mutation as GOF. After starting tocilizumab therapy at the age of 6, hospital stays decreased, and the progression of pulmonary fibrosis was decelerated without increasing the steroid dose. New autoimmune diseases did not develop, and no apparent adverse effects on growth have been observed. Conclusions: Tocilizumab may be effective for patients with STAT3 GOF mutation, including those requiring long-term management of idiopathic pulmonary hemosiderosis. Diagnosis of patients with early-onset multiorgan autoimmune diseases in which STAT3 GOF is suspected should be confirmed by genetic testing and functional analysis to consider the introduction of targeted therapies.

Published in Journal of Allergy and Clinical Immunology: Global

ISSN: 2772-8293 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Specialties of internal medicine: Immunologic diseases. Allergy
Website: https://www.sciencedirect.com/journal/journal-of-allergy-and-clinical-immunology-global

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