Information on the following diseases can be found in the Related Disorders section of this report:

• Acquired Nonhereditary Angioedema
• Cutis Laxia
• .

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 "p" and a long arm designated "q". Chromosomes are further sub-divided into many bands that are numbered. For example, "chromosome 11q12-q13.1" 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.

Symptoms of the following disorders can be similar to those of hereditary angioedema. Comparisons may be useful for a differential diagnosis:

Acute nonhereditary angioedema affects the skin and mucous membranes. It commonly clears up on its own after 1 or 2 days. Any number of allergens may be responsible including drugs, insect stings, bites, and certain foods (e.g., eggs, shellfish, nuts, and fruits). Some people can have very severe allergic reactions (anaphylaxis) that may result in respiratory angioedema. Acquired angioedema can also occur because of immune disorders (e.g., B-cell lymphoproliferative disease), chronic lymphocytic leukemia, multiple myeloma, lupus (SLE), chronic sinusitis, dental infection, or certain blood disorders (essential cryoglobulinemias). Other acquired edemas may occur because of surgery (i.e., mastectomy), malignancy, and/or autoimmune diseases. Acquired angioedema may occur at any age. (For more information on these disorders, choose "Anaphylaxis," "Leukemia," "Myeloma," "Lupus," and "Cryoglobulinemia" as your search term in the Rare Disease Database.)

Cutis laxa is a rare congenital or acquired connective tissue disorder characterized by limp or slack skin. The affected areas of the skin may be thickened and dark. This disorder is usually diagnosed at birth or early in infancy. The initial symptom is usually an episode of swelling on the face and may be confused with hereditary angioedema. Cutis laxa progresses causing skin changes and damage to blood vessels. (For more information on this disorder, choose "Cutis Laxa" as your search term in the Rare Disease Database.)
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Diagnosis
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 (i.e. C1-1NH and C1).

Treatment
Hereditary angioedema does not respond to the routine treatment for acute or chronic angioedema. However, several drugs can help prevent attacks. Preventive drugs (prophylactics) that may give long-term protection include certain androgens, such as danazol and oxymetholone. Androgens with few masculinizing effects, such as stanozolol, may be prescribed for women with this disorder. The amounts should be maintained at the lowest possible effective dosage.

To avoid episodes of angioedema associated with surgery, dental work, and similar stresses, short-term treatment is suggested before surgery or dental procedures. Fresh frozen plasma, or preparations of the missing enzyme that are partially purified from whole blood, are effective in these situations.

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. Epinephrine and antihistamines may be prescribed, although it is not clear whether they are effective for the treatment of hereditary angioedema.

On Oct. 10 of 2008, the Food and Drug Administration has approved Cinryze, a C1 inhibitor therapy, for routine prevention of attacks of spontaneous swelling (angioedema) in adolescents and adults with the rare disease known as hereditary angioedema (HAE). This is the first drug approved for this purpose in the U.S. HAE, also known as C1 inhibitor deficiency, causes sudden, unpredictable, and sometimes life-threatening swelling in the extremities, face, respiratory system, and other parts of the body. Cinryze is a a product of Lev Pharmaceuticals, Inc.

For information about Cinryze, which is a human plasma protein, visit www.levpharma.com or contact the company at:

Lev Pharmaceuticals, Inc.
675 Third Avenue, Suite 2200
New York, NY 10017
(212) 8509120

Genetic counseling may be of benefit for people with hereditary angioedema and their families.

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:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For the most current information about HAE clinical trials and how to participate, go to the web site of the Hereditary Angioedema Association at www.haea.org or call the association at (401) 272-1327.

Several companies are conducting clinical trials on possible treatments for HAE.

Dyax Corporation is currently recruiting patients for a Phase III trial (EDEMA4) of subcutaneously administered ecallantide (DX-88), which blocks the generation of the chemical responsible for the swelling. People ten years and older with HAE may be eligible for the study. For information, call (888) 675-9575 or (617) 250-5501 or go to www.dyax.com/HAE/HAE-trial.html.

Pharming Healthcare, Inc., a subsidiary of Pharming Group NV of The Netherlands, is developing a recombinant C1 inhibitor (rhC1INH) concentrate product for acute attacks of HAE. This product is not derived from human blood, and is currently available to HAE patients through an ongoing clinical trial in the U.S. and Canada. Patients who are interested in obtaining more information about the clinical trial may contact Pharming Healthcare at (800) 762-7017 or via email at hae-trials@pharming.com.

ZLB Behring of Australia is conducting a Phase III clinical trial of its C1-Inhibitor concentrate product, Berinet.

In some European countries, C1 inhibitor taken from the blood of donors (plasma-derived C1 INH) is available for patients to use as treatment. In much of the world, however, including the U.S., there is no standard therapy available at this time for the treatment of acute attacks of HAE.

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: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=106100 Accessed on: December 19, 2004.

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