Dual novel homozygous mutations in ISG15 and MPO lead to classic type I interferonopathy and a new phenotype of recurrent parenchymal pneumonia

Abstract

Purpose ISG15 deficiency, a rare human inborn error of immunity characterized by susceptibility to Mycobacterium tuberculosis infection, shows neuropathic and dermatological manifestations. MPO deficiency is a common inherited defect of phagocytes, but it is not classified as an independent primary immune deficiency due to lack of clinical symptoms. Dual mutation of ISG15 and MPO has not been reported. Methods We analyzed the clinical, genetic, and immunological features of two siblings with ISG15 deficiency combined with MPO mutations, and explored therapeutic candidates. Results The major manifestation observed in patient 2 was necrotic skin lesions, while those in patient 1 were intracranial calcification and recurrent pneumonia. Whole-exome sequencing indicated novel, dual mutations in ISG15 and MPO, leading to lack of ISG15 expression and reduced MPO expression. PBMCs and B-cell lines derived from the patients showed hyperactivated JAK/STAT signaling and elevated oxidative stress. A "False-Positive" DHR test for MPO was reversed by exogenous peroxidase. RNA sequencing analyses identified baricitinib as an available therapeutic candidate for hyper-inflammation associated with ISG15 deficiency. Conclusions We reported two sibling patients with the same novel ISG5 mutation combined with partial MPO deficiency. These patients showed different presentations, and one of them harbored a new phenotype of recurrent pneumonia. These findings expand the clinical spectrum of ISG15 deficiency, reinforce its diversity, and identify a potential therapeutic candidate for this rare disease.