Clinical and Immunological Impact of JAK Inhibition in Concurrent Down Syndrome and STAT1 Gain of Function

Down 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 (IFNγR1/R2 and IFNαR1/R2) and responses to IFNα/γ 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 IFNα/γ. Both patients showed significant clinical improvement with the Janus kinase (JAK) inhibitor ruxolitinib. However, P1's key biomarkers (STAT1 levels, IFN signature, TNFα, 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.

Authors

Institutions

Publication Details

Journal
Journal of Clinical Immunology
Published
2025-11-25
DOI
https://doi.org/10.1007/s10875-025-01957-0
Primary Topic
Immunodeficiency and Autoimmune Disorders
Type
article
Field-Weighted Citation Impact
0.00

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

Clinical and Immunological Impact of JAK Inhibition in Concurrent Down Syndrome and STAT1 Gain of Function

Valle Velasco González, Olaf Neth, Jan Ramakers, J. Ivorra Cortés et al.
Journal of Clinical Immunology
Immunodeficiency and Autoimmune Disorders
article

Clinical and Immunological Impact of JAK Inhibition in Concurrent Down Syndrome and STAT1 Gain of Function

Valle Velasco González, Olaf Neth, Jan Ramakers, J. Ivorra Cortés, Anna Mensa‐Vilaró, Elisa Cordero, Pilar Blanco-Lobo, José Manuel Lucena, Peter Olbrich, Nieves Menéndez, Beatriz de Felipe, Cristina Roca-Oporto, Mirella Gáboli, Natalia Palmou‐Fontana, Inmaculada Guillén, Antonio Martı́nez, Juan I. Aróstegui, Paloma Guisado Hernández, David Moreno-Fuentes, Paula Gilabert-Prieto, Ana Ortiz-Ramírez
article en

Abstract

Down 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 (IFNγR1/R2 and IFNαR1/R2) and responses to IFNα/γ 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 IFNα/γ. Both patients showed significant clinical improvement with the Janus kinase (JAK) inhibitor ruxolitinib. However, P1's key biomarkers (STAT1 levels, IFN signature, TNFα, 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.

Journal of Clinical ImmunologyVol. 45(1)
Hospital Sant Joan de Déu Barcelona (ES), Hospital Universitario de Canarias (ES), Instituto de Salud Carlos III (ES), Hospital Universitari i Politècnic La Fe (ES), Marqués de Valdecilla University Hospital (ES), Fundación Marques de Valdecilla (ES), Centro de Investigación Biomédica en Red (ES), Hospital Clínic de Barcelona (ES), Health Research Institute of the Balearic Islands (ES), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (ES), Instituto de Biomedicina de Sevilla (ES), Hospital Universitario Son Espases (ES), Hospital Universitario Virgen del Rocío (ES), Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES), Universitat de Barcelona (ES), Universidad de Sevilla (ES)
Universidad de Sevilla, European Commission, Instituto de Salud Carlos III
Openalex Percentile: Top 59%
Immunodeficiency and Autoimmune Disorders
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.