Long-Term Outcomes of Successful Treatment with Ruxolitinib in a Pediatric Patient with Autoimmune Lymphoproliferative Syndrome and a Signal Transducer and Activator of Transcription 3 Gain-of-Function Mutation

Abstract

Loss or gain-of-function mutations in signal transducer and transcription activator genes, classified as combined immunodeficiency, can present with highly heterogeneous and life-threatening clinical presentations. We report an adolescent girl who has combined immunodeficiency associated with signal transducer and activator of transcription 3 gain-of-function, c.1032G > C, p.Met344Ile located in exon 10, identified by a next-generation sequencing panel performed due to short stature, hepatosplenomegaly, and decreased levels of both immunoglobulin G and immunoglobulin M. At 12 years of age, the patient was referred to the pediatric hematology outpatient clinic owing to hepatosplenomegaly and pancytopenia after initiating growth hormone treatment due to short stature. On physical examination, bilateral multiple posterior and anterior cervical micro-lymphadenopathies were detected, her liver was palpated 6 cm below the costal margin, and her spleen was palpated 10 cm below the costalmargin. The whole blood count revealed a leukocyte count of 2,300/mm³, neutrophils of 1,330/mm³, lymphocytes of 730/mm³, hemoglobin of 8 g/dL, platelets of 96,000/mm³, and reticulocytes of 2%. The bone marrow biopsy revealed a cellularity of 30–35%. After steroid-dependent treatment resulted in Cushing syndrome and treatment with sirolimus was ineffective, treatment with ruxolitinib 20 mg twice daily significantly resolved cytopenias and hepatosplenomegaly due to autoimmune lymphoproliferative syndrome.

Zusammenfassung

Funktionsverlust- oder Funktionsgewinnmutationen in Signaltransduktor- und Transkriptionsaktivator-(STAT)-Genen, die als kombinierte Immundefekte klassifiziert werden, können sich mit sehr heterogenen und lebensbedrohlichen klinischen Manifestationen manifestieren. Wir berichten über ein jugendliches Mädchen mit einer STAT3-Funktionsgewinnmutation (GOF), c.1032G>C, p.Met344Ile in Exon 10, die mittels Next-Generation-Sequenzierung (NGS) identifiziert wurde. Die Untersuchung wurde aufgrund von Kleinwuchs, Hepatosplenomegalie, erniedrigten Immunglobulin-G- und Immunglobulin-M-Spiegeln durchgeführt. Im Alter von 12 Jahren wurde die Patientin aufgrund von Hepatosplenomegalie und Panzytopenie, die nach Beginn einer Wachstumshormontherapie aufgrund des Kleinwuchses auftraten, in die pädiatrische Hämatologie-Ambulanz überwiesen. Bei der körperlichen Untersuchung wurden beidseitig multiple zervikale Mikrolymphadenopathien, posteriore und anteriore, festgestellt. Die Leber war 6 cm und die Milz 10 cm unterhalb des Rippenbogens tastbar. Das Blutbild zeigte folgende Werte: Leukozyten 2300/mm³, Neutrophile 1330/mm³, Lymphozyten 730/mm³, Hämoglobin 8 g/dl, Thrombozyten 96 000/mm³ und Retikulozyten 2 %. Die Knochenmarkbiopsie ergab eine Zellularität von 30–35 %. Nach einer vorangegangenen steroidabhängigen Behandlung, die zu einem Cushing-Syndrom und einem Nichtansprechen auf Sirolimus führte, besserten sich die Zytopenien und die Hepatosplenomegalie signifikant unter der zweimal täglichen Gabe von 20 mg Ruxolitinib aufgrund eines autoimmunen lymphoproliferativen Syndroms (ALPS).

Schlüsselwörter

ALPS - Ruxolitinib - STAT3-GOF - Erfolgreiche Behandlung - Veränderung

Keywords

ALPS - ruxolitinib - STAT3-GOF - successful treatment - mutation

Publication History

Received: 12 July 2025

Accepted after revision: 14 January 2026

Article published online:
27 February 2026

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