BackgroundHereditary angioedema with normal C1-INH may be linked to specific mutations in the coagulation factor 12 (FXII) gene (HAE-FXII) or mutations in genes that are still unknown (HAE-unknown). To assess the differences in transmission and inheritance, clinical features, and laboratory parameters between patients with HAE-FXII and HAE-unknown. MethodsSixty-nine patients with HAE-FXII from 23 unrelated families and 196 patients with HAE-unknown from 65 unrelated families were studied. ResultsBoth HAE-FXII and HAE-unknown are inherited as autosomal-dominant traits with incomplete penetrance. The male to female ratio was 1:68 in HAE-FXII and 1:6.3 in HAE-unknown. The maternal to paternal transmission ratio was 35:14 for HAE-FXII and 109:12 for HAE-unknown. Mean age at onset of clinical symptoms was 20.3years in patients with HAE-FXII and 29.6years in patients with HAE-unknown. The incidence of asphyxiation due to angioedema was similar for HAE-FXII and HAE-unknown. Oral contraceptives and pregnancies had a significantly higher impact on HAE-FXII than on HAE-unknown. Slightly decreased C1-INH activity and C4 concentration were observed in more patients with HAE-FXII than HAE-unknown. Tests for FXI and FXII activity, plasminogen activator inhibitor 1, and activated partial thromboplastin time showed variability but no significant differences between the groups. No abnormalities were found for C1-INH protein, C1q, alpha2-macroglobulin, antithrombin III, and angiotensin-converting enzyme. In families with HAE-FXII, the number of female offspring with F12 mutations was significantly increased and that of male offspring was significantly decreased. ConclusionsHAE-FXII and HAE-unknown differ in various respects, including gender distribution, genetics, symptoms, and estrogen impact.