Managing Diagnosis, Treatment, and Burden of Disease in Hereditary Angioedema Patients with Normal C1-Esterase Inhibitor

Hereditary angioedema (HAE) is a rare, chronic, and debilitating genetic disorder characterized by recurrent and unpredictable swelling episodes that primarily affect the subcutaneous and/or submucosal tissues of the extremities, larynx, face, abdomen, and genitals. Most cases of HAE are caused by mutations in the serpin family G member 1 gene (SERPING1), which encodes C1-esterase inhibitor (C1-INH) protein. Mutations in SERPING1 lead to deficient (type I HAE-C1-INH) or dysfunctional (type II HAE-C1-INH) C1-INH protein and subsequent dysregulation of the kallikrein–bradykinin cascade. However, some patients present with a third type of HAE (HAE-nI-C1-INH), which was first described in the year 2000 and is characterized by an absence of mutations in SERPING1. Although mutations in the coagulation factor XII, angiopoietin-1, plasminogen, kininogen-1, myoferlin, and heparan sulfate-glucosamine 3-O-sulfotransferase-6 genes have been identified in some patients with HAE-nI-C1-INH, genetic cause is still unknown in many cases, hindering full elucidation of the pathology of this HAE subtype. Diagnosis of HAE-nI-C1-INH is also further complicated by the fact that patients typically demonstrate normal plasma levels of C1-INH and complement component 4 protein and normal C1-INH functionality during laboratory analysis. Therefore, we review the challenges associated with diagnosing, treating, and living with HAE-nI-C1-INH. We conclude that raising awareness of the presenting features of HAE-nI-C1-INH within the clinical setting and among the general public is critical to aid earlier suspicion and diagnosis of the disease. Furthermore, adopting an individualized approach to HAE-nI-C1-INH treatment is essential to help address the current and significant unmet needs in this patient population.