Clinical features, genetics, treatment, and long-term outcomes of STAT3 hyper-IgE syndrome: Single-center cohort analysis

Alexandra F Freeman; Chen Wang; Amanda Urban; Iris Martin; Lauren Dang; Joie Davis; Jenna R E Bergerson; Sania Ali; Zixiao Annie An; Meera Patel; Hastings Williamson; Beatriz E Marciano; Christine Lafeer; Susan Roy; Jean Ulrick; Theo Heller; Disha Sharma; Leslie Castelo-Soccio; Edward W Cowen; Heidi H Kong; Sarthak Gupta; Rajarshi Ghosh; Bryce A Seifert; Mari J Tokita; Magdalena A Walkiewicz; Morgan Similuk; Jennifer Stoddard; Sergio D Rosenzweig; Jatin Raj Matta; Ahmed M Gharib; Golnar Jahanmir; Laurie Brenchley; Kalpakam Shastri; Niki M Moutsopoulos; Takashi Kitani; Danielle E Arnold; Dimana Dimitrova; Corina E Gonzalez; Sung-Yun Pai; Harry L Malech; John I Gallin; Kevin Fennelly; Kenneth N Olivier; Joseph Mackie; Stuart G Tangye; Amy P Hsu; Joshua D Milner; Jennifer Heimall; Steven M Holland

doi:10.1016/j.jaci.2026.04.012

Clinical features, genetics, treatment, and long-term outcomes of STAT3 hyper-IgE syndrome: Single-center cohort analysis

J Allergy Clin Immunol. 2026 Apr 28:S0091-6749(26)00292-7. doi: 10.1016/j.jaci.2026.04.012. Online ahead of print.

Authors

Alexandra F Freeman¹, Chen Wang², Amanda Urban³, Iris Martin², Lauren Dang⁴, Joie Davis², Jenna R E Bergerson², Sania Ali², Zixiao Annie An², Meera Patel², Hastings Williamson², Beatriz E Marciano², Christine Lafeer², Susan Roy², Jean Ulrick², Theo Heller⁵, Disha Sharma⁶, Leslie Castelo-Soccio⁷, Edward W Cowen⁷, Heidi H Kong⁸, Sarthak Gupta⁹, Rajarshi Ghosh¹⁰, Bryce A Seifert¹⁰, Mari J Tokita¹⁰, Magdalena A Walkiewicz¹⁰, Morgan Similuk¹⁰, Jennifer Stoddard¹¹, Sergio D Rosenzweig¹¹, Jatin Raj Matta¹², Ahmed M Gharib¹², Golnar Jahanmir¹³, Laurie Brenchley¹⁴, Kalpakam Shastri¹³, Niki M Moutsopoulos¹⁵, Takashi Kitani¹⁶, Danielle E Arnold¹⁷, Dimana Dimitrova¹⁸, Corina E Gonzalez¹⁷, Sung-Yun Pai¹⁷, Harry L Malech², John I Gallin², Kevin Fennelly¹⁹, Kenneth N Olivier²⁰, Joseph Mackie²¹, Stuart G Tangye²¹, Amy P Hsu², Joshua D Milner²², Jennifer Heimall²³, Steven M Holland²

Affiliations

¹ Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Md. Electronic address: freemaal@mail.nih.gov.
² Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Md.
³ Clinical Research Directorate, Frederick National Laboratory for Cancer Research, Frederick, Md.
⁴ Biostatistics Research Branch, NIAID, NIH, Bethesda, Md.
⁵ Translational Hepatology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), Bethesda, Md.
⁶ Digestive Diseases Branch, NIDDK, Bethesda, Md.
⁷ Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NIH, Bethesda, Md.
⁸ Cutaneous Microbiome and Inflammation Section, Dermatology Branch, NIAMS, NIH, Bethesda, Md.
⁹ Lupus Clinical Trials Unit, NIAMS, NIH, Bethesda, Md.
¹⁰ Centralized Sequencing Program, NIAID, NIH, Bethesda, Md.
¹¹ Immunology Service, Department of Laboratory Medicine, Clinical Center, NIH, Bethesda, Md.
¹² Biomedical and Metabolic Imaging Branch, NIDDK, NIH, Bethesda, Md.
¹³ Dental Clinic, National Institute of Dental and Craniofacial Research, NIH, Bethesda, Md.
¹⁴ Dental Clinic, National Institute of Dental and Craniofacial Research, NIH, Bethesda, Md; Laboratory of Host Immunity and Microbiome, NIAID, NIH, Bethesda, Md.
¹⁵ Laboratory of Host Immunity and Microbiome, NIAID, NIH, Bethesda, Md.
¹⁶ National Institute of Neurologic Disorders and Stroke, NIH, Bethesda, Md.
¹⁷ Immune Deficiency Cellular Therapy Program, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Md.
¹⁸ Center for Immuno-Oncology, National Cancer Institute, NIH, Bethesda, Md.
¹⁹ Laboratory of Chronic Airway Infection, National Heart, Lung, and Blood Institute, NIH, Bethesda, Md.
²⁰ Division of Pulmonary Diseases and Critical Care Medicine, Department of Medicine, University of North Carolina, Chapel Hill, NC.
²¹ Garvan Institute of Medical Research, Darlinghurst, Australia; School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales Sydney, Sydney, Australia.
²² Division of Pediatric Allergy, Immunology and Rheumatology, NewYork-Presbyterian/Columbia University Irving Medical Center, New York, NY.
²³ Division of Allergy Immunology, The Children's Hospital of Philadelphia, Philadelphia, Pa.

Abstract

Background: Signal transducer and activator of transcription 3 hyper-IgE syndrome (STAT3-HIES) is a multisystem disorder with both immunologic and nonimmunologic manifestations.

Objective: We sought to characterize the spectrum of clinical manifestations, genetics, treatment approaches, and long-term outcomes of patients with STAT3-HIES.

Methods: Clinical features, laboratory findings, treatment, and survival were reviewed in the largest single-center STAT3-HIES cohort (n = 164) prospectively followed under a natural history protocol (NCT00006150).

Results: In addition to the classic skin, lung, dental, and musculoskeletal manifestations captured in the 1999 scoring system, we comprehensively characterized disease phenotypes across multiple organ systems, including previously underrecognized features. Lung disease remained the major morbidity with both infectious and parenchymal complications. During longitudinal follow-up, age-related vascular and skeletal degeneration emerged and significantly affected quality of life in patients 45 years and older. No genotype-phenotype correlations were identified. In terms of management, optimal supportive measures, including antimicrobials and immunoglobulin replacement therapy, tailored to disease features and individual risk factors, remained the primary approach. Dupilumab was used primarily for the eczematous dermatitis and demonstrated significant clinical benefit. In highly selected cases (n = 6), allogeneic hematopoietic stem cell transplantation was performed and showed reduction in infection burden. The median overall survival was 55 years-significantly shorter than that of the general United States population-and was not affected by sex, variant location, or proband status.

Conclusions: STAT3-HIES is a multisystem disorder that requires multidisciplinary care. Early diagnosis and supportive measures have altered its natural history. Recognition and improved understanding of the nonimmunologic manifestations of this disorder will further improve patient outcomes.

Keywords: STAT3; aging; hyper-IgE syndrome; natural history; phenotype.

Published by Elsevier Inc.

Associated data

ClinicalTrials.gov/NCT00006150