Interferon receptor dysfunction in a child with malignant atrophic papulosis and CNS involvement

Malignant atrophic papulosis is a rare, thrombo-obliterative vasculopathy, with either a cutaneous benign presentation or a systemic severe presentation, predominantly affecting the gastrointestinal tract, lungs, and CNS.1 We report a heterozygous de-novo variant in the interferon α/β receptor subunit 1 gene (IFNAR1, MIM_107450) in a girl with malignant atrophic papulosis and CNS involvement who presented to our clinic in August, 2019, at age 9 years. At the protein level, the variant leads to a stop codon at position 277 (NP_000620.2; Trp277X), predicted to result in a truncated IFNAR1 protein, without the transmembrane and cytoplasmic domains responsible for signal transduction (figure 2A; appendix pp 1, 4). Laboratory analyses of whole blood revealed a severely elevated interferon score (representing the median fold change [2–ΔΔCt] in expression of six interferon-stimulated genes [IFI27, IFI44L, IFIT1, ISG15, RSAD2, and SIGLEC1], as measured by quantitative RT-PCR, normalised to the housekeeping gene HPRT1 and compared with a control; PAXgene Blood RNA Tubes, Qiagen, Venlo, Netherlands; figure 2E; appendix p 1). At first presentation to our centre (age 9 years), the patient received aspirin (50 mg/day) and levetiracetam (40 mg/kg per day). Because of their rapid disease progression and evidence of increased interferon pathway activation, we initiated off-label oral treatment with baricitinib (initial dose 0·025 mg/kg per day [0·5 mg/day]).