Journal Article

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

Gaboli, Mirella, Gilabert-Prieto, Paula, Mensa-Vilaró, Anna, Ramakers, Jan, Aróstegui, Juan I., Velasco Gonzalez, Valle, Blanco-Lobo, Pilar, Deyà Martinez, Ángela, Neth, Olaf, Valerdiz Menéndez, Nicolás, Lucena, José Manuel, Olbrich, Peter, Guisado Hernández, Paloma, Cordero, Elisa, Ivorra-Cortés, José, de Felipe, Beatriz, Ortiz-Ramírez, Ana, Palmou, Natalia, Guillen, Inmaculada, Moreno-Fuentes, David, Roca, Cristina

2025

Overview

Purpose 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.

• Publisher: Springer US,Springer Nature B.V
• Subject: Antibodies / Arthritis / Bacterial infections / Biomarkers / Biomedical and Life Sciences / Biomedicine / blood groups / blood serum / Candidiasis / Chronic mucocutaneous candidiasis / Cloning / Congenital diseases / Cytokines / Cytokines - blood / Disease / Down syndrome / Down Syndrome - complications / Down Syndrome - diagnosis / Down Syndrome - drug therapy / Down Syndrome - genetics / Down Syndrome - immunology / Down's syndrome / Dysphagia / Female / Flow cytometry / Gain of Function Mutation / Genes / heterozygosity / Humans / hypertension / Hypothyroidism / Immunology / Infectious Diseases / Inflammation / interferons / interleukin-6 / Internal Medicine / Janus kinase / Janus Kinase Inhibitors - therapeutic use / Kinases / Male / Medical Microbiology / Nitriles / non-specific protein-tyrosine kinase / patients / pneumonia / Pneumonitis / Pyrazoles - therapeutic use / Pyrimidines / Software / Standard scores / Stat1 protein / STAT1 Transcription Factor - genetics / STAT1 Transcription Factor - metabolism / Stenosis / trisomics / Trisomy / Viral infections / α-Interferon