What is hereditary angioedema in a 35-year-old female with recurrent bilateral periorbital edema?

What is Hereditary Angioedema?

Hereditary angioedema (HAE) is a rare genetic disorder characterized by recurrent episodes of bradykinin-mediated swelling affecting the deep tissues of the skin, respiratory tract, and gastrointestinal tract, which can be life-threatening, particularly when involving the larynx. 1, 2

Core Pathophysiology

HAE results from dysregulation of the kallikrein-kinin system, leading to excessive bradykinin production. 2 Bradykinin is a vasodilator that increases vascular permeability, causing fluid extravasation into tissues and resulting in the characteristic localized swelling, inflammation, and pain. 2, 3

Classification of HAE

HAE with C1-Inhibitor Deficiency (HAE-C1INH)

• Type I HAE-C1INH: Decreased amounts of C1-INH protein (most common form) 4, 5
• Type II HAE-C1INH: Dysfunctional C1-INH protein with normal or elevated levels 4, 5
• Both types result from mutations in the SERPING1 gene on chromosome 11q, inherited as autosomal dominant with high penetrance 2, 6
• Prevalence ranges from 1 in 64,000 to 1 in 93,000 across various populations 1

HAE with Normal C1-Inhibitor (HAE-nC1INH)

This subtype has normal C1-INH levels and function but similar clinical presentation. 1, 5 Known genetic variants include:

• HAE-FXII: Most common subtype with incomplete penetrance, predominantly affecting females (average onset age 20 years, range 1-65 years); estimated prevalence 1 in 150,000 1
• HAE-PLG: Tongue swellings are frequent; death from asphyxiation has been reported 1
• HAE-ANGPT1: Rare, affects face, lips, mouth, and abdomen 1
• HAE-KNG1, HAE-MYOF, HAE-HS3ST6, HAE-CPN, HAE-DAB2IP: Extremely rare variants described in single or few families 1
• HAE-UNK (unknown cause): No identified genetic mutation despite typical HAE phenotype 1

Clinical Presentation in Your 35-Year-Old Female Patient

Key Features Relevant to Periorbital Edema

Females are disproportionately affected by HAE-nC1INH subtypes, with facial swelling being a prominent feature. 1 Specifically:

• HAE-nC1INH typically presents in early adulthood with facial and tongue involvement 1
• HAE-MYOF begins in the second decade, mainly involving face, lips, and oral mucosa 1
• HAE-HS3OST6 affects only females with onset between ages 12-20 years, involving face, extremities, abdomen, larynx, and tongue 1
• HAE-UNK most often involves the face and tongue 1

Critical Triggers to Assess

• Estrogen exposure is a very important trigger in the majority of women with HAE-FXII and worsens symptoms in HAE-HS3OST6 and HAE-DAB2IP 1
• Women frequently present during pregnancy or when taking estrogen-containing contraceptives 1
• Other triggers include stress, physical trauma, infection, menstruation, and warm weather 1

Attack Characteristics

• Swelling typically worsens over the first 24 hours before gradually subsiding over 48-72 hours 7
• Attacks may be preceded by prodrome and/or accompanied by erythema marginatum 7
• Episodes are non-pruritic, non-pitting, and occur without hives (urticaria) 1, 7
• Attack frequency is highly variable, ranging from 1.2 to 36 per year in some subtypes 1

Critical Mortality Risk

Laryngeal edema poses the greatest mortality risk, with historical mortality rates of approximately 30% before modern treatments became available. 1, 8 More than half of HAE patients experience at least one episode of laryngeal angioedema during their lifetime. 7

Diagnostic Pitfalls in HAE-nC1INH

Why This is Challenging to Diagnose

• Family history may be absent or unreliable due to recall bias, estrangement, adoption, de novo mutations, or variable penetrance resulting in asymptomatic carriers 1
• Laboratory testing shows normal C1-INH levels, normal C1-INH function, and normal C4 levels, unlike HAE-C1INH 1, 5
• Clinical symptoms show significant inter- and intra-individual variability even within families with the same genetic mutation 1
• The condition can be easily confused with mast cell-mediated angioedema or other forms of recurrent angioedema 1, 5

Key Distinguishing Features from Allergic Angioedema

Standard angioedema treatments (antihistamines, corticosteroids, epinephrine) are completely ineffective for HAE because the mechanism is bradykinin-mediated, not histamine-mediated. 9, 8, 10 This lack of response to conventional therapy is a critical diagnostic clue, though angioedema may resolve spontaneously regardless of treatment. 1

Essential Next Steps for Your Patient

Given recurrent bilateral periorbital edema in a 35-year-old female:

1. Obtain detailed medication history immediately, particularly ACE inhibitors, ARBs, NSAIDs, DPP-4 inhibitors, neprilysin inhibitors, and tissue plasminogen activators 9
2. Document family history of recurrent swelling episodes, though absence does not exclude HAE 1
3. Assess estrogen exposure including oral contraceptives, hormone replacement therapy, or pregnancy 1
4. Confirm absence of urticaria (hives) during swelling episodes 1, 7
5. Measure C4, C1-INH antigen, and C1-INH function to exclude HAE-C1INH 1
6. If above tests are normal and clinical suspicion remains high, consider targeted gene sequencing for known HAE-nC1INH mutations 1