C4 deficiency in chronic angioedema
Authors: J. Azofra, M. López‐Trascasa
Journal: Allergy (2001)

Hereditary angioedema (HAE) is an autosomal dominant disorder caused by decreased level, or functional deficiency, of the C1 inhibitor protein. We describe a patient with diminished levels of the C4 and C2 complement components, with episodes of chronic angioedema, and showing a genetic deficiency of C4 protein. The patient was a 46-year-old woman with a 2-year history of episodic angioedema. The parts of the body involved were the eyelids, cheeks, tongue, and upper airway. She also suffered from abdominal attacks with cramp-like pains and vomiting. Skin swellings were very frequent (two or three per month) without apparent cause. There was neither pregnancy nor estrogen administration during these 2 years. The laboratory results were as follows: C4 3.8 mg % (normal range 15–47); C2 <4 mg % (4–24); C3 80 mg % (100–185). All these values had been reproduced at several time points. C1 inhibitor levels and function, C1q, C4bp, AP50, and CH50 were in the normal range, as was IgG, IgM, and IgA. Antinuclear antibodies, rheumatoid factor, cryoglobulins, HBsAg, Anti-HBc, Anti-HCV, and immunocomplexes were negative. The complement profile in her family showed normal values in her mother and brother, while C4 was low in her other two brothers and in her three children (9.6–13.4), one of whom had had several episodes of angioedema during puberty. C3 was slightly diminished in her sister and two of her children (82–92). C1 inhibitor, C2, and the functional activity of C1 inhibitor were normal in all her family members. Data from the patient's father were not available because he was dead. The patient was treated with tranexamic acid 500 mg/h, and remained almost asymptomatic. Our patient had a clinical disorder with characteristics of HAE, including a low C4 and a good response to tranexamic acid. However, the normal levels and function of C1 inhibitor ruled out this disease. A partial genetic deficiency of C4 was observed in several members of her family. In addition, the patient had a low level of C2, and a slight reduction in C3. The latter was also found in some members of her family. These facts suggest an associated deficiency in C4 and C2, which could be explained by the close location of both genes at chromosome 6. The reduction in C3, however, cannot be ascribed to the same reason, because it is placed at chromosome 19. Although a reduction in levels of these complement proteins might be due to activation of the classic pathway, we did not find any evidence of such a process. The patient had neither clinical symptoms nor analytic markers of diseases, such as dermatomyositis and vasculitis, associated with C4 or C2 deficiency. Recently, HAE with normal C1 inhibitor and its activity has been described in women (1). For this disorder, the authors proposed the term “hereditary angioedema type 3”. The presence of diminished C4, and the absence of symptoms depending on high estrogen levels (pregnancy, oral contraceptives, and hormone replacement therapy) exclude such a disease. Lately, Llatser & Guillaumet (2) have described a family with C4 and C2 deficiency, and two brothers affected by angioedema. In conclusion, the association of a clinical process which resembles HAE with a decrease in C4 level is not always caused by a deficiency or dysfunction of the C1 inhibitor component.