RESUMEN
Aicardi-Goutières syndrome (AGS) is a rare hereditary early-onset encephalopathy. The syndrome was first described in 1984, and is characterised by upregulation of the type I interferon (IFN) pathway, which is involved in the host immune response against viral infections, including SARS-CoV-2. Whilst defects in type I IFN pathways have been described in association with severe coronavirus disease 2019 (COVID-19), less is known about the outcomes of upregulation. We describe an unusual case of generalised panniculitis as a post-COVID-19 phenomenon in a child with AGS. Our patient was initially managed with systemic steroid therapy, but due to relapse of symptoms on weaning, an alternative therapy was sought. In this case, a novel use of ruxolitinib, a JAK inhibitor, has resulted in lasting remission without complications. We discuss the probable protective role of IFN upregulation following COVID-19 infection in AGS and possible immunological mechanisms driving the panniculitis and therapeutic response in our case.
RESUMEN
Human natural killer cell deficiency (NKD) arises from inborn errors of immunity that lead to impaired NK cell development, function, or both. Through the understanding of the biological perturbations in individuals with NKD, requirements for the generation of terminally mature functional innate effector cells can be elucidated. Here, we report a cause of NKD resulting from compound heterozygous mutations in minichromosomal maintenance complex member 10 (MCM10) that impaired NK cell maturation in a child with fatal susceptibility to CMV. MCM10 has not been previously associated with monogenic disease and plays a critical role in the activation and function of the eukaryotic DNA replisome. Through evaluation of patient primary fibroblasts, modeling patient mutations in fibroblast cell lines, and MCM10 knockdown in human NK cell lines, we have shown that loss of MCM10 function leads to impaired cell cycle progression and induction of DNA damage-response pathways. By modeling MCM10 deficiency in primary NK cell precursors, including patient-derived induced pluripotent stem cells, we further demonstrated that MCM10 is required for NK cell terminal maturation and acquisition of immunological system function. Together, these data define MCM10 as an NKD gene and provide biological insight into the requirement for the DNA replisome in human NK cell maturation and function.
