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JAK Inhibitor Therapy in a Child with Inherited USP18 Deficiency

2020; Massachusetts Medical Society; Volume: 382; Issue: 3 Linguagem: Inglês

10.1056/nejmoa1905633

1533-4406

Fahad Alsohime, Marta Martín-Fernández, Mohamad‐Hani Temsah, Majed Alabdulhafid, Tom Le Voyer, Malak Alghamdi, Xueer Qiu, Najla Alotaibi, Areej Alkahtani, Sofija Buta, Emmanuelle Jouanguy, Ayman Al‐Eyadhy, Conor Gruber, Gamal Hasan, Fahad A. Bashiri, Rabih Halwani, Hamdy H. Hassan, Saleh Al‐Muhsen, Nouf Alkhamis, Zobaida Alsum, Jean‐Laurent Casanova, Jacinta Bustamante, Dusan Bogunovic, Abdullah Alangari,

Immunodeficiency and Autoimmune Disorders

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.).