Hereditary angioedema with normal C1-Inhibitor: Clinical and genetic characterization of 15 Portuguese unrelated families.

BACKGROUND: Hereditary angioedema with normal C1-INH (HAE-nC1-INH) is a rare genetic disease with similar phenotype to HAE-C1-INH, but different genetic background. Currently six subtypes are recognized, based on the underlying mutations. Several aspects need further clarification.

OBJECTIVE: To assess clinical features of patients with genetically characterized HAE-nC1-INH, from the North of Portugal.

METHODS: Retrospective assessment of clinical data from all patients with HAE-nC1-INH followed at a HAE Reference Center.

RESULTS: Forty-one patients were identified, four with no family history. The FXII-mutation Thr328Lys (38 carriers) was the most prevalent. Three new potentially disease causing variants linked to HAE-nC1-INH were identified (c.529+4A>G:FXII; Cys248*:Kininogen-1; Arg261His:Plasminogen). The HAE-FXII cohort included 82% females and 71.8% symptomatic patients. Penetrance rate was significantly higher in females (81.3% vs 28.6; p=0.012). A hormonal influence was observed in 96.2% of the symptomatic females, although 62.5% remained symptomatic after oral estrogens withdrawal. Trauma and dental procedures were frequent triggers (82.6% and 45.5%, respectively). Main locations were facial (described by 96%), lips (82.1%) and eyelids (64.3%). One patient reported erythema marginatum as prodrome. Plasma derived C1-INH was effective as short-term prophylaxis in all treated patients, but only in 80% as on demand treatment. Icatibant was effectively used on demand in 9 patients, but with relapses in five (57%).

CONCLUSION: We described the first Portuguese series of patients with HAE-nC1-INH genetically characterized. Differences with others may contribute to improve current unmet needs and raise awareness of this rare disease. We highlight the identification of 3 new variants(additional molecular studies are ongoing) and the first report of erythema marginatum in HAE-n-C1INH.