JAK Inhibitor Therapy in a Child with Inherited USP18 Deficiency.
Fahad AlsohimeMarta Martin-FernandezMohammad-Hani TemsahMajed AlabdulhafidTom Le VoyerMalak AlghamdiXueer QiuNajla AlotaibiAreej AlkahtaniSofija ButaEmmanuelle JouanguyAyman Al-EyadhyConor GruberGamal M HasanFahad A BashiriRabih HalwaniHamdy H HassanSaleh Al-MuhsenNouf AlkhamisZobaida AlsumJean-Laurent CasanovaJacinta BustamanteDusan BogunovicAbdullah A AlangariPublished in: The New England journal of medicine (2020)
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.).
Keyphrases
- respiratory failure
- dendritic cells
- replacement therapy
- extracorporeal membrane oxygenation
- pregnant women
- small molecule
- single cell
- mechanical ventilation
- binding protein
- early onset
- intensive care unit
- immune response
- copy number
- mesenchymal stem cells
- dna methylation
- amino acid
- transcription factor
- protein protein
- brain injury
- cerebrospinal fluid
- cell therapy
- acute respiratory distress syndrome