What enzyme deficiency has been associated with childhood onset Polyarteritis Nodosa?
Childhood-onset PAN is a systemic necrotizing vasculitis affecting small- and medium-sized arteries causing arterial aneurysms and ischemia leading to multisystem organ dysfunction. A subset of patients with childhood-onset (and young adult) PAN has been associated with adenosine deaminase 2 deficiency (DADA2) . This enzyme deficiency is caused by one of over 60 reported loss-of-function mutations of the CECR1 gene and inherited as an autosomal recessive trait. Patients present with a vasculopathy ranging from livedo reticularis to a life-threatening vasculitis affecting multiple organs. Particularly common manifestations include fever (90%), livedo reticularis (85%) and other rashes, hemorrhagic and/or ischemic strokes (66%), and peripheral nervous system involvement (60%). Other organs (intestine, liver, and kidney) can be involved. Hypogammaglobulinemia (25%) and various cytopenias can occur. The pathogenesis of how DADA2 leads to a vasculopathy is unclear. ADA2 acts a growth factor important in endothelial cell and hematopoietic cell development. Furthermore, this enzyme induces monocyte proliferation and macrophage differentiation. Patients with DADA2 have an increase in M1 (proinflammatory) macrophages. Treatment of DADA2-associated PAN is markedly different than classic PAN. Antitumor necrosis factor agents are most effective, whereas traditional immunosuppressives (e.g., cyclophosphamide) are ineffective. Notably, relapses are common when therapy is discontinued. Hematopoietic stem cell transplantation has been successful in treatment-resistant cases.
