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Last updated: March 26, 2021
Years published: 1986, 1987, 1989, 1991, 1992, 1993, 1996, 1997, 1999, 2002, 2005, 2007, 2008
Hereditary angioedema is a rare inherited disorder characterized by recurrent episodes of the accumulation of fluids outside of the blood vessels, blocking the normal flow of blood or lymphatic fluid and causing rapid swelling of tissues in the hands, feet, limbs, face, intestinal tract, or airway. Usually, this swelling is not accompanied by itching, as it might be with an allergic reaction. Swelling of the gastrointestinal tract leads to cramping. Swelling of the airway may lead to obstruction, a potentially very serious complication. These symptoms develop as the result of deficiency or improper functioning of certain proteins that help to maintain the normal flow of fluids through very small blood vessels (capillaries). In some cases, fluid may accumulate in other internal organs. The severity of the disease varies greatly among affected individuals.
The most common form of the disorder is hereditary angioedema type I, which is the result of abnormally low levels of certain complex proteins in the blood (C1 esterase inhibitors), known as complements. They help to regulate various body functions (e.g., flow of body fluids in and out of cells). Hereditary angioedema type II, a more uncommon form of the disorder, occurs as the result of the production of abnormal complement proteins.
The characteristic symptom of hereditary angioedema is recurrent episodes of swelling of affected areas due to the accumulation of excessive body fluid (edema). The areas of the body most commonly affected include the hands, feet, eyelids, lips, and/or genitals. Edema may also occur in the mucous membranes that line the respiratory and digestive tracts, which is more common in people with hereditary angioedema than in those who have other forms of angioedema (i.e., acquired or traumatic). People with this disorder typically have areas of swelling that are hard and painful, not red and itchy (pruritic). A skin rash (urticaria) rarely is present.
The symptoms of hereditary angioedema may recur and can become more severe. Injury, severe pain, surgery, dental procedures, viral illness, and/or stress can trigger or worsen the recurring symptoms.
Symptoms associated with swelling in the digestive system (gastrointestinal tract) include nausea, vomiting, acute abdominal pain, and/or other signs of obstruction. Edema of the throat (pharynx) or voice-box (larynx) can result in pain, difficulty swallowing (dysphagia), difficulty speaking (dysphonia), noisy respiration (stridor), and potentially life-threatening asphyxiation.
Hereditary angioedema is inherited as an autosomal dominant trait. Genetic diseases are determined by two genes, one received from the father and one from the mother.
Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a spontaneous new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.
The symptoms of hereditary angioedema type I develop due to a deficiency of a protein known as complement component C1 esterase inhibitor. Hereditary angioedema type II is a more uncommon form of the disorder and may occur because of abnormal C1 esterase proteins that do not function properly.
The gene that causes hereditary angioedema is located on the long arm of chromosome 11 (11q12-q13.1). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Pairs of human chromosomes are numbered from 1 through 22, and an additional 23rd pair of sex chromosomes which include one X and one Y chromosome in males and two X chromosomes in females. Each chromosome has a short arm designated โpโ and a long arm designated โqโ. Chromosomes are further sub-divided into many bands that are numbered. For example, โchromosome 11q12-q13.1โ refers to bands 12-13.1 on the long arm of chromosome 11. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
Hereditary angioedema is a rare disorder that affects males and females in equal numbers. Symptoms typically begin in early childhood. An estimated one in 50,000 to 150,000 individuals is affected by this disorder worldwide.
The diagnosis of hereditary angioedema is made by a thorough clinical evaluation, a detailed patient history, and blood tests that detect decreased levels of complement proteins. In instances of high clinical suspicion and recurrent episodic angioedema of uncertain etiology, genetic testing is indicated.
Treatment
In 2008, the Food and Drug Administration (FDA) approved Cinryze, a C1 inhibitor therapy, for routine prevention (prophylaxis) of attacks of spontaneous swelling (angioedema) in adolescents and adults with HAE. This is the first drug approved for this purpose in the U.S.
In 2009, FDA approved Berinert, to treat acute abdominal attacks and facial swelling associated with HAE in adults and adolescents. It is a protein product derived from human plasma. In 2016, FDA approved Berinert, as the first and only pediatric treatment for HAE. Also in 2009, FDA approved Kalbitor (ecallantide) to treat sudden and potentially life-threatening fluid buildup related to HAE. Kalbitor is a liquid that is intended to be injected under the skin of people age 16 and older with HAE.
In 2014, FDA approved Ruconest, a recombinant C1-esterase inhibitor for the treatment of acute attacks in adult and adolescent patients with HAE.
In 2017, FDA approved Haegarda (C1-esterase inhibitor) for administration under the skin to prevent HAE attacks.
Most recently, in 2020, FDA approved Orladeyo (berotralstat) to prevent attacks in patients 12 years of age and older with HAE. Orladeyo is an oral capsule taken one time per day.
To avoid episodes of angioedema associated with surgery, dental work, and similar stresses, short-term treatment is suggested before surgery or dental procedures. Patients should discuss options with their physicians.
In acute attacks with the danger of severe airway swelling and obstruction, it is essential to maintain or establish an airway. A temporary surgical opening in the throat (tracheotomy) may be created and oxygen may have to be supplied.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, in the main, contact:
www.centerwatch.com
For more information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
TEXTBOOKS
Joynt GM, Ho AMH. Hereditary Angioedema. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:375-6.
Beers MH, Berkow R., eds. The Merck Manual, 17th ed. Whitehouse Station, NJ: Merck Research Laboratories; 1999:1056.
Fauci AS, et al., eds. Harrisonโs Principles of Internal Medicine, 14th Ed. New York, NY: McGraw-Hill, Inc; 1998:1864-66.
Bennett JC, Plum F., eds. Cecil Textbook of Medicine. 20th ed. Philadelphia, PA: W.B. Saunders Co; 1996:1411-12.
Buyce ML, ed. Birth Defects Encyclopedia. Dover, MA: Blackwell Scientific Publications; For: The Center for Birth Defects Information Services Inc; 1990:143-4.
JOURNAL ARTICLES
Zuraw BL. Current and future therapy for hereditary angioedema. Clin Immunol. 2005;114:10-6.
Davis AE 3rd. The pathophysiology of hereditary angioedema. Clin Immunol. 2004;114:3-9.
Bower T, et al., Canadian 2003 International Consensus Algorithm for the Diagnosis, Therapy and Management of Hereditary Angioedema. J Allergy Clin Immunol. 2004;114:629-37.
Nzeako UC, Frigas E, Tremaine WJ. Hereditary angioedema: a broad review for clinicians. Arch Int Med. 2001;161:2417-29.
Borum ML et al. Hereditary angioedema. Complex symptoms can make diagnosis difficult. Postgrad Med. 1998;103:251, 255-6.
M. Kunschak et al. A randomized, controlled trial to study the efficacy and safety of c1 inhibitor concentrate in treating hereditary angioedema. Transfusion. 1998;38:540-9.
Wyates AT et al., Treatment of hereditary angioedema with a vapor-heated c1 inhibitor concentrate. N Eng J Med. 1996;334:1630-4.
Cicardi M, et al., Hereditary angioedema. N Eng J Med. 1996;334:1666-7.
Leimgruber A. Hereditary angioedema: uncomplicated maxillofacial surgery using short- term c1 inhibitor replacement therapy. Int Arch Allergy Immunol. 1993;101:107-12.
Elnicki DM. Hereditary angioedema. South Med J. 1992;85:1084-90.
Cicardi C. Long-term treatment of hereditary angioedema with attenuated androgens: a survey of a 13 year experience. J Allergy Clin Immunol. 1991;87:768-73.
Atkinson JC. Oral manifestations and dental management of patients with hereditary angioedema. J Oral Pathol Med. 1991;20:139- 42.
FROM THE INTERNET
McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:106100; Last Update:4/25/02.
Available at: https://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=106100 Accessed on: December 19, 2004.
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