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 muta...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-04-01
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| Series: | Pediatric Rheumatology Online Journal |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12969-022-00686-7 |
| _version_ | 1818022615020732416 |
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| author | Philip Broser Ursula von Mengershausen Katrin Heldt Deborah Bartholdi Dominique Braun Christine Wolf Min Ae Lee-Kirsch |
| author_facet | Philip Broser Ursula von Mengershausen Katrin Heldt Deborah Bartholdi Dominique Braun Christine Wolf Min Ae Lee-Kirsch |
| author_sort | Philip Broser |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-10T03:31:14Z |
| format | Article |
| id | doaj.art-6b45a43e73554bc2b076042f53de380c |
| institution | Directory Open Access Journal |
| issn | 1546-0096 |
| language | English |
| last_indexed | 2024-12-10T03:31:14Z |
| publishDate | 2022-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Pediatric Rheumatology Online Journal |
| spelling | doaj.art-6b45a43e73554bc2b076042f53de380c2022-12-22T02:03:49ZengBMCPediatric Rheumatology Online Journal1546-00962022-04-012011610.1186/s12969-022-00686-7Precision treatment of Singleton Merten syndrome with ruxolitinib: a case reportPhilip Broser0Ursula von Mengershausen1Katrin Heldt2Deborah Bartholdi3Dominique Braun4Christine Wolf5Min Ae Lee-Kirsch6Department of Pediatric Neurology, Children’s Hospital of Eastern SwitzerlandDepartment of Pediatric Neurology, Children’s Hospital of Eastern SwitzerlandDepartment of Pediatric Endocrinology, Children’s Hospital of Eastern SwitzerlandDepartment of Human Genetics, University Hospital BernDepartment of Human Genetics, University Hospital BernDepartment of Pediatrics, Medizinische Fakultät Carl Gustav Carus, Technische Universität DresdenDepartment of Pediatrics, Medizinische Fakultät Carl Gustav Carus, Technische Universität DresdenAbstract 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.https://doi.org/10.1186/s12969-022-00686-7Singleton Merten syndromeType I interferonTherapyJanus kinase inhibitorRuxolitinibAuto inflammation |
| spellingShingle | Philip Broser Ursula von Mengershausen Katrin Heldt Deborah Bartholdi Dominique Braun Christine Wolf Min Ae Lee-Kirsch Precision treatment of Singleton Merten syndrome with ruxolitinib: a case report Pediatric Rheumatology Online Journal Singleton Merten syndrome Type I interferon Therapy Janus kinase inhibitor Ruxolitinib Auto inflammation |
| title | Precision treatment of Singleton Merten syndrome with ruxolitinib: a case report |
| title_full | Precision treatment of Singleton Merten syndrome with ruxolitinib: a case report |
| title_fullStr | Precision treatment of Singleton Merten syndrome with ruxolitinib: a case report |
| title_full_unstemmed | Precision treatment of Singleton Merten syndrome with ruxolitinib: a case report |
| title_short | Precision treatment of Singleton Merten syndrome with ruxolitinib: a case report |
| title_sort | precision treatment of singleton merten syndrome with ruxolitinib a case report |
| topic | Singleton Merten syndrome Type I interferon Therapy Janus kinase inhibitor Ruxolitinib Auto inflammation |
| url | https://doi.org/10.1186/s12969-022-00686-7 |
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