JAK Inhibitor Therapy in a Child with Inherited USP18 Deficiency

N Engl J Med. 2020 Jan 16;382(3):256-265. doi: 10.1056/NEJMoa1905633.

Abstract

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.).

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Exome Sequencing
  • Hereditary Autoinflammatory Diseases / drug therapy*
  • Homozygote
  • Humans
  • Hydrocephalus / genetics
  • Infant, Newborn
  • Interferons / metabolism*
  • Interleukins / metabolism*
  • Janus Kinase 1 / antagonists & inhibitors*
  • Janus Kinase Inhibitors / therapeutic use*
  • Loss of Function Mutation*
  • Male
  • Nitriles
  • Pyrazoles / therapeutic use*
  • Pyrimidines
  • Receptors, Interferon / metabolism
  • Remission Induction
  • Shock, Septic / genetics
  • Signal Transduction / genetics
  • Ubiquitin Thiolesterase / deficiency*
  • Ubiquitin Thiolesterase / genetics

Substances

  • interferon-lambda, human
  • Interleukins
  • Janus Kinase Inhibitors
  • Nitriles
  • Pyrazoles
  • Pyrimidines
  • Receptors, Interferon
  • ruxolitinib
  • Interferons
  • JAK1 protein, human
  • Janus Kinase 1
  • USP18 protein, human
  • Ubiquitin Thiolesterase