Precision treatment of Singleton Merten syndrome with ruxolitinib: a case report

Research output: Contribution to journalCase reportContributedpeer-review

Contributors

  • Philip Broser - , Children's Hospital of Eastern Switzerland (Author)
  • Ursula von Mengershausen - , Children's Hospital of Eastern Switzerland (Author)
  • Katrin Heldt - , Children's Hospital of Eastern Switzerland (Author)
  • Deborah Bartholdi - , University of Bern (Author)
  • Dominique Braun - , University of Bern (Author)
  • Christine Wolf - , Department of Paediatrics (Author)
  • Min Ae Lee-Kirsch - , Department of Paediatrics (Author)

Abstract

Background: Singleton-Merten syndrome 1 (SGMRT1) is a rare type I interferonopathy caused by heterozygous mutations in the IFIH1 gene. IFIH1 encodes the pattern recognition receptor MDA5 which senses viral dsRNA and activates antiviral type I interferon (IFN) signaling. In SGMRT1, IFIH1 mutations confer a gain-of-function which causes overactivation of type I interferon (IFN) signaling leading to autoinflammation. Case presentation: We report the case of a nine year old child who initially presented with a slowly progressive decline of gross motor skill development and muscular weakness. At the age of five years, he developed osteoporosis, acro-osteolysis, alveolar bone loss and severe psoriasis. Whole exome sequencing revealed a pathogenic de novo IFIH1 mutation, confirming the diagnosis of SGMRT1. Consistent with constitutive type I interferon activation, patient blood cells exhibited a strong IFN signature as shown by marked up-regulation of IFN-stimulated genes. The patient was started on the Janus kinase (JAK) inhibitor, ruxolitinib, which inhibits signaling at the IFN-α/β receptor. Within days of treatment, psoriatic skin lesions resolved completely and the IFN signature normalized. Therapeutic efficacy was sustained and over the course muscular weakness, osteopenia and growth also improved. Conclusions: JAK inhibition represents a valuable therapeutic option for patients with SGMRT1. Our findings also highlight the potential of a patient-tailored therapeutic approach based on pathogenetic insight.

Details

Original languageEnglish
Article number24
JournalPediatric Rheumatology
Volume20
Issue number1
Publication statusPublished - Dec 2022
Peer-reviewedYes

External IDs

PubMed 35410415

Keywords

Keywords

  • Auto inflammation, Autoimmunity, Janus kinase inhibitor, Ruxolitinib, Singleton Merten syndrome, Therapy, Type I interferon