Elsevier

The Lancet

Volume 356, Issue 9225, 15 July 2000, Pages 213-217
The Lancet

Early Report
Hereditary angioedema with normal C1-inhibitor activity in women

https://doi.org/10.1016/S0140-6736(00)02483-1Get rights and content

Summary

Background

Hereditary angioedema (HAE) is a well defined autosomal dominant disease (Mendelian Inheritance in Man #106100) that results from an inherited deficiency of C1 (the activated first component of complement) inhibitor function. We report an unusual variant of HAE with normal biochemical C1-inhibitor function, occurring only in women.

Methods

We screened 574 patients with recurrent angioedema of the skin for presence of HAE. 283 patients were selected, in whom angioedema was associated with abdominal pain attacks or recurrent life-threatening episodes of upper-airway obstruction, or both, rather than with urticaria. We measured C1-inhibitor concentration and functional activity as well as complement C4 concentration and took pedigrees to characterise patients.

Findings

94 HAE cases with C1-inhibitor deficiency, positive family history, or both were identified. Biochemical testing showed that 84 patients from 49 families had a functional C1-inhibitor deficiency. 11 of these patients had no affected family members (probably representing de-novo mutations). Ten women with HAE, from ten families, had normal C1-inhibitor protein concentrations and function, and normal C4 concentration. A more detailed study of these families identified another 26 affected members, who were also all women. Of those women, 14 could be studied and also had normal C1-inhibitor concentration and function. The disease was seen in successive generations, and in offspring of affected mothers, the sex ratio (M/F) was shifted to 1/1·5.

Interpretation

HAE with normal C1-inhibitor concentration and function represents a unique genetic disease arising only in women. The formal genetics of this entity are suggestive of an X-linked dominant mode of inheritance. For this disorder we propose the term hereditary angioedema type 3 (HAE III).

Introduction

Recurrent angioedema of the skin is a commonly diagnosed clinical symptom that can be seen in various clinical entities.1, 2, 3 Some types of angioedema of the skin are associated with episodes of upper-airway obstruction that might be life-threatening. Asphyxiation by laryngeal oedema is well known in hereditary angiodema (HAE) due to C1-inhibitor (deficiency)4, 5, 6 and in recurrent angioedema induced by angiotensin-converting-enzyme (ACE) inhibitors.7, 8, 9, 10 Therefore, the exact type of angioedema must be identified in each patient.

In many patients, angioedema is associated with urticaria. If relapsing urticaria occurs simultaneously or otherwise with angioedema, the two disorders are assumed to be symptoms of the same disease. This assumption is valid in: chronic idiopathic urticaria and angioedema; IgE-mediated reactions to foods, drugs, insect toxins, and other substances; serum sickness; urticaria and angioedema induced by aspirin and nonsteroidal anti-inflammatory drugs, azo dyes, and benzoates; and reactions caused by substances that induce direct histamine release from mast cells.

Recurrent angioedema in patients without urticaria can be due to several pathogenetic mechanisms. Most frequently, recurrent angioedema is part of the above entities, in many patients as the combination of urticaria and angioedema, but in some patients as recurrent angioedema alone. Furthermore, recurrent angioedema without urticaria can result from inherited or acquired C1-inhibitor deficiency,11, 12, 13, 14 or be induced by ACE inhibitors. HAE due to C1-inhibitor deficiency is not associated with urticaria, whereas ACE inhibitors may cause recurrent angioedema alone, or in association with urticaria. In recurrent angioedema C1-inhibitor deficiency, antihistamines and corticosteroids are not effective. Other types of angioedema without urticaria are rare and include local angioedema secondary to physical stress, such as vibratory angioedema. Some patients with recurrent angioedema have clinical symptoms that cannot be ascribed to one of these disorders. This type of angioedema is referred to as idiopathic angioedema.3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15

In 1985, we (KB) assessed a large family, in which five women had recurrent angioedema of the skin associated with relapsing episodes of abdominal pain and upper-airway obstruction. All of them had normal C1-inhibitor function. One family member had asphyxiated by sudden laryngeal oedema. We assessed other families with similar cases and present our findings here.

Section snippets

Study patients

The study was done in our angioedema outpatient clinic at the Department of Dermatology of the University of Mainz, Germany, from 1986 to 1999. We screened 574 angioedema patients for the presence of HAE. All patients underwent thorough clinical examination and we took detailed medical and family histories. The patients originated from various regions of Germany and were referred to us because of our interest in angioedema.

Methods

Patients' medical histories were supplemented by reports from the family

Patients

291 (51%) of 574 patients with relapsing cutaneous angioedema had associated urticaria. The remaining 283 (49%) patients with recurrent angioedema alone included 94 patients from 59 unrelated families. In 84 patients from 49 of these families, a deficiency of C1-inhibitor function was seen. In 79 of these 84 patients (from 46 families), HAE I could be diagnosed because of concurrent lowered C1-inhibitor protein concentrations. In 11 patients with HAE I no further family members were affected

Discussion

Currently, two different types of HAE or hereditary angioneurotic oedema have been distinguished. We have outlined the clinical and genetic features of a possible third type. HAE, first described clinically by Osler,17 refers to an autosomal dominant disorder caused by deficiency of functional C1 inhibitor. The underlying defect was discovered by Donaldson and Evans, in 1963.12 Clinically, this disorder is characterised by episodic local subcutaneous oedema and submucosal oedema of the

References (27)

  • EW Nielsen et al.

    Dodsfall av hereditaert angiooedem

    Tidsskr Nor Laegeforen

    (1995)
  • PJ Giannoccaro et al.

    Fatal angioedema associated with enalapril

    Can J Cardiol

    (1989)
  • DR Jason

    Fatal angioedema associated with captopril

    J Forensic Sci

    (1992)
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