Hereditary angioedema (HAE) is an autosomal dominant genetic disease characterized by recurrent attacks of localized subcutaneous and mucosal swelling.1,2
Angioedema attacks most commonly affect the face, extremities, abdomen and urogenital area and are often painful and debilitating.1,2
Less commonly, they can occur in the laryngeal area causing airway obstruction and potentially becoming life-threatening.2
HAE is a rare condition with an estimated prevalence of 1 in 50,000, though exact prevalence may vary due to misdiagnosis and geographical region.1,2,3 Symptoms are unpredictable and can manifest at any age, but typically appear during childhood (5 to 11 years), worsen during puberty (particularly among females), and persist throughout life.2,4,5,6,7
HAE is an autosomal dominant disorder resulting from a deficiency of C1 inhibitor (C1-INH), which is a naturally occurring protein that inhibits plasma kallikrein, a key mediator of inflammation.1,8,9,10,11 C1-INH deficiency results in uncontrolled kallikrein activity, leading to increased generation of the vasoactive peptide bradykinin and associated symptoms of pain and swelling.8,9,10,11,12
The disease is marked by its genetic variability – more than 510 different mutations of the C1-INH gene (SERPING1) have been identified.13 However, it is generally classified into 3 types according to the underlying cause and levels of C1-INH:
Type I (~85% of cases) is associated with low plasma levels of the C1-INH protein2,14,15
Type II (~15% of cases) is associated with a dysfunctional C1-INH protein despite normal plasma levels2,14,15
HAE with normal C1-inhibitor levels (formerly type III, estrogen-dependent) is very rare and is associated with normal C1-INH levels and function but has been linked to a number of other mutations2,14,15
Due to its rarity and symptom overlap with other conditions, HAE is frequently under-recognized leading to delayed diagnosis.4,7,16,17 Historically, the rate of mortality has been higher in undiagnosed HAE patients due to lack of awareness of potential fatal laryngeal attacks and inadequate treatment.18 The two most common forms of HAE (types I/II) should be suspected when a patient presents with a history of recurrent angioedema attacks and further substantiated by:19
Positive family history (may be absent in 25% of cases)
Onset of symptoms in childhood/adolescence
Recurrent and painful abdominal symptoms
Occurrence of upper airway edema
Failure to respond to antihistamines, glucocorticoids, or epinephrine
Presence of prodromal signs/symptoms before swellings
Absence of urticaria (wheals/hives)
To confirm diagnosis, patients should be assessed for blood levels of C1-INH protein, C4 and C1-INH function.19
The condition is associated with a substantial and multifaceted burden of illness affecting various aspects of a patient's quality of life (e.g., emotional state, career and education progression, and the decision to have children).2,7,20,21,22,23,24 Types I/II are indistinguishable in their clinical presentation, having identical symptoms characterized by edema attacks that can vary in location, frequency, duration, and severity.1,25,26 Swelling and other symptoms gradually worsen over 12 to 36 hours, intensifying in a relentless manner, sometimes spreading to other sites, and then resolving over 2 to 5 days.7,14,27
A variety of possible triggers for attacks have been proposed, most commonly mechanical trauma, mental stress, and airway infection.2,4,28 Nevertheless, many attacks occur without an obvious trigger, particularly in children, highlighting the need for individualized treatment plans.2,4,19
Lumry WR.Am J Manag Care 2013;19(Suppl 7):S111-S118.
Lumry WR. Am J Manag Care 2013;19(Suppl 7):S103-S110.
Aygören-Pürsün E, Mageri M, Maetzel A, et al. Orphanet J Rare Dis. 2018;13(1):73.
Farkas H, Martinez-Saguer I, Bork K, et al. Allergy 2017;72(2):300-313.
Christiansen SC, Davis DK, Castaldo AJ, et al. Clin Pediatr. 2016;55(10):935-942.
Schöffl C, Wiednig M, Koch L, et al. J Dtsch Dermatol Ges. 2019;17(4):416-423.
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