Hereditary Angioedema: Symptoms, Types, Causes and Treatment

Hereditary Angioedema (HAE) is a rare but potentially life-threatening genetic condition that causes recurrent swelling episodes in various parts of the body. These unpredictable attacks can disrupt daily life and, in severe cases, threaten a person’s airway and survival. Despite its rarity, understanding HAE is crucial for patients, families, and healthcare providers to ensure timely diagnosis and effective management. In this article, we’ll explore the hallmark symptoms, the distinct types, underlying causes, and the latest advances in treatment for hereditary angioedema.

Symptoms of Hereditary Angioedema

Recognizing the symptoms of hereditary angioedema is vital for early diagnosis and management. HAE attacks often develop without warning and can affect different organs. While swelling is the most obvious sign, the syndrome’s manifestations can be complex and vary from person to person—even within the same family.

Symptom	Description	Frequency/Severity	Source(s)
Skin swelling	Non-pitting, non-itchy edema of extremities, face, genitals, trunk	Most common (97%)	1, 5, 3
Abdominal pain	Crampy pain, vomiting, diarrhea, sometimes severe	Very common (50–97%)	2, 5, 3
Airway edema	Swelling of larynx, tongue, soft palate; can cause obstruction	Rare but life-threatening (0.9–25%)	1, 5, 3
Rash	Erythema marginatum, a non-itchy rash	~33% of patients	5, 1

Table 1: Key Symptoms of Hereditary Angioedema

Skin Swellings

The most frequent symptom of HAE is swelling of the skin. Attacks typically affect the hands, feet, face, genitals, and trunk. These episodes are not accompanied by itching or hives, which distinguishes HAE from allergic reactions. Swelling develops over several hours and resolves within days, often leaving the skin tender or bruised 1, 5.

Abdominal Attacks

Swelling in the intestinal tract can cause severe and disabling abdominal pain. Attacks often feature crampy pain, vomiting (up to 73% of episodes), and diarrhea (41%). These symptoms may mimic an "acute abdomen," sometimes leading to unnecessary surgery before HAE is recognized. In some patients, abdominal symptoms precede skin swellings or may be the only manifestation for years 2, 3, 5.

• Attacks can be classified as mild, moderate, or severe, with severe attacks being most common.
• Abdominal attacks may be associated with complications like circulatory collapse or loss of consciousness in a minority of cases 2.

Airway (Laryngeal) Involvement

Swelling of the upper airway—including the larynx, tongue, and soft palate—is the most dangerous symptom. Although less frequent (0.9% of all attacks in classic HAE; higher in some subtypes), it can cause life-threatening airway obstruction and suffocation if not treated promptly. Rapid recognition and immediate treatment are critical 1, 5.

Rash

About one-third of people experience a non-itchy rash called erythema marginatum during attacks. This may be mistaken for urticaria, but it is not accompanied by wheals or pruritus 5, 1. Notably, this rash is absent in some HAE subtypes 3.

Types of Hereditary Angioedema

HAE is not a single disorder but a group of related conditions, each with distinct genetic causes and clinical features. Accurate classification is essential for diagnosis and management.

Type	Key Features	Common Population	Source(s)
Type I	Low C1 inhibitor levels & function	Most common, all ages	6, 11, 12, 9, 13
Type II	Normal/high C1 inhibitor levels, low function	Less common	6, 11, 12, 9, 13
HAE-nC1-INH	Normal C1 inhibitor, mutations in FXII, ANGPT1, PLG, or unknown	Mainly women, adult onset	3, 4, 7, 10, 8
HAE-FXII	Factor XII gene mutation	Women, estrogen-sensitive	4, 8

Table 2: Main Types of Hereditary Angioedema

HAE with C1 Inhibitor Deficiency (Type I and Type II)

• Type I HAE: The classic and most common form, caused by low levels of C1 inhibitor (C1-INH) protein and reduced function. It accounts for about 85–90% of cases 6, 9.
• Type II HAE: Characterized by normal or increased C1-INH protein levels but reduced functional activity. It is less common (about 10–15% of cases) 6, 9.
• Both types present with similar symptoms but differ in laboratory findings and exact genetic mutations 11, 12.

HAE with Normal C1 Inhibitor (nC1-INH)

Also known as HAE type III or HAE-nC1-INH, this group includes patients with normal C1-INH levels and function but recurring angioedema. Several genetic forms are recognized:

• HAE-FXII: Linked to mutations in the F12 gene (coagulation factor XII), seen predominantly in women and often triggered or worsened by estrogens (e.g., oral contraceptives, pregnancy) 3, 4, 8.
• HAE-PLG, HAE-ANGPT1: Mutations in the plasminogen (PLG) or angiopoietin-1 (ANGPT1) genes have been identified in some families 7, 10.
• Unknown genetic defects: Some cases remain genetically unexplained 7.

Clinical Distinctions

• HAE with C1-INH deficiency usually starts in childhood or adolescence.
• HAE-nC1-INH often begins in adulthood, may have more facial and tongue involvement, and is more common in women 3, 4.
• Estrogen sensitivity is a key feature in some HAE-nC1-INH forms 4, 8.

Causes of Hereditary Angioedema

At its core, HAE is a genetic disorder. However, the disease's underlying mechanisms differ based on its type. Understanding these causes sheds light on why attacks occur and how they can be prevented or treated.

Cause	Explanation	Impact	Source(s)
SERPING1 mutations	Defective or deficient C1 inhibitor protein	Uncontrolled bradykinin, swelling	11, 12, 13
F12 mutations	Factor XII gene mutations	Increased bradykinin, estrogen role	4, 8
ANGPT1/PLG mutations	Angiopoietin-1 or plasminogen gene defects	Vascular permeability, rare forms	7, 10
Unknown genetics	No mutation yet identified	HAE persists, research ongoing	7

Table 3: Genetic and Molecular Causes of Hereditary Angioedema

C1 Inhibitor Deficiency or Dysfunction

Most cases of HAE are caused by mutations in the SERPING1 gene, which codes for the C1 inhibitor protein. This protein regulates several systems involved in inflammation, including:

• The complement system
• The contact (kallikrein-kinin) pathway
• Coagulation and fibrinolysis pathways

When C1-INH is deficient (Type I) or dysfunctional (Type II), it cannot effectively control the production of bradykinin, a peptide that increases blood vessel permeability. Unchecked bradykinin levels result in recurrent swelling 11, 12, 13.

Other Genetic Defects (HAE-nC1-INH)

• Factor XII (F12) mutations: These mutations (especially at the Thr309 position) cause increased activation of factor XII, leading to excessive bradykinin formation. This form is often triggered by estrogens 4, 8.
• ANGPT1 and PLG mutations: Recently identified rare genetic causes. ANGPT1 mutations alter vascular integrity, while PLG mutations are linked to abnormal fibrinolysis 7, 10.
• Unknown genes: Some families with HAE have no identifiable mutation, highlighting the complexity and ongoing research in this field 7.

Pathophysiology: The Role of Bradykinin

In all forms of HAE, the final common pathway is the overproduction of bradykinin. Unlike histamine-mediated allergic angioedema, bradykinin-induced swelling is not associated with itching or urticaria and does not respond to antihistamines or corticosteroids 11, 12.

• Bradykinin acts on B2 receptors in blood vessels, making them leaky and causing swelling 11.
• Attacks occur when C1-INH levels fall below a critical threshold or when bradykinin is overproduced due to other mutations 12.

Treatment of Hereditary Angioedema

While HAE attacks can be sudden and severe, effective treatments are available for both acute episodes and long-term prevention. Advances in understanding the disease have led to the development of targeted therapies that can dramatically improve quality of life.

Treatment	Purpose	Notes/Effectiveness	Source(s)
C1-INH replacement	Acute and prophylactic	IV or subcutaneous, effective	14, 15, 17, 18, 16
Kallikrein inhibitors	Acute/Prophylactic	Block bradykinin production	12, 18, 16
Bradykinin receptor antagonists	Acute	Block bradykinin effects	12, 18, 16
Antifibrinolytics	Prophylaxis (esp. children)	Moderate efficacy, safe	15, 16
Attenuated androgens	Prophylaxis	Used at lowest effective dose	15, 16
Avoid triggers	Prevention	Stress, trauma, estrogens	4, 15, 16

Table 4: Overview of HAE Treatment Options

C1 Inhibitor Replacement Therapy

• Acute attacks: Intravenous or subcutaneous C1-INH concentrates (plasma-derived or recombinant) are the first-line treatment for acute swelling in patients with C1-INH-HAE. They provide rapid relief, often within 2 hours 14, 17, 18.
• Prophylaxis: Regular C1-INH infusions can prevent attacks in patients with frequent or severe episodes. Subcutaneous formulations are improving convenience and adherence 14, 17, 18.

Kallikrein Inhibitors and Bradykinin Receptor Antagonists

• Kallikrein inhibitors: These drugs (e.g., ecallantide, lanadelumab) block the enzyme responsible for generating bradykinin, interrupting the attack at its source 12, 18, 16.
• Bradykinin receptor antagonists: Icatibant is a synthetic peptide that blocks the bradykinin B2 receptor, quickly reducing swelling during acute attacks 12, 18, 16.

Antifibrinolytics

• Drugs such as tranexamic acid and epsilon-aminocaproic acid are used for long-term prevention, especially in children, due to their relatively mild side effect profile. They are less effective than C1-INH or androgens 15, 16.

Attenuated Androgens

• Medications like danazol or stanozolol increase hepatic production of C1-INH. Used at the lowest effective dose, they are suitable for some adults but have potential long-term side effects (weight gain, virilization, liver toxicity) 15, 16.

Trigger Avoidance and Lifestyle Measures

• Identifying and avoiding triggers—such as minor trauma, emotional stress, infections, and estrogen-containing medications—is essential, particularly in HAE-nC1-INH forms where estrogen sensitivity is pronounced 4, 15, 16.

Special Considerations

• Children and pregnant women: Treatment choices must be tailored. Antifibrinolytics and C1-INH replacement are preferred due to safety. Androgens are generally avoided in these groups 15, 16.
• Patient education and support: Training in self-administration of medications and providing emergency action plans are key components of comprehensive care 16, 15.

Conclusion

Hereditary angioedema is a complex, rare disorder that demands awareness and individualized care. Recent advances in genetics and targeted therapies have transformed the outlook for patients, but early recognition and expert management remain crucial.

Key takeaways from this article:

• Symptoms: Recurrent, non-itchy swellings of the skin, abdomen, and airway are the hallmarks. Abdominal and airway attacks can be severe or life-threatening.
• Types: HAE includes classic forms with C1 inhibitor deficiency (Type I/II) and newer forms with normal C1 inhibitor but other genetic mutations.
• Causes: All types involve genetic mutations leading to excessive bradykinin production and vascular leakage.
• Treatment: Modern therapies target the underlying mechanisms and include C1-INH replacement, kallikrein inhibitors, and bradykinin receptor antagonists. Preventive strategies and patient education are essential.

With continued research and improved therapies, the future for people living with HAE is brighter than ever.