期刊
NEW ENGLAND JOURNAL OF MEDICINE
卷 382, 期 3, 页码 256-265出版社
MASSACHUSETTS MEDICAL SOC
DOI: 10.1056/NEJMoa1905633
关键词
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资金
- Deanship of Scientific Research, King Saud University, Riyadh, Saudi Arabia [RGP-190]
- National Institute of Allergy and Infectious Diseases, National Institutes of Health [R01AI127372, R21AI134366, R21AI129827]
- Hirschl Scholar Award
- March of Dimes
- St. Giles Foundation
- Jeffrey Modell Foundation
- Rockefeller University Center for Clinical and Translational Science
- National Center for Research Resources [8UL1TR000043]
- National Center for Advancing Sciences
- National Institute of Allergy and Infectious Diseases [5R01AI089970-02, 5R37AI095983]
- French National Research Agency from the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence [ANR-10-LABX-62-IBEID]
- French National Research Agency from the Investments for the Future program [ANR-10-IAHU-01]
- French National Research Agency from the GENMSMD (Human Genetic Dissection of Mendelian Susceptibility to Mycobacterial Disease) [ANR-16-CE17-0005-01]
Deficiency of ubiquitin-specific peptidase 18 (USP18) is a severe type I interferonopathy. USP18 down-regulates type I interferon signaling by blocking the access of Janus-associated kinase 1 (JAK1) to the type I interferon receptor. The absence of USP18 results in unmitigated interferon-mediated inflammation and is lethal during the perinatal period. We describe a neonate who presented with hydrocephalus, necrotizing cellulitis, systemic inflammation, and respiratory failure. Exome sequencing identified a homozygous mutation at an essential splice site on USP18. The encoded protein was expressed but devoid of negative regulatory ability. Treatment with ruxolitinib was followed by a prompt and sustained recovery. (Funded by King Saud University and others.) A neonate with a loss-of-function mutation in USP18 and exuberant expression of interferon-stimulated genes was experimentally treated with ruxolitinib, which suppresses interferon signaling. The initiation of treatment was followed by an improvement in the child's clinical course.
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