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What

Angioedema is a condition in which tissues in the body become swollen or full of fluid. This swelling can be caused by a number of factors including food or drug allergies or inherited genetic alterations. Hereditary angioedema (HAE) is one type of angioedema. It is a genetic disorder caused by a diminished activity or decreased amount of a blood protein known as C1 inhibitor.  This C1 inhibitor protein in the immune system normally prevents the release of substances that cause swelling in the human body, thus when the C1 inhibitor protein is decreased in amount or activity, this can lead to increased swelling or angioedema.  Patients with HAE have periodic episodes of swelling in the extremities, face, abdomen, intestines, or upper airway. Although HAE is a life-long condition that may have serious consequences, the prognosis for people with HAE is generally very positive.

Who

Current estimates of the incidence of HAE range from 1 in 10,000 to 1 in 50,000 births. HAE is present in all races and occurs equally in both sexes. Most people develop the disease during adolescence. However, a significant number children show symptoms in earlier childhood, while some people are asymptomatic until well into their adult life.   Children who develop symptoms earlier than age 5 tend to have a higher frequency of swelling episodes. HAE is a genetic disorder which means that it runs in families who have certain genes. A child has two copies of every gene-one from each parent. One broken copy of the gene related to HAE is enough to cause a child to develop the disease. Thus, even if a child inherits a second normal gene copy, one altered gene will lead to HAE. Because a child receives a broken gene from a parent, that parent is or will eventually be affected by HAE as well. Each child born to an affected parent has a 50% chance of inheriting the broken gene and developing HAE (known as "autosomal dominant" inheritance in genetics). It is important to understand that a parent with HAE has no control over whether his or her child receives the normal or broken gene copy. In approximately 25% of HAE cases, the individual is born to parents who have no personal or family history of HAE.  In this case, HAE is caused by a newly arising genetic change.

Signs and Symptoms

Usually people with HAE will have symptoms by age 20, but the frequency, duration, and severity of attacks differ from one person to the next. For this reason, HAE can sometimes be missed until later in life.  Even within a single individual, symptoms and length of attacks can vary.  Some people only experience attacks about once a year while others are affected every week. Attacks can last from several hours  to 2- 4 days.  An attack generally starts out mildly, becomes increasingly uncomfortable, and then slowly goes away. It is important to remember that not all of these symptoms apply to every child. The three most common symptoms of angioedema are skin swelling, abdominal pain, and airway swelling. 

Skin swelling is normally not itchy or red with well-defined borders.   Almost all patients with HAE will experience this symptom.  It usually is seen on the arms and legs, but can also develop on the face, neck, genitals, and body.  This swelling goes away without medication, but can last 2-4 days.  In children, this swelling is often caused by physical damage to the skin (such as scrapes, cuts, and other common injuries) or upper respiratory infections (like the common cold).

Abdominal pain is usually diffuse (that is, not located to a particular point in the abdomen) and may be accompanied by vomiting, diarrhea, or in serious cases, a non-functioning intestinal tract.  This is caused by swelling of the internal organs, which can result in blockage of the bowels or even decreased circulation of the blood.  Abdominal pain is a common complaint in children so it is important to distinguish HAE-related symptoms from other causes of abdominal pain.  One important note is abdominal pain related to HAE usually is not accompanied by a fever and may occur with skin swelling.  Abdominal swelling is known to occur in 97% of individuals with HAE.  

Airway swelling is the rarest symptom of HAE, but the most serious.  It accounts for only 0.9% of HAE attacks, but is life-threatening because it can lead to suffocation, especially in children.  Symptoms include hoarseness or other voice changes, harsh breathing noise, difficulty breathing, difficulty swallowing, or the feeling that something is lodged in the throat.  A child with HAE who has these symptoms should report immediately to an emergency room for evaluation. Other symptoms may result from swelling in other locations in the body.  Only 2% of HAE attacks present with headache (from swelling in the brain), difficulty urinating (from swelling in the bladder or urinary tract), muscle or joint pain, or chest pain and shortness of breath (from swelling in the chest).

Possible Causes

A broken copy of the gene related to HAE results in the impaired activity or decreased amount of the blood protein known as C1 inhibitor. C1 inhibitor protein helps control certain immune system processes such as defending against infection and controlling inflammation. It also plays a role in the regulation of blood clotting. When too little C1 inhibitor protein is present or when that protein does not function properly, the balance of other biochemical proteins is affected. It is thought that a resulting increased level of some protein causes small blood vessels known as capillaries to leak fluid into tissues, causing swelling (edema). While most attacks are not linked to a precipitating factor, instigators of attack may include anxiety, stress, sickness, surgery, dental work, injury, menstruation, or usage of oral contraceptives (birth control pills). HAE may improve or worsen with pregnancy.

Diagnosis

Diagnosis of HAE should ideally be done as early as possible, especially in people  who have a family history of the disorder.  Blood will be drawn and the level of C1 inhibitor protein and its activity will be measured. Levels of the C1 inhibitor protein or its activity are decreased in patients with HAE. Decreased levels of related proteins known as C4 and C2 with normal levels of C1 will also be present in a patient with HAE. This pattern of complement protein levels, with a family history of episodic swelling, suggests the diagnosis.  However, children develop these proteins as they mature and will not have their true levels of the proteins until around age 3.  Therefore, testing is not always accurate on very young children.  For that reason, it is recommended that if testing is done before 1 year of age, it should be repeated after 1 year of age and then confirmed 4 weeks after that test.

Treatment

The most important aspect of managing HAE is education.  Parents and patients should be aware of  signs and  symptoms of an HAE attack.  Additionally, people who have regular contact with the patient (e.g. daycare staff, school teachers, or babysitters) should be made aware of HAE symptoms. Ask your physician for a card that summarizes HAE, the common symptoms, and who to contact in case of an emergency.  It is also important to keep a record of HAE attacks, including what the attacks were, how long they lasted, and what may have brought on the attacks (including reactions to medications).  Patients with HAE are advised to avoid unnecessary trauma that can cause an attack; although athletic activity is encouraged, contact sports should be avoided.  To reduce the risks of infection, children with HAE are cautioned about attending child care before kindergarten.  Psychological stress can sometimes cause attacks and should be minimized as much as possible.  Adolescent females should not take oral contraceptives (birth control pills).  In general, during puberty, patient's symptoms may change, so teenagers should be closely watched closely  for changes in HAE attacks.  Although not commonly prescribed in pediatrics, medications known as ACE inhibitors should be avoided because they can cause angioedema.

During an HAE attack a patient should have immediate medical attention for the following reasons: (1) swelling that includes the face and the lips may lead to upper airway involvement, (2) symptoms of hoarseness, voice changes, difficulty swallowing, feeling a lump in the throat or difficulty breathing indicate upper airway swelling, (3) severe abdominal pain or (4) the patient is pale, sweaty, or unwell can indicate more extensive involvement.   A solution of C1 inhibitor protein may be administered emergently, and some physicians allow for parents to keep supplies of the protein at home or during travel.  Speak to your doctor about the availability of this medication.  This medication may be administered in an emergency room.  Additionally, supportive care such as intravenous hydration may be helpful.

Short-term preventative treatment should be considered for patients with HAE prior to surgery or any imaging studies that involve the head and neck region.  Preventative treatment can consist of androgens (male hormone which increases C1 inhibitor protein), blood thickening medication, or C1 inhibitor replacement.  Fresh frozen plasma (blood without cells) is an alternative to C1 inhibitor replacement.

Long-term preventative treatment is usually unnecessary for children under the age of 6.  Preventative treatment should be considered if HAE attacks occur more than once a month or if the patient had a serious HAE attack that was life-threatening.  Blood thickening medications like tranexamic acid (TA) have been shown to reduce the frequency of HAE attacks with decreased side effects.  Side-effects of TA include muscle weakness, muscle pain, muscle damage, eye damage, unstable blood pressure, and blood clots; this medication should not be used in any patient with a previous or family history of blood clotting disorders.  If this medication does not attain satisfactory results, androgens such as danazol and stanozolol may be used, although experience in children is limited.  By using these medications at low levels, the adverse effects of these medications (such as hair growth, weight gain, muscle pain, headache, liver damage, menstrual irregularity, increased cholesterol, and deepened voice) may be limited.  Oxandrolone is another androgen currently undergoing investigation in pediatric patients. 

Prognosis

The most serious consequence of HAE is obstruction of the upper airway. Patients with HAE who notice progressive swelling need emergent therapy. However, despite the potential severity of HAE, patients who seek appropriate medical attention and use androgen therapy when necessary can expect to do very well. While HAE is a lifelong condition, it can be managed.

  

Connect with other parents

In the spirit of community and support, Madisons Foundation offers the unique service of connecting parents of children with rare diseases. If you would like to be connected to other parents of children with this disease, please fill out this brief form.

Connect with other parents

In the spirit of community and support, Madisons Foundation offers the unique service of connecting parents of children with rare diseases. If you would like to be connected to other parents of children with this disease, please fill out this brief form.

Weblinks

Hereditary Angioedema Association

http://www.hereditaryangioedema.com/

A comprehensive site with an overview of HAE, as well as useful links to ongoing research and clinical trials. There are also testimonials from people living with the condition.   

Canadian Hereditary Angioedema Society

http://www.haecanada.com/

A nice website with educational information as well as information about support groups as well as ongoing support.

MEDLINE plus

http://www.nlm.nih.gov/medlineplus/ency/article/001456.htm

A good review article on the condition with nice definitions of medical terms.

HAE Registry
An international registry of patients with HAE, to monitor their courses and treatment.  Talk to your physician about registering on this site.

Google Search for Hereditary Angioedema (HAE)

References and Sources

Cicardi, Marco, et al. "Established and New Treatments for Hereditary Angioedema: An Update," Molecular Immunology Volume 44, Issue 16, September 2007, Pages 3858-3861.

Farkas, H, et al. "Management of Hereditary Angioedema in Pediatric Patients." Pediatrics Vol. 120 No. 3 September 2007, pp. e713-e722 (doi:10.1542/peds.2006-3303), http://pediatrics.aappublications.org/cgi/content/full/120/3/e713

Heymann WR, "Angioedema, Hereditary," eMedicine, 2007,http://www.emedicine.com/derm/topic24.htm,

Frank MM, "Herediatry Angioedema," eMedicine, 2006,

http://www.emedicine.com/med/topic420.htm ,

"Urticaria and Angioedema," p. 1444, Goldman: Cecil Textbook of Medicine, 21st ed., home.mdconsult.com/das/book/29689177/view/882/283.html/top, 2000.