D2.46 - Patient with the overlap of Hereditary angioedema and Chronic spontaneous urticaria

Chronic spontaneous urticaria (CSU) is a complex inflammatory skin disorder characterized by the degranulation of cutaneous mast cells and basophils, which release histamine and other pro-inflammatory mediators, leading to vasodilation, increased vascular permeability, and dermal edema. Management typically follows a stepwise protocol beginning with standard-dose second-generation H1-antihistamines, which may be escalated up to fourfold, while refractory cases require immunosuppressive drugs or monoclonal antibodies. In contrast, hereditary angioedema (HAE) is an orphan disease caused by a deficiency or dysfunction of the C1 inhibitor, resulting in the uncontrolled release of bradykinin, a potent vasodilator responsible for increased vascular permeability and angioedema.

A 33-year-old female with asthma presented with recurrent angioedema and urticaria, initially receiving a diagnosis of CSU after a dermatological work-up; however, while antihistamines successfully ameliorated the urticaria, the angioedema persisted and recurred periodically. Further diagnostic evaluation revealed low levels of C1-inhibitor and C4, and after her twin sister reported similar symptoms, the patient was diagnosed with HAE. Genetic sequencing of the SERPING1 gene identified a heterozygous, likely pathogenic variant, (NM_000062.3): c.816_818del (p.Asn272del), making the patient the index case for subsequent cascade family screening.

This case highlights a rare overlap of two distinct disorders—one driven by histamine and the other by bradykinin—emphasizing that the differential diagnosis for patients presenting with both urticaria and angioedema must consider the simultaneous presence of CSU and HAE.