D1.355 - Familial Recurrent Angioedema with Normal C1-Inhibitor: A Clinical Case Series Suggestive of HAE with Normal C1-INH

Background:Hereditary angioedema (HAE) is a rare bradykinin-mediated disorder characterized by recurrent angioedema without urticaria. While most cases are caused by quantitative or functional C1-inhibitor deficiency (HAE type I/II), a subset of patients presents with normal C1-INH levels and function (HAE with normal C1-INH, HAE-nC1INH). Diagnosis remains challenging, particularly in regions with limited access to genetic testing.

Case presentation:We report two brothers aged 38 and 34 years who presented with recurrent episodes of non-pruritic angioedema involving the lips, face, extremities, and abdomen. Symptom onset occurred at 24 and 22 years of age, respectively. Attacks were not accompanied by urticaria and showed poor response to antihistamines and systemic corticosteroids. Complement evaluation performed during and between attacks demonstrated normal C4 levels and normal quantitative and functional C1-INH in both patients. No consistent allergic triggers were identified. Recently, the 12-year-old daughter of the elder brother developed similar recurrent angioedema without urticaria. Complement parameters were also within normal limits. The familial clustering across two generations strongly supports a hereditary condition.

Discussion:The absence of urticaria, normal complement studies, lack of response to antihistamines, and positive family history suggest a bradykinin-mediated mechanism consistent with HAE-nC1INH. Pathogenic variants in genes such as F12, PLG, ANGPT1, KNG1, and MYOF have been described in association with this phenotype; however, genetic testing was not available.

Conclusion:Familial recurrent angioedema with normal complement studies should prompt consideration of HAE-nC1INH. Early recognition is essential to avoid misdiagnosis and ineffective therapies and to reduce the risk of potentially life-threatening laryngeal attacks.