Dermatologic Manifestations of Hereditary Angioedema 

  • Author: Warren R Heymann, MD; Chief Editor: Dirk M Elston, MD   more...
 
Updated: Jan 6, 2012
 

Background

Hereditary angioedema (HAE) is an autosomal dominant disorder of C1 inhibitor (C1-INH) deficiency manifested by painless, nonpruritic, nonpitting swelling of the skin. Type I HAE is defined by low plasma levels of a normal C1-INH protein. Type II HAE is characterized by the presence of normal or elevated levels of a dysfunctional C1-INH. Type III HAE has been recently identified as an estrogen-dependent inherited form of angioedema occurring mainly in women with normal functional and quantitative levels of C1-INH.

A related eMedicine article is Angioedema, Acquired.

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Pathophysiology

The gene for C1-INH (SERPING1) has been mapped to 11q12-q13.1. C1-INH is a multifunctional serine protease inhibitor that is normally present in high concentrations in plasma. It is the only known plasma inhibitor of C1r and C1s, the activated proteases of the first component of complement. It is also the major plasma inhibitor of activated factor XII (Hageman factor), the first protease in the contact system. Additionally, C1-INH is one of the major inhibitors of plasma kallikrein, the contact system protease that cleaves kininogen and releases bradykinin.

Presumably, uncontrolled activation of the contact system allows for the release of kininlike mediators, resulting in edema of subcutaneous or submucosal tissues. Although the issue of which vasoactive peptide is ultimately responsible for these changes remains controversial, direct evidence supports the importance of bradykinin in the clinical manifestations of angioedema. For example, vascular permeability has been shown to increase in mice deficient in C1-INH, but not in mice with a deficiency in both C1-INH and the bradykinin B2 receptor.[1]

Other kinins may also be pathogenic. The inciting factor responsible for inducing the release of these vasoactive peptides is unclear. Factor XII activation may be secondary to a genetic mutation or phospholipid release from damaged or apoptotic cells and may be important in the generation of bradykinin from endothelial activation.[2] This hypothesis encompasses the role of illness or tissue injury in the generation of bradykinin.[3, 4]

Hereditary angioedema (HAE) is due to mutations within the C1-INH gene (C1NH) and is transmitted as an autosomal dominant trait. Approximately 150 different genetic mutations have been described in HAE, and a spontaneous mutation rate of 25% has been reported. The 2 variants of HAE related to C1-INH function are type I (85%) and type II (15%).

Type I HAE is caused by mutations occurring throughout the gene, which result in either a truncated or misfolded protein. This protein is not secreted efficiently, resulting in low antigenic and functional plasma levels of a normal C1-INH protein. Even though one normal allele is present, less than 50% of functional C1-INH is present. A possible explanation is that the normal C1-INH protein is down-regulated, and this is supported by the finding of decreased levels of C1-INH mRNA in patients with HAE.[1]

Type II HAE is caused by mutations that involve the active site of exon 8. These mutations result in a dysfunctional protein.[1] Therefore, patients with type II HAE have normal or elevated antigenic levels of a dysfunctional mutant protein together with reduced levels of the functional protein. C1-INH deficiency allows autoactivation of C1, with consumption of C4 and C2.

In type III HAE, the C1-INH protein is both qualitatively and functionally normal. The exact mechanism of action responsible for the link between estrogen and angioedema is unclear, thus the term "estrogen-dependent" should be avoided. One theory suggests that estrogen plays a role in up-regulating the production of bradykinin and decreasing its degradation by angiotensin-converting enzyme (ACE). More recently, mutations in factor XII have been identified in some, but not all patients. These factor XII mutations allow for the inappropriate activation of the kinin cascade.[5]

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Epidemiology

Frequency

United States

Hereditary angioedema (HAE) incidence is 1 case in 10,000-50,000 people.[6]

International

Hereditary angioedema (HAE) is estimated to occur in 1 in 50,000-150,000 individuals.

Mortality/Morbidity

Mortality rates for hereditary angioedema (HAE) are estimated at 15-33%, resulting from laryngeal edema and asphyxiation.

HAE leads to 15,000-30,000 emergency department visits per year. An abdominal attack can lead to unnecessary surgery and delay in diagnosis, as well as narcotic dependence due to severe pain. Cutaneous attacks are both disfiguring and disabling, resulting in a diminished quality of life.[6]

Race

Persons of any race can be affected by hereditary angioedema (HAE), with no reported bias in different ethnic groups.

Sex

Men and women are equally affected for hereditary angioedema (HAE) types I and II, although women tend to have more severe attacks.[6] HAE type III was initially thought to occur only in women, but recent family studies have described males with HAE and normal C1 inhibitor levels. Although a few male cases have been cited in the literature, HAE type III is still thought to predominantly affect women.

Age

C1-INH deficiency is present at birth, although only a few patients have been reported with perinatal angioedema. Symptoms usually become apparent in the first or second decade of life. Approximately 40% of people with hereditary angioedema (HAE) experience their first episode before age 5 years, and 75% present before age 15 years.[7] Patients typically experience minor swelling in childhood that may go unnoticed, with increased severity around puberty. However, type III HAE is found in the second decade of life or later and occurs only rarely before puberty.[5] HAE is a lifelong affliction, although some report decreased symptoms with age. Five percent of adults with HAE are asymptomatic while carrying the C1NH mutation, and they are only identified after their children are found to be symptomatic.

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Contributor Information and Disclosures
Author

Warren R Heymann, MD  Head, Division of Dermatology, Professor, Department of Internal Medicine, University of Medicine and Dentistry of New Jersey-New Jersey Medical School

Warren R Heymann, MD is a member of the following medical societies: American Academy of Dermatology, American Society of Dermatopathology, and Society for Investigative Dermatology

Disclosure: Nothing to disclose.

Coauthor(s)

Amanda T Moon, MD  Resident Physician, Department of Dermatology, University of Rochester, Strong Memorial Hospital

Amanda T Moon, MD, is a member of the following medical societies: American Academy of Dermatology, American Medical Association, American Medical Student Association/Foundation, and Society for Pediatric Dermatology

Disclosure: Nothing to disclose.

Specialty Editor Board

Robert A Schwartz, MD, MPH  Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, University of Medicine and Dentistry of New Jersey-New Jersey Medical School

Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and Sigma Xi

Disclosure: Nothing to disclose.

Michael J Wells, MD  Associate Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine

Michael J Wells, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, and Texas Medical Association

Disclosure: Nothing to disclose.

Paul Krusinski, MD  Director of Dermatology, Fletcher Allen Health Care; Professor, Department of Internal Medicine, University of Vermont College of Medicine

Paul Krusinski, MD is a member of the following medical societies: American Academy of Dermatology, American College of Physicians, and Society for Investigative Dermatology

Disclosure: Nothing to disclose.

Catherine M Quirk, MD  Clinical Assistant Professor, Department of Dermatology, University of Pennsylvania

Catherine M Quirk, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Dermatology

Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD  Director, Ackerman Academy of Dermatopathology, New York

Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

Additional Contributors

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous author, Kathleen M. Rossy, MD, to the development and writing of this article.

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