[Hereditary angioedema with normal C1 inhibitor associated with mutation in the gene encoding factor XII: two familial cases].

Hereditary angioedema (HAE) with normal C1 inhibitor (HAE-nC1INH) linked to mutations in the F12 gene represents a form of bradykinin-mediated angioedema that is clinically indistinguishable from other bradykinin-driven variants. We report two familial cases of recurrent angioedema without urticaria, refractory to antihistamines and corticosteroids, with normal levels of C1 inhibitor -both antigenic and functional- and C4. Genealogical analysis revealed multiple individuals at risk, and sequencing of exon 9 of the F12 gene identified the c.983C>A (p.Thr328Lys) variant in heterozygosis, previously associated with HAE (HAE-FXII). In one patient, exacerbation of episodes was observed during tamoxifen treatment, followed by clinical improvement with anastrozole, suggesting a possible link between hormonal profile and attack frequency. Additionally, she showed a favorable response to icatibant during an isolated pharyngeal episode, reinforcing the underlying bradykinin-mediated mechanism. These findings highlight the importance of considering HAE-FXII in the differential diagnosis of recurrent angioedema with normal biochemical studies, and of implementing effective therapeutic strategies to improve quality of life and reduce the risk of severe complications in patients and at-risk relatives.