Hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE) is an autosomal dominant condition with an estimated prevalence of approximately 1:50,000 [1,2]. It results in random and often unpredictable attacks of painful swelling typically affecting the extremities, bowel mucosa, genitals, face and upper airway . Attacks are associated with significant functional impairment, decreased Health Related Quality of Life (HRQoL), and mortality in the case of laryngeal attacks[4,5]. The swelling in HAE is a result of impaired regulation of bradykinin synthesis . Bradykinin is a nonapeptide kinin formed from high molecular weight kininogen by the action of plasma kallikrein. Bradykinin is a very powerful vasodilator and increases capillary permeability, constricts smooth muscle and stimulates pain receptors .
HAE can be categorized into 3 different types depending on the level and function of C1inhibitor (C1-INH): type 1(HAE-1), type 2 (HAE-2), and HAE with normal C1-INH function (HAE-nC1INH) previously referred to as type 3 (Table 1). HAE-1 is the most prevalent, representing approximately 85% of cases and results from low antigenic and functional levels of C1-INH. HAE-2 accounts for approximately 15% of cases and is associated with a normal C1-INHprotein level but impaired C1-INH function [7,8]. C4 is reduced in 98% of cases for both HAE-1 and HAE-2, and nearly 100% of the time during an attack .
HAE-nC1INH (previously referred to as type 3 HAE), is much less prevalent than HAE-1 and HAE-2. The true prevalence is not known as there are no reliable assays to screen for this condition. In about 20% to 25% of identified patients, causative mutations in the gene coding for the coagulation factor XII (F12) have been found (HAE-nC1INH-FXII) whereas in the remaining patients no genetic cause has been identified up to now (HAE-nC1INH-unknown) [11–13]. The exact pathogenesis, however, including the mode of action of the F12 gene mutations and the role of estrogens is still unknown. The lack of laboratory and genetic assays (with the exception of F12 gene mutations) to diagnose HAE-nC1INH, has made the identification of these patients more difficult than patients with HAE-1 or HAE-2. A recent international consensus group has published criteria to make the diagnosis of HAE-nC1INH . These included a history of recurrent angioedema in the absence of concomitant hives or use of medication known to cause angioedema; documented normal or near normal C4, C1-INH antigen and function; and either aF12gene mutation associated with the disease, or family history of angioedema and documented lack of efficacy of chronic high dose non-sedating antihistamine therapy .