Track

Abstract

We present two cases highlighting distinct vascular inflammatory syndromes in patients with mitochondrial disorders associated with increased type I interferon signaling. A 27-year-old female with an EARS2-related mitochondrial disorder developed bilateral lower extremity purpuric lesions over 24 hours. A skin biopsy revealed a striking pandermal leukocytoclastic vasculitis associated with prominent deposition of C3d, C4d and C5b-9. A 31-year-old male presented with recurrent spontaneous compartment syndrome of his lower extremities and acral based papular lesions that were biopsied showing a brisk pandermal angiocentric lymphocytic vascular reaction. There was endothelial and perivascular MXA expression, along with microvascular C5b-9 deposition. A diagnosis of a perniotic presentation of a primary interferonopathy was made. Subsequent investigations showed a myotonic dystrophy 2 mutation which has been associated with enhanced type I interferon signaling. These cases underscore the categorization of mitochondrial disorders as interferonopathy syndromes associated with autoimmune stigmata. Mitochondrial dysfunction can lead to the cytoplasmic accumulation of mitochondrial DNA which in turn is an impetus to excessive interferon signaling via the immune sensor cGAS-STING pathway designed to detect cytoplasmic DNA. In the context of a primary interferonopathy, a myriad of inflammatory reactions in the skin might be seen such as those unique to a primary interferonopathy (i.e. perniosis) or one attributable to an enhanced humoral immune response manifesting as a leukocytoclastic vasculitis. The compartment syndrome in our patient was likely an abortive expression of interferon driven systemic capillary leak syndrome since interferon may paradoxically increase vasopermeability.