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Article Abstract
Background: Germline signal transducer and activator of transcription 3 (STAT3) mutations cause 2 distinct syndromes with predominant infectious or autoimmune phenotype.
Objective: The objective of this study is to compile literature reports on gain-of-function (GOF) and dominant-negative (DN) mutations in the STAT3.
Methods: We searched 3 main databases including PubMed, Scopus, and Web of Science from 1990 to 2023. All full-text articles and major reviews were manually searched for additional studies.
Results: A total of 490 patients were reported in 107 articles including 265 patients with DN-STAT3 and 225 patients with GOF-STAT3 mutations. Major clinical differences between STAT3-DN and STAT3-GOF patients were observed in rates of infectious complication (98.2% vs 85.4%, P < .001), pneumonia (67.3% vs 52.1%, P = .006), sinusitis (17.5% vs 2.1%, P < .001), otitis (27.7% vs 5.2%, P < .001), abscess (52.7% vs 17.7%, P < .001), dermatologic manifestation (88.3% vs 58.4%, P < .001), atopic disorders (66.4% vs 40.2%, P < .001), interstitial lung disease (0.7% vs 17.7%, P < .001), dental/gingival disorders (38.5% vs 11.7%, P < .001), and endocrinopathies (0.9% vs 16.5%, P < .001), respectively. Most patients had normal counts of lymphocyte subsets, with the exceptions of higher CD3+ T cells and lower natural killer cells in STAT3-DN patients, and lower CD4+ T cells in STAT3-GOF patients. Most STAT3-DN patients had either normal or high serum concentrations of IgG, IgA, and IgM with almost universal raised serum IgE. Most STAT3-GOF patients had a low level of IgG, but normal levels of IgA, IgM, and IgE.
Conclusions: Patients with STAT3-DN had recurrent dermatological and pulmonary infections, eczema, elevated IgE, and eosinophilia, whereas patients with STAT3-GOF had early-onset polyautoimmunity and frequently require immunosuppressive therapy.
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