Clinical Research Study| Volume 120, ISSUE 11, P987-992, November 2007

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Hereditary Angioedema with Normal C1 Inhibitor: Clinical Symptoms and Course



      A new type of hereditary angioedema was described recently. It was characterized by recurrent bouts of angioedema in various organs and normal C1 inhibitor and was observed mainly in women. Our aim was to conduct a detailed study of the clinical features of this condition.


      A total of 138 patients with hereditary angioedema and normal C1 inhibitor who belonged to 43 unrelated families were examined through the use of standardized questionnaires.


      A majority of patients with hereditary angioedema and normal C1 inhibitor had skin swellings (92.8%), tongue swellings (53.6%), and abdominal pain attacks (50%). Laryngeal edema (25.4%) and uvular edema (21.7%) also were frequent, whereas edema episodes of other organs were rare (3.6%). Facial swellings and tongue involvement occurred considerably more frequently compared with hereditary angioedema caused by C1 inhibitor deficiency. The number of patients with recurrent edema of only 1 organ was higher than in classic hereditary angioedema. The number of patients with disease onset in adulthood was significantly higher in hereditary angioedema with normal C1 inhibitor compared with classic hereditary angioedema. Erythema marginatum was not observed. A subgroup of patients from families with coagulation factor XII mutations showed the same symptoms as the other patients.


      Hereditary angioedema with normal C1 inhibitor levels shows a characteristic pattern of clinical symptoms. The main clinical features include skin swellings, tongue swellings, and abdominal pain attacks. There are many differences in the clinical symptoms and course of disease between this type of hereditary angioedema and classic hereditary angioedema caused by a genetic C1 inhibitor deficiency.


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        • Quincke H.I.
        Über akutes umschriebenes Hautödem.
        Monatsh Prakt Dermatol. 1882; 1: 129-131
        • Osler W.
        Hereditary angioneurotic edema.
        Am J Med Sci. 1888; 95: 362-367
        • Donaldson V.H.
        • Evans R.R.
        A biochemical abnormality in hereditary angioneurotic edema: absence of serum inhibitor of C1-esterase.
        Am J Med. 1963; 31: 37-44
        • Drouet C.
        • Blanch A.
        • Roche O.
        • et al.
        HAE: mutation analysis of the C1INH gene.
        J Allergy Clin Immunol. 2004; 114: S66-S74
        • Bork K.
        • Barnstedt S.
        • Koch P.
        • Traupe H.
        Hereditary angioedema with normal C1-inhibitor activity in women.
        Lancet. 2000; 356: 213-217
        • Binkley K.E.
        • Davis A.
        Clinical, biochemical, and genetic characterization of a novel estrogen-dependent inherited form of angioedema.
        J Allergy Clin Immunol. 2000; 106: 546-550
        • Martin L.
        • Degenne D.
        • Toutain A.
        • et al.
        Hereditary angioedema type III: an additional French pedigree with autosomal dominant transmission.
        J Allergy Clin Immunol. 2001; 107: 747-748
        • Bork K.
        • Gül D.
        • Dewald G.
        Hereditary angio-oedema with normal C1 inhibitor in a family with affected women and men.
        Br J Dermatol. 2006; 154: 542-545
        • Dewald G.
        • Bork K.
        Missense mutations in the coagulation factor XII (Hageman factor) gene in hereditary angioedema with normal C1 inhibitor.
        Biochem Biophys Res Commun. 2006; 343: 1286-1289
        • Cichon S.
        • Martin L.
        • Hennies H.C.
        • et al.
        Increased activity of coagulation factor XII (Hageman factor) causes hereditary angioedema type III.
        Am J Hum Genet. 2006; 79: 1098-1104
        • Bork K.
        • Fischer B.
        • Dewald G.
        Recurrent episodes of skin angioedema and severe attacks of abdominal pain induced by oral contraceptives or hormone replacement therapy.
        Am J Med. 2003; 114: 294-298
        • Bork K.
        • Dewald G.
        Hereditary angioedema type III, angioedema associated with angiotensin II receptor antagonists, and female sex.
        Am J Med. 2004; 116: 644-645
        • Binkley K.E.
        • Davis A.E.
        Estrogen-dependent and estrogen-associated inherited angioedema (previously HAE type III).
        J Allergy Clin Immunol. 2004; 114: S62-S64
        • Bork K.
        Hereditary angioedema with normal C1 inhibitor activity including hereditary angioedema with coagulation factor XII gene mutations.
        Immunol Allergy Clin N Am. 2006; 26: 709-724
        • Bork K.
        • Meng G.
        • Staubach P.
        • Hardt J.
        Hereditary angioedema due to C1 inhibitor deficiency: new findings concerning symptoms, affected organs, and course of disease.
        Am J Med. 2006; 119: 267-274
        • Agostoni A.
        • Cicardi M.
        Hereditary and acquired C1-inhibitor deficiency: biological and clinical characteristics in 235 patients.
        Medicine (Baltimore). 1992; 71: 206-215
        • Frank M.M.
        • Gelfand J.A.
        • Atkinson J.P.
        Hereditary angioedema: the clinical syndrome and its management.
        Ann Intern Med. 1976; 84: 580-593
        • Farkas H.
        • Harmat G.
        • Fay A.
        • et al.
        Erythema marginatum preceding an acute oedematous attack of hereditary angioneurotic oedema.
        Acta Derm Venereol. 2001; 81: 376-377
        • Starr J.C.
        • Brasher G.W.
        • Rao A.
        • Posey D.
        Erythema marginatum and hereditary angioedema.
        South Med J. 2004; 97: 948-950
        • Stoppa-Lyonnet D.
        • Tosi M.
        • Laurent J.
        • et al.
        Altered C1 inhibitor genes in type I hereditary angioedema.
        N Engl J Med. 1987; 317: 1-6