Hereditary angioedema (HAE) is a disease characterized by recurrent episodes (also called attacks) of severe swelling of the skin and mucous membranes. The age at which attacks begin varies, but most people have their first one in childhood or adolescence. The frequency of attacks usually increases after puberty. Attacks most often affect 3 parts of the body:

• Skin - the most common sites are the face (such as the lips and eyes), hands, arms, legs, genitals, and buttocks. Skin swelling can cause pain, dysfunction, and disfigurement, although it is generally not dangerous and is temporary.
• Gastrointestinal tract - the stomach, intestines, bladder, and/or urethra may be involved. This may cause symptoms such as nausea, vomiting, diarrhea, and abdominal pain.
• Upper airway (such as the larynx and tongue) - this can cause upper airway obstruction and may be life-threatening. The majority of attacks affecting the airway resolve before complete airway obstruction.

Attacks may involve one area of the body at a time, or they may involve a combination of areas. They always go away on their own but last from 2 to 4 days. While people with HAE have reported various triggers of attacks, emotional stress, physical stress, and dental procedures are the most commonly reported triggers.

There are several types of HAE. Types I and II are caused by mutations in the C1NH gene (also called the SERPING1 gene), which provides instructions for making the C1 inhibitor protein. Type I is due to deficiency of C1 inhibitor, and type II is due to dysfunction of C1 inhibitor. These types are also characterized by abnormal complement protein levels. Inheritance of types I and II is autosomal dominant, but not all people with a SERPING1 gene mutation will develop symptoms of HAE. A third type is called HAE with normal C1 inhibitor. This type is characterized by normal C1 inhibitor and normal complement protein levels, and usually begins in adulthood. While some cases of type III are due to mutations in the F12 gene, in other cases the cause is not yet known. The inheritance of this form is also thought to be autosomal dominant.

Management of HAE involves treatment of sudden (acute) attacks and preventing attacks (prophylaxis). Treatment for acute attacks in types I and II includes replacement with C1 inhibitor concentrates, a kallikrein inhibitor, or fresh-frozen plasma (by infusion). Sudden attacks involving the upper airway may involve intubation if stridor or signs of respiratory distress are present. HAE with normal C1 inhibitor levels is treated similarly, however C1 inhibitor infusion is not effective. Prophylaxis may involve regular injections of C1 inhibitor concentrates, long-term androgen (male hormone) therapy, or antifibrinolytics.The long-term outlook varies depending on the frequency and location of attacks, and the severity of attacks in each person. Attacks generally continue throughout life, but the frequency of attacks can be significantly reduced with therapy.

Hereditary angioedema is estimated to affect 1 in 50,000 people. Type I is the most common, accounting for 85 percent of cases. Type II occurs in 15 percent of cases, and type III is very rare.

Mutations in the SERPING1 gene cause hereditary angioedema type I and type II. The SERPING1 gene provides instructions for making the C1 inhibitor protein, which is important for controlling inflammation. C1 inhibitor blocks the activity of certain proteins that promote inflammation. Mutations that cause hereditary angioedema type I lead to reduced levels of C1 inhibitor in the blood, while mutations that cause type II result in the production of a C1 inhibitor that functions abnormally. Without the proper levels of functional C1 inhibitor, excessive amounts of a protein fragment (peptide) called bradykinin are generated. Bradykinin promotes inflammation by increasing the leakage of fluid through the walls of blood vessels into body tissues. Excessive accumulation of fluids in body tissues causes the episodes of swelling seen in individuals with hereditary angioedema type I and type II.

Mutations in the F12 gene are associated with some cases of hereditary angioedema type III. This gene provides instructions for making a protein called coagulation factor XII. In addition to playing a critical role in blood clotting (coagulation), factor XII is also an important stimulator of inflammation and is involved in the production of bradykinin. Certain mutations in the F12 gene result in the production of factor XII with increased activity. As a result, more bradykinin is generated and blood vessel walls become more leaky, which leads to episodes of swelling in people with hereditary angioedema type III.

The cause of other cases of hereditary angioedema type III remains unknown. Mutations in one or more as-yet unidentified genes may be responsible for the disorder in these cases.

Normal Function

The F12 gene provides instructions for making a protein called coagulation factor XII. Coagulation factors are a group of related proteins that are essential for normal blood clotting (coagulation). After an injury, clots protect the body by sealing off damaged blood vessels and preventing further blood loss. Factor XII circulates in the bloodstream in an inactive form until it is activated, usually by coming in contact with damaged blood vessel walls. Upon activation, factor XII interacts with coagulation factor XI. This interaction sets off a chain of additional chemical reactions that form a blood clot.

Factor XII also plays a role in stimulating inflammation, a normal body response to infection, irritation, or other injury. When factor XII is activated, it also interacts with a protein called plasma prekallikrein. This interaction initiates a series of chemical reactions that lead to the release of a protein called bradykinin. Bradykinin promotes inflammation by increasing the permeability of blood vessel walls, allowing more fluids to leak into body tissues. This leakage causes the swelling that accompanies inflammation.

Health Conditions Related to Genetic Changes

Hereditary angioedema

At least two mutations in the F12 gene are associated with hereditary angioedema type III. These mutations change single protein building blocks (amino acids) in factor XII, which increases the activity of the protein. As a result, more bradykinin is produced, which allows additional fluids to leak through blood vessel walls. The accumulation of fluids in body tissues leads to the episodes of swelling in people with hereditary angioedema type III.

Other disorders

Approximately 20 mutations in the F12 gene that cause factor XII deficiency have been identified. Factor XII deficiency is an inherited condition characterized by a shortage of factor XII in the blood. Individuals with this condition usually do not experience abnormal bleeding or other symptoms. Factor XII deficiency is typically discovered during routine blood testing because reduced levels of factor XII cause the blood to take longer to clot in a test tube. Most of the mutations that cause factor XII deficiency change single amino acids, which alters the structure of factor XII. It remains unclear why individuals with factor XII deficiency do not experience abnormal bleeding like those with deficiencies of other coagulation factors.

Other Names for This Gene

• coagulation factor XII (Hageman factor)
• FA12_HUMAN
• HAE3
• HAEX
• HAF
• Hageman factor

Genomic Location

Normal Function

The SERPING1 gene provides instructions for making a protein called C1 inhibitor, which is a type of serine protease inhibitor (serpin). Serpins help control several types of chemical reactions by blocking the activity of certain proteins. C1 inhibitor is important for controlling a range of processes involved in maintaining blood vessels, including inflammation. Inflammation is a normal body response to infection, irritation, or other injury.

C1 inhibitor blocks the activity of several proteins in the blood, including plasma kallikrein and the activated form of factor XII (called factor XIIa). These two proteins are involved in the production of bradykinin. Bradykinin is a protein that promotes inflammation by increasing the permeability of blood vessel walls, allowing fluids to leak into body tissues. C1 inhibitor attaches (binds) to plasma kallikrein and factor XIIa, which prevents them from completing any further reactions. These proteins are cleared from the bloodstream once they are bound to C1 inhibitor.

Health Conditions Related to Genetic Changes

Hereditary angioedema

More than 250 mutations in the SERPING1 gene have been found to cause hereditary angioedema types I and II. Mutations that cause type I occur throughout the gene and lead to reduced levels of C1 inhibitor in the blood. Mutations that cause type II usually occur in a specific region of the gene called exon 8 and result in the production of a C1 inhibitor that functions abnormally. Without the proper levels of functional C1 inhibitor, the activity of plasma kallikrein and factor XIIa cannot be blocked and excessive amounts of bradykinin are produced. Excess fluids leak through blood vessel walls and accumulate in body tissues, leading to the recurrent episodes of swelling seen in individuals with hereditary angioedema type I and type II.

Other Names for This Gene

• C1-INH
• C1IN
• C1INH
• C1NH
• complement component 1 inhibitor
• IC1_HUMAN
• plasma protease C1 inhibitor
• serine/cysteine proteinase inhibitor clade G member 1
• serpin peptidase inhibitor, clade G (C1 inhibitor), member 1

Genomic Location

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.

In some cases, an affected person inherits the mutation from one affected parent. Other cases result from new mutations in the gene and occur in people with no history of the disorder in their family.