Hereditary Angioedema (C1 Esterase Deficiency)

Hereditary Angioedema (C1 Esterase Deficiency) is a topic covered in the 5-Minute Pediatric Consult.

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Basics

Description

Hereditary angioedema (HAE) is an autosomal dominant condition characterized by recurrent, unpredictable, and potentially life-threatening swelling. The swelling results from excess production of bradykinin which is a potent vasodilator. Most commonly, this production results from a deficiency or dysfunction of C1 esterase inhibitor (C1-INH) which leads to unregulated activation of complement and plasma kinin–forming pathways and angioedema. There are three main classifications of HAE and one additional category of acquired angioedema:

  • Type I HAE: deficiency of C1-INH (~85% of patients)
  • Type II HAE: dysfunction of C1-INH (~15%)
  • HAE with normal C1-INH (previously called type III HAE): unclear mechanism (very rare)
  • Acquired angioedema, ACE inhibitor–induced angioedema, and idiopathic angioedema (These are not HAE and will be minimally discussed here)

Epidemiology

  • HAE type I or II
    • Prevalence between 1 in 10,000 and 1 in 150,000
    • All genders and races affected equally
    • Onset before puberty in ~50% of patients
    • Symptoms tend to worsen during puberty and persist into adulthood.
  • HAE with normal C1-INH
    • Only a few families described, mostly women of childbearing age

Risk Factors

Genetics

  • HAE type I or II
    • Autosomal dominant, high penetrance
    • 25% spontaneous mutations (may have family history negative for the disease)
    • Mutations on chromosome 11 in SERPING1 gene which codes for C1-INH
  • HAE with normal C1-INH
    • Autosomal dominant, low penetrance
    • Some patients with mutations in coagulation factor XII gene

Pathophysiology

  • Deficiency/dysfunction of C1-INH leads to unopposed activation of the classical complement pathway and conversion of prekallikrein to kallikrein.
  • Kallikrein increases formation of bradykinin, which produces angioedema.
  • Histamine and other mast cell mediators are NOT involved.

Commonly Associated Conditions

Mildly increased risk of autoimmunity

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