**2. Clinical presentation**

Symptoms primarily develop when the serum level of C1‐inh is below 35% but are not usually correlated with serum C1‐inh levels. Symptoms can be expected from birth in a heterozygote individual with a serum level of C1‐inh around 50% [14]. Although signs and symptoms can start at any age, including after 70, they are primarily seen starting around the second decade of life when the level of C1‐inh usually decreases and then continues to occur lifelong [14, 15].

Angioedema episodes can affect any cutaneous or mucosal sites of the body such as the face, larynx, extremities, gastrointestinal tract, and urogenital area [1]. A typical HAE episode worsens within the first 24 h, begins to improve after 48–72 h, and lasts approximately 72–96 h [11, 14]. Apart from visible angioedema, fluid extravasation on the gastrointestinal tractus through the intestinal wall or peritoneum leads to abdominal pain attacks. Nausea and emesis may accompany them [16]. The majority of the patients experience gastrointestinal angio‐ edema during their lives and the abdominal attacks accompany 50% of the overall attacks [17]. Due to these abdominal attacks, unnecessary operations like appendectomy and diagnostic laparotomy are sometimes performed [16]. Fever or leucocytosis is not observed during a typi‐ cal attack unless the cause is an infection [18]. Sometimes, fluid extravasation can be so severe that it causes hypotension or ascites [19]. The most severe complication is angioedema in the larynx and/or oropharynx, which can prevent air passage leading to asphyxiation or even death. Fortunately, this seems less frequent [16]. More than 50% of the patients experience laryngeal edema at least once in their lifetime [20].

Although the precipitating factors of attacks are not well determined in all attacks, some episodes of HAE can be triggered by factors such as stress, trauma, infection, angiotensin‐ converting enzyme inhibitors (ACEIs), estrogen‐containing hormones, oropharyngeal surgery, and minor medical procedures like tooth extraction [21–23]. Sometimes, the usage of ACEI or estrogen‐containing drugs can trigger the symptoms in patients with a silent disease [14]. Prodromal symptoms can precede the attacks; the most frequent symptoms are erythema marginatum, which is a nonurticarial erythematous rash and tingling on the angioedema site. Fatigue, malaise, irritability, hyperactivity, mood changes, and nausea are other preceding factors [21, 24].

The severity of HAE is variable and usually unpredictable. While some patients do not expe‐ rience any attacks in their lives, others experience swelling up to twice a week. Similarly, the attacks of some patients can be so severe that treatment in an intensive care unit may be needed while the attacks of other patients can be so mild that treatment is unnecessary [15, 17]. The disease severity and the course of the disease cannot be predicted according to the initial symptoms [9].

Types I and II HAE are very similar in their clinical presentation; however, HAE with nor‐ mal C1‐inh differs from the other two types with respect to some features. In HAE with normal C1‐inh, abdominal attacks are less frequently seen and angioedema on the face, lips, and tongue are the major symptoms. It predominantly affects females, rarely starts under the age of 10, symptoms recur less frequently, and asymptomatic intervals are more com‐ mon [21].
