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

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.