Clinical and Immunological Impact of JAK Inhibition in Concurrent Down Syndrome and STAT1 Gain of Function
Por:
Blanco-Lobo P, Gilabert-Prieto P, de Felipe B, Moreno-Fuentes D, Guisado Hernández P, Ortiz-Ramírez A, Mensa-Vilaró A, Aróstegui JI, Palmou N, Velasco Gonzalez V, Deyà-Martinez A, Ramakers J, Ivorra-Cortés J, Roca C, Cordero E, Guillen I, Valerdiz Menéndez N, Lucena JM, Gaboli M, Olbrich P and Neth O
Publicada:
25 nov 2025
Ahead of Print:
25 nov 2025
Resumen:
PurposeDown syndrome (DS) and STAT1 gain-of-function (GOF) share clinical and molecular features, including persistent inflammation. We aimed to investigate whether the coexistence of DS and a STAT1 GOF mutation in a patient synergistically enhances interferon (IFN) signaling and exacerbates inflammatory responses, posing additional management challenges. Two patients (P1 and P2) were studied: P1, with DS and a heterozygous p.P326S STAT1 variant, and P2, with the STAT1 p.P326S variant only. Individuals with isolated DS or STAT1 GOF served as controls. IFN receptor subunits (IFN gamma R1/R2 and IFN alpha R1/R2) and responses to IFN alpha/gamma stimulation were analyzed using flow cytometry and RT-PCR. Whole blood type I IFN signature and serum cytokines were evaluated using NanoString and Luminex assays. P1 experienced recurrent infections, chronic mucocutaneous candidiasis, interstitial pneumonitis, and pulmonary hypertension. P2 presented with esophageal candidiasis, dysphagia, and stenosis. The p.P326S variant led to increased STAT1/pSTAT1 levels in response to IFN alpha/gamma. Both patients showed significant clinical improvement with the Janus kinase (JAK) inhibitor ruxolitinib. However, P1's key biomarkers (STAT1 levels, IFN signature, TNF alpha, IL-6) remained altered, indicating persistent inflammation despite clinical improvement. This first report of a STAT1 GOF variant in DS provides a unique "experiment of nature", offering insights into the interplay between trisomy 21 and STAT1-mediated immune dysregulation. Although ruxolitinib demonstrated clinical benefits, the persistent inflammation observed in P1 highlights the need for further strategies to achieve complete immune resolution. These findings emphasize the importance of comprehensive genetic and immunological assessments in individuals with DS, particularly when immune dysfunction is suspected.
Filiaciones:
Blanco-Lobo P:
Instituto de Biomedicina de Sevilla, Research Group: "Inborn Errors of Immunity", Pediatric Infectious Diseases, Rheumatology and Immunology Unit, IBiS/Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Red de Investigación Traslacional en Infectología Pediátrica RITIP, Av. Manuel Siurot, s/n. 41013, Seville, Spain
Departamento de Farmacología, Pediatría y Radiología, Facultad de Medicina, Universidad de Sevilla, Seville, Spain
Gilabert-Prieto P:
Instituto de Biomedicina de Sevilla, IBiS/Hospital Universitario Virgen del Rocío, CSIC/Universidad de Sevilla, Seville, Spain
de Felipe B:
Instituto de Biomedicina de Sevilla, Research Group: "Inborn Errors of Immunity", Pediatric Infectious Diseases, Rheumatology and Immunology Unit, IBiS/Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Red de Investigación Traslacional en Infectología Pediátrica RITIP, Av. Manuel Siurot, s/n. 41013, Seville, Spain
Moreno-Fuentes D:
Instituto de Biomedicina de Sevilla, Research Group: "Inborn Errors of Immunity", Pediatric Infectious Diseases, Rheumatology and Immunology Unit, IBiS/Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Red de Investigación Traslacional en Infectología Pediátrica RITIP, Av. Manuel Siurot, s/n. 41013, Seville, Spain
Guisado Hernández P:
Instituto de Biomedicina de Sevilla, Research Group: "Inborn Errors of Immunity", Pediatric Infectious Diseases, Rheumatology and Immunology Unit, IBiS/Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Red de Investigación Traslacional en Infectología Pediátrica RITIP, Av. Manuel Siurot, s/n. 41013, Seville, Spain
Ortiz-Ramírez A:
Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y digestivas (CIBEREHD), Instituto de Salud Carlos III (ISCIII), 28009, Madrid, Spain
Departament de Bioquímica i Biomedicina molecular, Facultat de Biologia, Universitat de Barcelona, 08028, Barcelona, Spain
Mensa-Vilaró A:
Department of Immunology, CDB, Hospital Clínic Barcelona, Barcelona, Spain
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Aróstegui JI:
Department of Immunology, CDB, Hospital Clínic Barcelona, Barcelona, Spain
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Palmou N:
Department of Rheumatology and Pediatric Rheumatology, Immunology Group, Hospital Universitario Marqués de Valdecilla, Santander, Cantabria, Spain
Velasco Gonzalez V:
Pediatric Pulmonology, Canary Islands University Teaching Hospital, Tenerife, Spain
Deyà-Martinez A:
Institut de Recerca Hospital Sant Joan de Déu, Universitat de Barcelona, Esplugues, Spain
Clinical Immunology Unit Hospital, Sant Joan de Déu-Hospital Clínic de Barcelona, Barcelona, Spain
Department of Pediatrics, Hospital Universitari Son Espases, Palma, Spain
Ramakers J:
Multidisciplinary Group for Research in Pediatrics, Balearic Island Health Research Institute (IdISBa), Palma, Spain
Ivorra-Cortés J:
Servicio de Reumatología, Hospital Universitari I Politècnic La Fe, Valencia, Spain
Roca C:
Clinical Unit of Infectious Diseases, Microbiology and Parasitology, Institute of Biomedicine of Seville (IBiS), Virgen del Rocio University Hospital, CSIC/University of Seville, 41013, Seville, Spain
Cordero E:
Clinical Unit of Infectious Diseases, Microbiology and Parasitology, Institute of Biomedicine of Seville (IBiS), Virgen del Rocio University Hospital, CSIC/University of Seville, 41013, Seville, Spain
Department of Medicine, Faculty of Medicine, Universidad de Sevilla, Sevilla, Spain
Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain
Guillen I:
Pediatric Cardiology Unit, Hospital Universitario Virgen del Rocío, 41013, Seville, Spain
Valerdiz Menéndez N:
UGC Anatomía patológica, Hospital Universitario Virgen del Rocío, 41013, Seville, Spain
Lucena JM:
Immunology Unit, University Hospital Virgen del Rocío, Seville, Spain
Gaboli M:
Pediatric Pneumology Unit, Hospital Universitario Virgen del Rocío, 41013, Seville, Spain
Olbrich P:
Instituto de Biomedicina de Sevilla, Research Group: "Inborn Errors of Immunity", Pediatric Infectious Diseases, Rheumatology and Immunology Unit, IBiS/Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Red de Investigación Traslacional en Infectología Pediátrica RITIP, Av. Manuel Siurot, s/n. 41013, Seville, Spain
Departamento de Farmacología, Pediatría y Radiología, Facultad de Medicina, Universidad de Sevilla, Seville, Spain
Neth O:
Instituto de Biomedicina de Sevilla, Research Group: "Inborn Errors of Immunity", Pediatric Infectious Diseases, Rheumatology and Immunology Unit, IBiS/Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Red de Investigación Traslacional en Infectología Pediátrica RITIP, Av. Manuel Siurot, s/n. 41013, Seville, Spain
Canary Isl Univ, Teaching Hosp, Pediat Pulmonol, Tenerife, Spain
Univ Barcelona, Inst Recerca Hosp Sant Joan Deu, Esplugues, Spain
Sant Joan Deu Hosp Clin Barcelona, Clin Immunol Unit Hosp, Barcelona, Spain
Hosp Univ Son Espases, Dept Pediat, Palma De Mallorca, Spain
Canary Isl Univ, Teaching Hosp, Pediat Pulmonol, Tenerife, Spain
Univ Barcelona, Inst Recerca Hosp Sant Joan Deu, Esplugues, Spain
Sant Joan Deu Hosp Clin Barcelona, Clin Immunol Unit Hosp, Barcelona, Spain
Hosp Univ Son Espases, Dept Pediat, Palma De Mallorca, Spain
Green Submitted, hybrid
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