How Common Is Hereditary Angioedema?

Patient Presentation
An 8-year-old female came to clinic because of swelling in her right lower extremity x 1 day. She had noticed the problem the night before but didn’t tell her parents until that morning. She had some general discomfort and pruritus with moving her leg but denied any fever, limp or problems walking. She denied any problems breathing or swallowing. She had been playing outside the day before. The past medical history was positive for large local reactions to insect bites. The family history was negative for kidney problems, thromboses, or swelling of body parts. There was a family history of seasonal allergies but no specific asthma, food allergies or angioedema. The review of systems was negative.

The pertinent physical exam showed normal vital signs including temperature and growth parameters in the 75-95%. HEENT, lung and abdominal examinations were normal. Her extremities showed several bug bites with excoriations on both lower legs that also had some enlargement around the bug bites, but the right side was slightly larger than the left.

The diagnosis of bilateral lower leg swelling secondary to enlarged local reactions to bug bites was made. The family was educated about large local reactions and given the proper dosing for diphenhydramine to use for the pruritus. After seeing the patient, the attending discussed the differential diagnosis of edema with the medical student. She noted that if an allergic reaction was being considered, questions about problems such as difficulty swallowing or breathing should be asked, and the oropharynx and lungs inspected and ausculated. “It’s possible that the patient is having angioedema and doesn’t realize it,” said the attending. “I know you can have acute angioedema but isn’t there a genetic form too? How common is the genetic form?” he asked. “There is a genetic form called hereditary angioedema. It’s not very common, and I’d have to look that up,” the attending replied.

Angioedema is edema that is non-pitting, self-limited occurring in non-dependent areas usually in an asymmetric distribution usually on the lips, face, hands, feet, genitals and also in the bowel. It usually develops over minutes to hours (often 1-2 hours) with resolution usually within 24-48 hours. Angioedema often occurs with urticaria but 20% of patients may have isolated angioedema. Acute allergic angioedema is often caused by drugs (including antibiotics and non-steroidal anti-inflammatory drugs), foods, infections, insects, various organic substances (i.e. latex, preservatives, formaldehyde, etc.), and other allergens such as animal danders, dust mites, pollens and molds. Common triggers in children are infections including the viruses Coxsackie A, Epstein-Barr virus, Hepatitis B, and Herpes simplex. Bacterial causes include otitis media, pharyngitis, sinusitis and urinary tract infections. Parasitic infections causing angioedema include filariasis, strongyloides and toxocara. Physical factors can cause mast cell release causing angioedema. These include exposure to cold, heat, pressure, the sun and vibration.

Hereditary angioedema (HAE) is a rare genetic disorder. HAE is caused by decreased amount of C1 inhibitor (Type 1, 85% of cases), normal amount of C1 inhibitor but decreased functionality (Type II, 15%) and normal C1 inhibitor and functionality but with angioedema. Type I and Type II HAE are autosomal dominant diseases but up to 25% may have a de novo mutation. There is near complete penetrance. Most patients are heterozygous. C1 inhibitor is a serine protease inhibitor. As the C1 inhibitor is not able to regulate various enzymatic processes, bradykinin is released which causes increased vascular permeability and vasodilation.

Type I and Type II HAE clinical phenotypes are the same. Patients may have symptoms from childhood but have worsening around puberty and adolescence. Some are not diagnosed usually until adolescence to young adulthood. The average diagnosis delay is 11-20 years because of non-recognition of symptoms, misdiagnosis and patients lacking a family history. Patients have subcutaneous and submucosal edema that is non-pruritic and not associated with urticaria. Patients with HAE do not respond to antihistamines, epinephrine and corticosteroids. Initial presentation can be a fatal laryngeal attack. Swelling progresses over hours (peak around 24 hours) and subsides over days (2-5 days) Subcutaneous and submucosal swelling especially of peripheral extremities and the abdomen is the most common but orolaryngeal or genital edema also occurs. Single or multiples areas can be affected and affected sites may be non-contiguous. Cutaneous swollen areas are noticeable, asymmetric, and non-pitting – which can cause disfigurement and functional problems during the attacks. Abdominal attacks may cause pain (generalized or colicky), nausea, and emesis and may mimic surgical causes of abdominal pain. Facial and laryngeal edema are less common but can occur and patients are at an increased risk of asphyxiation. As noted initial presentation can be a fatal laryngeal attack. The genitalia can also be involved. A prodrome may or may not occur including erythema marginatum (i.e. non-pruritic, serpigenous rash), local discomfort, tingling, weakness, and fatigue.

Severity and frequency of attacks vary within and among individuals even in the same family. Without treatment, average frequency is 7-14 days but can occur every 3 days to never again. Each attack may be similar or different. The exact initiating mechanism(s) is unknown but stress (including mental stress, fatigue), trauma, infection, and increased estrogen states can be triggers. Exogenous estrogen as a form of family planning is not recommended and other forms should be used instead. Dental manipulation may cause a laryngeal or oral attack.

Diagnosis is by protein level and functional assay. It is usually made after 1 year of age because C1 inhibitor levels are low before then. Gene sequencing is also available. As this is autosomal dominant, first-degree relatives should be screened along with appropriate second-degree relatives. Treatments are available and are highly effective. Berinert® is an on demand treatment for children and adolescent that was approved in July 2016. It works as a human C1 esterase inhibitor. Other on demand treatment for adolescents and adults include a kallikrein inhibitor, bradykinin receptor antagonist and recombinant human C1 inhibitor. Short- and long-term prophylactic treatments are also available. In addition to drug treatment, a comprehensive management plan needs to be developed and re-visited frequently. This includes specialty care from an HAE specialist, understanding signs and symptoms of the disease, when to treat and potentially re-treat, where to treat (i.e. home or medical facility), and how to access medical facilities and specialty care among other elements of the plan.

HAE with normal C1 inhibitor was identified in 2000. It appears to be less common and more complex. Testing for some mutations is positive (F12). Patients still have a family history and clinical history of angioedema which indicates this disease.

Learning Point
In the United States the exact prevalence is unknown but estimated at a range of 1:10,000 to 1:100,000 persons and appears to affect all ethnic groups equally.

Questions for Further Discussion
1. How is acute angioedema treated?
2. What are physical urticarias and how are they treated?
3. How is lymphedema different than angioedema?

Related Cases

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at, the National Guideline Clearinghouse and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for these topics: Vascular Diseases and Insect Bites and Stings.

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

To view videos related to this topic check YouTube Videos.

Kuhlen JL, Banerji A. Hereditary angioedema: special consideration in children, women of childbearing age, and the elderly. Allergy Asthma Proc. 2015 Nov-Dec;36(6):425-32.

Zuraw BL, Christiansen SC. How we manage persons with hereditary angioedema. Br J Haematol. 2016 Jun;173(6):831-43.

Frank MM, Zuraw B, Banerji A, Bernstein JA, Craig T, Busse P, Christiansen S, Davis-Lorton M, Li HH, Lumry WR, Riedl M; US Hereditary Angioedema Association Medical Advisory Board.
Management of Children With Hereditary Angioedema Due to C1 Inhibitor Deficiency. Pediatrics. 2016 Nov;138(5).

Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa