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

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.

• Authors: Philip Broser, Ursula von Mengershausen, Katrin Heldt, Deborah Bartholdi, Dominique Braun, Christine Wolf, Min Ae Lee-Kirsch
• Journal: Pediatric rheumatology online journal (Pediatr Rheumatol Online J) Vol. 20 Issue 1 Pg. 24 (Apr 11 2022) ISSN: 1546-0096 [Electronic] England
• PMID: 35410415 (Publication Type: Case Reports, Journal Article)
• Copyright: © 2022. The Author(s).

Chemical References

• Interferon Type I
• Nitriles
• Pyrazoles
• Pyrimidines
• ruxolitinib
• Interferon-Induced Helicase, IFIH1

Topics

• Aortic Diseases
• Child
• Child, Preschool
• Dental Enamel Hypoplasia
• Humans
• Interferon Type I
• Interferon-Induced Helicase, IFIH1 (genetics)
• Male
• Metacarpus (abnormalities)
• Muscle Weakness
• Muscular Diseases
• Nitriles
• Odontodysplasia
• Osteoporosis (genetics)
• Pyrazoles
• Pyrimidines
• Vascular Calcification