Hereditary angioedema

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Hereditary angioedema is a disorder characterized by recurrent episodes of severe swelling (angioedema). The parts of the body that are most often affected by swelling are the limbs, face, intestinal tract, and airway. Minor trauma or stress may trigger an attack, but swelling often occurs without a known trigger. Episodes involving the intestinal tract cause severe abdominal pain, nausea, and vomiting. Swelling in the airway can restrict breathing and lead to life-threatening obstruction of the airway. About one-third of people with this condition develop a non-itchy rash called erythema marginatum during an attack.

Symptoms of hereditary angioedema typically begin in childhood and worsen during puberty. On average, untreated individuals have swelling episodes every 1 to 2 weeks, and most episodes last for about 3 to 4 days. The frequency and duration of attacks vary greatly among people with hereditary angioedema, even among people in the same family.

Hereditary angioedema is broadly divided into two types, which are distinguished by levels of a protein called C1 inhibitor (C1-INH) in the blood. These types are known as hereditary angioedema due to C1-INH deficiency and hereditary angioedema with normal C1-INH.

Hereditary angioedema due to C1-INH deficiency is further divided into two types: type I occurs when C1-INH levels are low, and type II occurs when the C1-INH protein is not functioning correctly.

The different types of hereditary angioedema have similar signs and symptoms.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

Variants (also called mutations) in the SERPING1 gene cause hereditary angioedema due to C1-INH deficiency. The SERPING1 gene provides instructions for making the C1-INH protein, which is important for controlling the immune response and inflammation. The C1-INH protein blocks the activity of certain proteins that promote inflammation.

SERPING1 gene variants that cause hereditary angioedema due to C1-INH deficiency type I lead to reduced levels of C1-INH in the blood, while variants that cause type II result in the production of a C1-INH protein that functions abnormally. When the body does not have enough normal C1-INH protein, it ends up with excessive amounts of a protein fragment (peptide) called bradykinin. Bradykinin promotes inflammation by increasing the amount of fluid that leaks through the walls of blood vessels into body tissues (vascular permeability). The accumulation of fluids in body tissues causes the episodes of swelling seen in individuals with hereditary angioedema due to C1-INH deficiency.

Variants in the F12 gene cause most cases of hereditary angioedema with normal C1-INH. The F12 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.

In people with hereditary angioedema with normal C1-INH, variants in the F12 gene cause cells to produce a factor XII protein that is easier to activate than normal. As a result, a greater-than-normal amount of bradykinin is released. More bradykinin leads to increased inflammation and leaky blood vessel walls, which causes the episodes of swelling seen in people with hereditary angioedema with normal C1-INH.

Variants in a few other genes are responsible for a small number of additional cases of hereditary angioedema with normal C1-INH. The cause of other cases of hereditary angioedema with normal C1-INH remain unknown.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

This condition is inherited in an autosomal dominant pattern, which means one copy of an altered gene in each cell is sufficient to cause the disorder. In some cases, an affected person inherits the variant from one affected parent. Other cases result from a new (de novo) variant in a gene that occur during the formation of reproductive cells (eggs or sperm) in an affected individual's parent or in early embryonic development. These affected individuals have no history of the disorder in their family.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

Hereditary angioedema is estimated to affect 1 in 50,000 people worldwide. Hereditary angioedema due to C1-INH deficiency accounts for the vast majority of cases.

Which doctor should you see?

The suggested department for discussing Hereditary angioedema is Clinical Genetics, with a clinical geneticist as the relevant type of clinician. Paediatrician (children) or physician (adults), with clinical geneticist referral.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• Does the exact genetic or chromosome finding explain the observed features?
• Would a genetic counsellor help the family understand the result?
• Which organ-specific assessments are appropriate for this particular diagnosis?

Treatment discussions and follow-up

Where the source describes treatments, these are an overview of possible care, not a prescription for an individual. Ask which option applies to the confirmed diagnosis, what benefit is expected, what adverse effects to watch for and how progress will be assessed. Availability, approvals and local practice can differ from the country described in the source.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

The collected references do not establish a complete prevention or long-term outlook section for this entry. Missing information should not be interpreted as proof that prevention is impossible or that a particular outcome is inevitable. Ask what is known for the exact subtype, stage and personal circumstances, and which uncertainties remain.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.