Diagnosis and treatment of hereditary angioedema with normal C1 inhibitor
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ALLERGY, ASTHMA & CLINICAL IMMUNOLOGY
REVIEW
Open Access
Diagnosis and treatment of hereditary angioedema with normal C1 inhibitor Konrad Bork
Abstract Until recently it was assumed that hereditary angioedema is a disease that results exclusively from a genetic deficiency of the C1 inhibitor. In 2000, families with hereditary angioedema, normal C1 inhibitor activity and protein in plasma were described. Since then numerous patients and families with that condition have been reported. Most of the patients by far were women. In many of the affected women, oral contraceptives, hormone replacement therapy containing estrogens, and pregnancies triggered the clinical symptoms. Recently, in some families mutations in the coagulation factor XII (Hageman factor) gene were detected in the affected persons. Introduction Angioedema is clinically characterized by self-limiting episodes of marked edema involving the skin, gastrointestinal (GI) tract and other organs. Various forms of acquired and hereditary angioedema (HAE) share this clinical presentation. “Classic” HAE is associated with a quantitative (type I) or qualitative (type II) deficiency of C1 esterase inhibitor (C1-INH) caused by mutations of the C1-INH gene. Until recently it was assumed that HAE is a disease that results exclusively from a genetic deficiency of the C1-INH. In 2000, 10 families with this disease were described [1]. In these families a total of 36 women, but not a single man, were affected. All patients had normal C1-INH concentration and activity with respect to C1 esterase inhibition, ruling out both types of HAE (HAE type I and HAE type II). This hitherto unknown disease was proposed to be termed as “hereditary angioedema with normal C1 inhibitor occurring mainly in women” or “hereditary angioedema type III.” Subsequently, two additional families were described, with seven affected women in one family and four in the other [2,3]. Later on, clinical data on an additional 29 women with HAE type III were presented [4]. Because all 76 patients from the studies cited above were women, it was assumed that the clinical phenotype might be limited to the female sex. However, in 2006 a family with dominantly inherited angioedema and normal C1-INH was described in which not only five Correspondence: [email protected] Department of Dermatology, Johannes Gutenberg University, Mainz, Germany
female but also three male family members were clinically affected [5]. Later on, a number of further patients with HAE type III were reported [6-10]. In 2001 the author of this article initiated a microsatellite scan of the total genom (performed by Dr. C. Hennies, Max-Delbrück Center, Berlin) in four HAE type III families which revealed major linkage signals for chromosomes 6 and 16 but not for chromosome 5 (unpublished data). By following a functional hypothesis that the genetic defect might be located in the coagulation factor XII (FXII) gene the factor XII gene on chromosome 5 was then selectively investigated [11]. In May 2006, the causative gen
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