Figure 2 (facing page). Clinical Course of the Patient and Identification of a USP18 Mutation.

In Panel A, at the age of 13 days, the patient was admitted to the pediatric intensive care unit (PICU), where he underwent chest radiography, which showed patches of space opacification with an air bronchogram of both lungs characteristic of severe acute respiratory distress syndrome (ARDS) (subpanel a). At that time, multiple organ failure (MOF) and disseminated intravascular coagulopathy (DIC) had also developed, along with septic shock. Computed tomography (CT) of the brain at the age of 23 days showed mildly dilated lateral ventricles with intraventricular hyperdense acute hemorrhage more marked on the left, corresponding to grade II intraventricular hemorrhage (subpanel b). At the age of 45 days, the patient was readmitted with necrotizing cellulitis at the site of a peripheral venous catheter in the right forearm (subpanel c). Magnetic resonance imaging (MRI) of the brain at the age of 6 weeks showed a well–defined high–intensity signal in the right occipital region (subpanel d, arrow). MRI of the brain at the age of 11 weeks showed a well–defined high–intensity signal in the bilateral cerebellum owing to subacute infarction (subpanel e, arrows). One month after the diagnosis of USP18 deficiency and the initiation of ruxolitinib (at a dose of 5 mg twice daily [BID]) at the age of 7 months, CT of the brain showed resolution of hydrocephalus, hemorrhage, and ischemia with only small areas of residual calcifications in the left putamen (subpanel f, arrow) and the formation of scar tissue on the forearm after healing of the necrotizing cellulitis (subpanel g). Chest radiography after 2 months of ruxolitinib therapy showed sufficient improvement for weaning from mechanical ventilation (subpanel h). Panel B shows familial segregation of the c.1073+1G→A USP18 allele. The unaffected parents, who were first cousins (as indicated by the double horizontal line), were heterozygous for the mutation, and the patient was homozygous. Panel C shows the localization of the USP18 mutation in the genomic DNA and messenger RNA, with coding regions in blue, untranslated regions in gray, and the mutation indicated by red arrows, with the predicted transcript skipping exon 10. Panel D shows the electro-pherographic results of the homozygous c.1073+1G→A USP18 mutation in the patient and the heterozygous mutation in the unaffected parents.