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Last updated: 1/6/2025
Years published: 1986, 1987, 1989, 1991, 1992, 1993, 1996, 1997, 1999, 2002, 2005, 2007, 2008, 2025
NORD gratefully acknowledges Gioconda Alyea, MD (FMG), MS, National Organization for Rare Disorders, for assistance in the preparation of this report.
Hereditary angioedema (HAE) is a rare genetic disorder that causes recurrent episodes of localized swelling. This swelling can affect the hands, feet, face, gastrointestinal tract, or airway and is not typically associated with itching, as seen in allergic reactions. Swelling in the gastrointestinal tract may cause severe cramping, while swelling in the airway can lead to life-threatening obstruction.
Most cases of HAE are caused by changes (variants) in the SERPING1 gene, which encodes the C1 inhibitor protein, a key regulator of the complement system, a group of proteins present in the blood plasma that work alongside the immune system to protect the body from infections.
HAE can be classified in three types. Type I, the most common, is due to abnormally low levels of C1 inhibitor, type II is due to the production of a dysfunctional C1 inhibitor protein and type III (the less common) has normal C1 inhibitor levels and is caused by variants in several different genes.
HAE is inherited in an autosomal dominant pattern, but new variants account for up to 25% of cases without a family history.
Signs and symptoms include episodes of swelling with abdominal pain. Breathing difficulties are rare but may be potentially fatal due to asphyxiation. Several factors such as stress, trauma, infections, certain medications and hormonal changes may trigger the episodes.
Diagnosis involves assessing C1 inhibitor antigenic and functional levels, C4 complement levels, and potentially genetic testing. Without proper treatment, the condition is highly disabling. Diagnosis is often delayed by up to 10 years after symptom onset, which usually occurs in childhood.
Treatment aims to prevent the episodes, reduce their severity, and restore normal quality of life. New medications are under development to address unmet needs and further improve patient outcomes.
Hereditary angioedema (HAE) is characterized by acute episodic swelling (angioedema) that can affect various parts of the body. These episodes result from fluid leakage from blood vessels into surrounding tissues, driven by a dysfunction in bradykinin regulation. Symptoms typically begin in childhood or young adulthood and get worse around puberty. Most symptomatic cases occur before age 20; however, young children may remain asymptomatic. Typically, it presents with recurrent episodes of swelling or abdominal pain.
The signs and symptoms that may be present are as follows:
Cutaneous Angioedema
Visceral Angioedema
HAE episodes can be triggered by physical or emotional stress, trauma, infections, or surgical/dental procedures, hormonal factors (e.g., oral contraceptives, pregnancy) or certain medications like ACE inhibitors or NSAIDs.
Notably, many episodes occur without identifiable triggers, and response to the same trigger can vary significantly between individuals. For example, a specific trigger may cause a severe response in one patient but a mild or negligible response in another.
HAE is episodic, with acute swelling attacks typically resolving over 2 to 5 days. This pattern helps distinguish HAE from other chronic, non-episodic conditions.
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.
Most cases of HAE are caused by variants in the SERPING1 gene. The SERPING1 gene has instructions to produce the C1-INH (C1 inhibitor protein), a key regulator of the complement system (a group of proteins present in the blood that works alongside the immune system to protect the body from infections and complementing the antibodies in the body), and other pathways such as coagulation and fibrinolysis.
There are three types of HAE:
Current guidelines now recommend subdividing “hereditary angioedema with normal C1 esterase inhibitor gene” (HAE-nl-C1-INH formerly known as HAE type III) based on underlying variants such as in kininogen-1 (HAE-KNG1), plasminogen gene (PLG-HAE), myoferlin gene variant (MYOF-HAE), heparan sulfate-glucosamine 3-sulfotransferase 6 (HS3ST6), a variant in Hageman factor (factor XII), and in angiopoietin-1 (HAE-ANGPT-1).
Inheritance
HAE is an autosomal dominant genetic disorder. Dominant genetic disorders occur when only a single copy of a disease-causing gene variant is necessary to cause the disease. The gene variant can be inherited from either parent or can be the result of a new (de novo) changed gene in the affected individual that is not inherited. The risk of passing the gene variant from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.
Up to 25% of cases result from spontaneous (de novo) gene variants.
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 are 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.
To rule out non-HAE causes of angioedema, consider the following:
Administering an ACE inhibitor can help confirm HAE; symptoms will typically worsen in patients with HAE.
In HAE with normal C1-INH levels:
Hereditary angioedema (HAE) management has advanced in recent years, with a focus on both acute treatment and long-term prophylaxis. The development of more convenient, fast-acting and effective therapies has improved patient care, offering individualized plans tailored to attack frequency, severity and patient preferences.
Acute treatments aim to stop swelling episodes rapidly and prevent progression to severe complications. These therapies include:
These treatments have transformed HAE care by enabling faster responses to acute attacks, especially outside of healthcare settings.
Prophylactic treatments aim to reduce the frequency and severity of HAE attacks. Several options are available:
Recent developments aim to address the limitations of traditional therapies. New subcutaneous and oral treatments, such as icatibant and sebetralstat, allow for at-home management, reducing the need for hospital visits. Lanadelumab and other treatments requiring administration every 2–4 weeks significantly reduce dosing frequency, easing the treatment burden. Advances in monoclonal antibodies (e.g., garadacimab) and gene therapies under development aim for complete disease control or even curative approaches.
Individualized treatment plans now incorporate patient preferences, attack patterns and response to therapies. Patients may switch between therapies to optimize efficacy and minimize side effects.
Short-term prophylaxis with C1-INH products is recommended before procedures to prevent HAE attacks. Gene therapies are under investigation to address the underlying genetic cause of HAE, potentially offering a cure rather than symptom management.
Current therapies have limitations, such as the need for regular injections and incomplete disease control. New oral treatments and gene therapies hold promise for reducing the treatment burden, achieving attack-free remission and providing more targeted and curative approaches.
With these advancements, the future of HAE management may offer patients a life with fewer disruptions and improved overall quality of life.
The Hereditary Angioedema Association has updated information about the FDA approved drugs for hereditary angioedema in the following link: Approved HAE treatment. The recommendations regarding a comprehensive care plan for HAE, including development of an overall management plan, treatment of angioedema attacks, prophylactic treatment and patient monitoring have been published in the peer-reviewed Journal of Allergy and Clinical Immunology: In Practice and can be downloaded at the Hereditary Angioedema Association Website.
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 website.
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: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
Costanzo G, Sambugaro G, Sartorio S, Zanichelli A, Firinu D. New drugs for the treatment of hereditary angioedema. Expert Opin Biol Ther. 2024 Dec 14:1-13. doi:jjuui 10.1080/14712598.2024.2441845. Epub ahead of print. PMID: 39664008.
Covella B, Giliberti M, Montinaro A, Rossi L, Montinaro V. Hereditary angioedema: novel molecules for treatment of acute attacks and long-term prophylaxis. Future Pharmacol. 2024, 4(1), 41-53; https://doi.org/10.3390/futurepharmacol4010005
Costanzo G, Sambugaro G, Firinu D. Hereditary angioedema due to C1-inhibitor deficiency: current therapeutic approaches. Curr Opin Allergy Clin Immunol. 2024 Dec 1;24(6):488-495. doi: 10.1097/ACI.0000000000001042. Epub 2024 Oct 15. PMID: 39407363; PMCID: PMC11537475.
Sinnathamby ES, Issa PP, Roberts L, Norwood H, Malone K, Vemulapalli H, Ahmadzadeh S, Cornett EM, Shekoohi S, Kaye AD. Hereditary angioedema: diagnosis, clinical implications, and pathophysiology. Adv Ther. 2023 Mar;40(3):814-827. doi: 10.1007/s12325-022-02401-0. Epub 2023 Jan 7. PMID: 36609679; PMCID: PMC9988798. https://pmc.ncbi.nlm.nih.gov/articles/PMC9988798/
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