Question
Hereditary angioneurotic edema
Answer
Hereditary angioneurotic oedema (HANE) is an autosomal dominant disorder caused by a deficiency (Type I, ~85% of cases) or dysfunction (Type II) of C1 esterase inhibitor (C1-INH), a key regulatory protein of the complement system (classical pathway) that also regulates the kinin and coagulation/fibrinolytic cascades.
Pathogenesis: C1-INH normally inhibits activated C1r/C1s (preventing uncontrolled classical complement activation) and also inhibits kallikrein and activated Factor XII, thereby restraining bradykinin generation. Deficiency/dysfunction of C1-INH leads to uncontrolled activation of these pathways, and the resulting excess bradykinin production is the principal mediator of the characteristic swelling — causing markedly increased vascular permeability.
Clinical features: recurrent, episodic, non-pitting, non-pruritic oedema (unlike typical allergic angioedema, it is not urticarial/itchy, since it is not histamine/mast-cell mediated) affecting the skin (face, extremities, genitalia), gastrointestinal tract (causing colicky abdominal pain, sometimes mimicking an acute abdomen), and — most dangerously — the larynx, where laryngeal oedema can cause life-threatening airway obstruction. Attacks are often triggered by minor trauma, stress, dental procedures, or surgery.
Laboratory diagnosis: low C4 level (a sensitive screening test, since C4 is continuously consumed even between attacks due to unchecked C1 activation), low/dysfunctional C1-INH level or function, and (during acute attacks) low C2.
Treatment: acute attacks — C1-INH concentrate, or bradykinin-receptor antagonist (icatibant) / kallikrein inhibitor (ecallantide); notably, standard treatments for allergic angioedema (antihistamines, corticosteroids, adrenaline) are ineffective since the mechanism is not histamine-mediated. Long-term prophylaxis — attenuated androgens (danazol, which increase hepatic C1-INH synthesis) or regular C1-INH replacement.