Skin Signs of Hereditary Angioedema

Hereditary angioedema (HAE) is a rare, genetic, autosomal dominant disorder characterized by recurrent episodes of severe swelling in various parts of the body, including the skin, gastrointestinal tract, and upper airway.¹ While the condition is not commonly encountered in dermatology clinics, it is crucial for dermatologists to recognize its skin-related signs and symptoms to facilitate early diagnosis and management.

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Pathophysiology of HAE

HAE is typically caused by a deficiency or dysfunction of the C1 esterase inhibitor (C1-INH), leading to uncontrolled activation of the complement and contact system pathways. This results in the overproduction of bradykinin, a potent vasodilator that increases vascular permeability and leads to localized swelling.

There are 3 main types of HAE:²

• Type I HAE: Characterized by low levels of functional C1-INH, accounting for 85% of cases.
• Type II HAE: Normal or elevated levels of dysfunctional C1-INH.
• Type III HAE: A rare subtype, often associated with mutations in the F12 gene and normal C1-INH levels, predominantly affecting women.

The skin is a common site for HAE attacks, and dermatology clinicians play a pivotal role in recognizing these manifestations, which can mimic other dermatologic conditions.

Cutaneous Manifestations of HAE

Non-Pitting Edema

The hallmark skin manifestation of HAE is non-pitting, non-pruritic edema, which can occur on the face, extremities, genitals, and trunk. The swelling typically develops over several hours and may persist for 2-5 days before resolving spontaneously.¹ It is often asymmetric and can cause significant disfigurement and discomfort.

Facial Edema

Facial swelling, particularly involving the lips, eyelids, and cheeks, is a common presentation. Dermatologists should differentiate HAE-induced facial edema from other causes such as allergic reactions, infections, or autoimmune diseases.³ Swelling of the tongue or larynx, though rare, requires immediate medical attention due to the risk of airway obstruction.

Urticaria-Like Rash

Unlike allergic angioedema, HAE does not usually present with urticaria or hives. However, some patients may report erythematous skin changes that resemble a non-itchy urticarial rash. This can lead to misdiagnosis as chronic idiopathic urticaria or other hypersensitivity reactions.⁴

Peripheral Edema

Swelling of the hands and feet can be particularly disabling, affecting patients' ability to perform daily tasks. This presentation may be mistaken for conditions such as lymphangitis, cellulitis, or chronic venous insufficiency.⁵ A thorough patient history and assessment of systemic symptoms are essential for accurate diagnosis.

Subcutaneous Edema

Subcutaneous edema may occur without visible swelling, particularly in the abdominal region. Patients may present with localized tenderness or pain, mimicking conditions like panniculitis or even deep vein thrombosis.⁶ Dermatologists should consider HAE in the differential diagnosis when encountering unexplained subcutaneous induration or pain.

Differentiating HAE from Other Dermatologic Conditions

The clinical presentation of HAE can overlap with various dermatologic and systemic conditions, making diagnosis challenging. Key differentiating factors include:

• Absence of Pruritus: Unlike allergic or histamine-mediated angioedema, HAE-associated edema is typically not itchy.
• Recurrent Episodes: A history of recurrent, episodic swelling without identifiable triggers should raise suspicion for HAE.⁷
• Lack of Response to Antihistamines or Corticosteroids: Standard treatments for allergic angioedema are generally ineffective in HAE, highlighting the need for targeted therapies such as C1-INH replacement or bradykinin receptor antagonists.⁸
• Family History: A positive family history of similar symptoms or a known diagnosis of HAE strongly suggests the condition.⁹

Diagnostic Workup

The diagnosis of HAE is confirmed by laboratory testing, including measurement of C4 and C1-INH levels and function. Dermatologists should collaborate with allergists or immunologists when HAE is suspected. In some cases, genetic testing may be warranted, particularly for patients with a family history of HAE or those with normal C1-INH levels but typical clinical features.¹⁰

Management of HAE

While dermatologists are unlikely to manage HAE independently, they can play a crucial role in patient education and referral. Acute attacks are treated with agents such as C1-INH concentrates, ecallantide, or icatibant, which target the underlying bradykinin-mediated pathways. Long-term prophylaxis may involve androgens, antifibrinolytics, or regular C1-INH infusions.¹¹

References

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3. Swanson TJ, Patel BC. Acquired angioedema. StatPearls; National Library of Medicine. Updated August 14, 2023. Accessed September 20, 2024. https://www.ncbi.nlm.nih.gov/books/NBK430889/
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6. Ellenson S. Subcutaneous edema: symptoms, causes and treatment. Tactile Medical. May 22, 2023. Accessed September 20, 2024. https://tactilemedical.com/resource-hub/cellulitis-and-edema/subcutaneous-edema-symptoms-causes-and-treatment/
7. Sardana N, Craig TJ. Recent advances in management and treatment of hereditary angioedema. Pediatrics. 2011;128(6):1173-1180. doi:10.1542/peds.2011-0546
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9. Bowen T, Cicardi M, Farkas H, et al. 2010 International consensus algorithm for the diagnosis, therapy and management of hereditary angioedema. Allergy Asthma Clin Immunol. 2010;6(1):24. July 28, 2010. doi:10.1186/1710-1492-6-24
10. Nzeako UC, Frigas E, Tremaine WJ. Hereditary angioedema: a broad review for clinicians. Arch Intern Med. 2001;161(20):2417-2429. doi:10.1001/archinte.161.20.2417
11. Maurer M, Magerl M, Betschel S, et al. The international WAO/EAACI guideline for the management of hereditary angioedema-The 2021 revision and update. Allergy. 2022;77(7):1961-1990. doi:10.1111/all.15214