{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T18:33:22Z","timestamp":1793730802768,"version":"4.6.1"},"reference-count":18,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2022,4,11]],"date-time":"2022-04-11T00:00:00Z","timestamp":1649635200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,4,11]],"date-time":"2022-04-11T00:00:00Z","timestamp":1649635200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Pediatr Rheumatol"],"published-print":{"date-parts":[[2022,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>Singleton-Merten syndrome 1 (SGMRT1) is a rare type I interferonopathy caused by heterozygous mutations in the <jats:italic>IFIH1<\/jats:italic> gene. <jats:italic>IFIH1<\/jats:italic> encodes the pattern recognition receptor MDA5 which senses viral dsRNA and activates antiviral type I interferon (IFN) signaling. In SGMRT1, <jats:italic>IFIH1<\/jats:italic> mutations confer a gain-of-function which causes overactivation of type I interferon (IFN) signaling leading to autoinflammation.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Case presentation<\/jats:title>\n                <jats:p>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<jats:italic> IFIH1<\/jats:italic> 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-\u03b1\/\u03b2 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.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>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.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12969-022-00686-7","type":"journal-article","created":{"date-parts":[[2022,4,11]],"date-time":"2022-04-11T07:04:09Z","timestamp":1649660649000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Precision treatment of Singleton Merten syndrome with ruxolitinib: a case report"],"prefix":"10.1186","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4477-1432","authenticated-orcid":false,"given":"Philip","family":"Broser","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ursula","family":"von Mengershausen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katrin","family":"Heldt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deborah","family":"Bartholdi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominique","family":"Braun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Wolf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min Ae","family":"Lee-Kirsch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,4,11]]},"reference":[{"key":"686_CR1","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1016\/j.ajhg.2014.06.007","volume":"95","author":"H Oda","year":"2014","unstructured":"Oda H, Nakagawa K, Abe J, Awaya T, Funabiki M, Hijikata A, et al. Aicardi-Gouti\u00e8res syndrome is caused by IFIH1 mutations. Am J Hum Genet. 2014;95:121\u20135.","journal-title":"Am J Hum Genet"},{"key":"686_CR2","doi-asserted-by":"publisher","first-page":"503","DOI":"10.1038\/ng.2933","volume":"46","author":"GI Rice","year":"2014","unstructured":"Rice GI, Del Toro DY, Jenkinson EM, Forte GM, Anderson BH, Ariaudo G, et al. Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling. Nat Genet. 2014;46:503\u20139.","journal-title":"Nat Genet"},{"key":"686_CR3","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1016\/j.ajhg.2014.12.014","volume":"96","author":"F Rutsch","year":"2015","unstructured":"Rutsch F, MacDougall M, Lu C, Buers I, Mamaeva O, Nitschke Y, et al. A specific IFIH1 gain-of-function mutation causes Singleton-Merten syndrome. Am J Hum Genet. 2015;96:275\u201382.","journal-title":"Am J Hum Genet"},{"key":"686_CR4","doi-asserted-by":"publisher","first-page":"566","DOI":"10.1038\/nri.2016.78","volume":"16","author":"M Schlee","year":"2016","unstructured":"Schlee M, Hartmann G. Discriminating self from non-self in nucleic acid sensing. Nat Rev Immunol. 2016;16:566\u201380.","journal-title":"Nat Rev Immunol"},{"key":"686_CR5","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1146\/annurev-med-050715-104506","volume":"68","author":"MA Lee-Kirsch","year":"2017","unstructured":"Lee-Kirsch MA. The type I Interferonopathies. Annu Rev Med. 2017;68:297\u2013315.","journal-title":"Annu Rev Med"},{"key":"686_CR6","doi-asserted-by":"publisher","first-page":"837","DOI":"10.1002\/humu.23975","volume":"41","author":"GI Rice","year":"2020","unstructured":"Rice GI, Park S, Gavazzi F, Adang LA, Ayuk LA, Eyck LV, et al. Genetic and phenotypic spectrum associated with IFIH1 gain-of-function. Hum Mutat. 2020;41:837\u201349.","journal-title":"Hum Mutat"},{"key":"686_CR7","doi-asserted-by":"publisher","first-page":"1505","DOI":"10.1111\/bjd.14073","volume":"173","author":"A-C Bursztejn","year":"2015","unstructured":"Bursztejn A-C, Briggs TA, del Toro DY, Anderson BH, O\u2019Sullivan J, Williams SG, et al. Unusual cutaneous features associated with a heterozygous gain-of-function mutation in IFIH1: overlap between Aicardi-Gouti\u00e8res and Singleton-Merten syndromes. Br J Dermatol. 2015;173:1505\u201313.","journal-title":"Br J Dermatol"},{"key":"686_CR8","doi-asserted-by":"publisher","first-page":"214","DOI":"10.1089\/jir.2017.0004","volume":"37","author":"I Buers","year":"2017","unstructured":"Buers I, Rice GI, Crow YJ, Rutsch F. MDA5-associated neuroinflammation and the singleton-merten syndrome: two faces of the same type I Interferonopathy Spectrum. J Interferon Cytokine Res. 2017;37:214\u20139.","journal-title":"J Interferon Cytokine Res"},{"key":"686_CR9","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1007\/s11926-018-0743-3","volume":"20","author":"M Bienias","year":"2018","unstructured":"Bienias M, Br\u00fcck N, Griep C, Wolf C, Kretschmer S, Kind B, et al. Therapeutic approaches to type I Interferonopathies. Curr Rheumatol Rep. 2018;20:32.","journal-title":"Curr Rheumatol Rep"},{"key":"686_CR10","doi-asserted-by":"publisher","first-page":"986","DOI":"10.1056\/NEJMc2001362","volume":"383","author":"A Vanderver","year":"2020","unstructured":"Vanderver A, Adang L, Gavazzi F, McDonald K, Helman G, Frank DB, et al. Janus Kinase Inhibition in the Aicardi-Gouti\u00e8res syndrome. N Engl J Med. 2020;383:986\u20139.","journal-title":"N Engl J Med"},{"key":"686_CR11","doi-asserted-by":"publisher","first-page":"3041","DOI":"10.1172\/JCI98814","volume":"128","author":"GAM Sanchez","year":"2018","unstructured":"Sanchez GAM, Reinhardt A, Ramsey S, Wittkowski H, Hashkes PJ, Berkun Y, et al. JAK1\/2 inhibition with baricitinib in the treatment of autoinflammatory interferonopathies. J Clin Invest. 2018;128:3041\u201352.","journal-title":"J Clin Invest"},{"issue":"6","key":"686_CR12","doi-asserted-by":"publisher","first-page":"1439","DOI":"10.1016\/j.jaci.2020.04.002","volume":"146","author":"C Wolf","year":"2020","unstructured":"Wolf C, Br\u00fcck N, Koss S, Griep C, Kirschfink M, Palm-Beden K, Fang M, R\u00f6ber N, Winkler S, Berner R, Latz E, G\u00fcnther C, Lee-Kirsch MA. Janus kinase inhibition in complement component 1 deficiency. J Allergy Clin Immunol. 2020;146(6):1439-1442.e5 (Epub 2020 Apr 20. PMID: 32325142).","journal-title":"J Allergy Clin Immunol"},{"key":"686_CR13","doi-asserted-by":"publisher","first-page":"214","DOI":"10.1111\/j.1469-8749.1997.tb07414.x","volume":"39","author":"R Palisano","year":"1997","unstructured":"Palisano R, Rosenbaum P, Walter S, Russell D, Wood E, Galuppi B. Development and reliability of a system to classify gross motor function in children with cerebral palsy. Dev Med Child Neurol. 1997;39:214\u201323.","journal-title":"Dev Med Child Neurol"},{"key":"686_CR14","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1007\/BF00972817","volume":"1","author":"EB Singleton","year":"1973","unstructured":"Singleton EB, Merten DF. An unusual syndrome of widened medullary cavities of the metacarpals and phalanges, aortic calcification and abnormal dentition. Pediatr Radiol. 1973;1:2\u20137.","journal-title":"Pediatr Radiol"},{"key":"686_CR15","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1148\/118.2.389","volume":"118","author":"BB Gay Jr","year":"1976","unstructured":"Gay BB Jr, Kuhn JP. A syndrome of widened medullary cavities of bone, aortic calcification, abnormal dentition, and muscular weakness (the Singleton-Merten syndrome). Radiology. 1976;118:389\u201395.","journal-title":"Radiology"},{"key":"686_CR16","doi-asserted-by":"publisher","first-page":"360","DOI":"10.1002\/ajmg.a.35732","volume":"161A","author":"A Feigenbaum","year":"2013","unstructured":"Feigenbaum A, M\u00fcller C, Yale C, Kleinheinz J, Jezewski P, Kehl HG, et al. Singleton-Merten syndrome: an autosomal dominant disorder with variable expression. Am J Med Genet A. 2013;161A:360\u201370.","journal-title":"Am J Med Genet A"},{"key":"686_CR17","doi-asserted-by":"publisher","unstructured":"Ozyuksel A, Ersoy C, Canturk E, Akcevin A. Progressive supra-aortic stenosis in a young adult with the findings of Singleton Merten Syndrome. BMJ Case Rep. 2014;2014:bcr2014205985. https:\/\/doi.org\/10.1136\/bcr-2014-205985.","DOI":"10.1136\/bcr-2014-205985"},{"issue":"6","key":"686_CR18","doi-asserted-by":"publisher","first-page":"1535","DOI":"10.1002\/ajmg.a.61556","volume":"182","author":"J Vengoechea","year":"2020","unstructured":"Vengoechea J, DiMonda J. A case of Singleton-Merten syndrome without cardiac involvement harboring a novel IFIH1 variant. Am J Med Genet A. 2020;182(6):1535\u20136. https:\/\/doi.org\/10.1002\/ajmg.a.61556 (Epub 2020 Mar 23 PMID: 32202700).","journal-title":"Am J Med Genet A"}],"container-title":["Pediatric Rheumatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12969-022-00686-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12969-022-00686-7\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12969-022-00686-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,11]],"date-time":"2022-04-11T07:12:31Z","timestamp":1649661151000},"score":1,"resource":{"primary":{"URL":"https:\/\/ped-rheum.biomedcentral.com\/articles\/10.1186\/s12969-022-00686-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4,11]]},"references-count":18,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2022,12]]}},"alternative-id":["686"],"URL":"https:\/\/doi.org\/10.1186\/s12969-022-00686-7","relation":{},"ISSN":["1546-0096"],"issn-type":[{"value":"1546-0096","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,4,11]]},"assertion":[{"value":"31 January 2022","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 April 2022","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 April 2022","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Treatment was conducted with informed consent by the patient and his parents. The patient was enrolled in an ongoing study on the pathogenesis of interferonopathies approved by the Ethics Committee of the Medical Faculty, Technische Universit\u00e4t, Dresden.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"The patient and his parents gave consent that his photos and medical data are published.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"24"}}