Pathophysiology and underlying mechanisms in hereditary angioedema

Abstract

This review aims to summarize the main pathophysiological events involved in the development of hereditary angioedema (OMIM#106100).Hereditary angioedema is a rare genetic disease inherited in an autosomal dominant manner and caused by a loss of control over theplasma contact system or kallikrein-kinin system, which results in unrestrained bradykinin generation or signaling. In patients with hereditary angioedema, BK binding to endothelial cells leads to recurrentepisodes of swelling at subcutaneous or submucosal tissues that can belife threatening when affecting the upper respiratory tract. The diseasecan either present with hypocomplementemia owing to the presenceof pathogenic variants in the gene encoding complement C1 inhibitor(hereditary angioedema with C1-inhibitor deficiency) or present withnormocomplementemia and associate with elevated estrogen levelsowing to gain-of-function variants in the genes encoding coagulationproteins involved in the kallikrein-kinin system (namely, coagulationFXII [FXII-associated hereditary angioedema], plasminogen [PLG-associated hereditary angioedema], and high-molecular-weight kininogen[KNG1-associated hereditary angioedema]). Moreover, in recent years,novel pathogenic variants have been described in the genes encodingangiopoietin 1 (ANGPT1-associated hereditary angioedema) and myoferlin (MYOF-associated hereditary angioedema), which further expand the pathophysiological picture of hereditary angioedema.