Clinical features of HAE are largely indistinguishable across all types, but type 1 is characterized by a prodromal period in which a nonpruritic, nonpitting rash appears and is known as erythema marginatum  . Soon after, the rapid onset of edema of the extremities, face, and/or the upper airway (angioedema) occurs and is considered to be the hallmark of HAE  . Abdominal pain and cramping that may be quite severe develop concomitantly and diffuse tenderness is noted during physical examination as a result of profound gastrointestinal angioedema . These symptoms are recurrent and occur in an unpredictable and abrupt fashion, but in the majority of cases, attacks spontaneously resolve within 12-72 hours, although therapy is frequently necessary . It must be noted that urticaria is never a part of the clinical presentation of HAE and its presence universally excludes HAE as an underlying cause of symptoms .
The combination of recurrent angioedema and gastrointestinal attacks, as well as positive family history, should be highly suggestive of HAE, but laboratory tests are necessary to confirm the diagnosis. Very low levels of C4 and C1-INH in serum are definite indicators of type I HAE and their values should be obtained at rest and during attacks, but persistently low C4 serum levels are observed in these patients  .
HAE is not responsive to antihistamines, corticosteroids, or epinephrine, suggesting that other agents have to be used in the acute setting, but in prophylaxis as well. Recombinant or human C1-INH, icatibant (a bradykinin B2-receptor antagonist that is able to reverse profound vascular permeability and reduce extravasation of fluid) or ecallantide (human plasma kallikrein inhibitor) are first-line therapy for acute attacks , while danazol, stanozolol, and oxandrolone are androgens used for both short-term and long-term prophylaxis . Numerous side-effects have been reported, including reduced efficacy when used for a prolonged period of time, affected growth and development in children, weight gain, menstrual changes, depression, fatigue, hypertension and many other , but the benefit of prophylactic treatment substantially outweighs the risks for their appearance . Androgens are contraindicated in pregnant women, however, and antifibrinolytics (tranexamic or aminocaproic acid) are used as alternatives in that particular setting . HAE, regardless of the type, is unpredictable and a sudden onset of attacks can be provoked by daily-life situations (eg. stress). For this reason, patients are instructed and trained for self-administration of therapy, the primary reason being the reduction of complications that can occur as a result of treatment delay .
The diagnosis is often made late, as isolated reports have shown that recognition of HAE may take between 8-22 years after the first attack . Having in mind the fact that life-threatening laryngeal edema and asphyxiation has been reported in these patients, a strong clinical suspicion must exist when patients present with symptoms suggestive of HAE.
Mutations involving genes responsible for C1-INH production is the cause of HAE type I . Specifically, serine (or cysteine) peptidase inhibitor (SERPIN) genes located on chromosome 11 code for C1-INH and more than 450 missense, nonsense, deletions, or insertion mutations have been described in the literature .
C1-INH is an enzyme responsible for suppression of the C1 complement system and in its absence, this pathway activates factors XIIa, XIIf, XIa and kallikrein, the precursor of bradykinin, which is considered to be the main mediator of the symptoms in HAE .
Prevention of acute attacks is the most important part of long-term management, primarily because adequate therapy may substantially reduce the frequency of symptom occurrence. Prophylaxis prior to stressful situations or procedures that may trigger an attack (such as invasive medical or dental procedures, but also emotional stress induced by daily-life situations) is pivotal for preventing angioedema and other associated symptoms.
Hereditary angioedema (HAE) is a rare genetic disease that affects approximately 1 in 50,000 individuals and is classified into three types . Type 1 accounts for the majority of HAE patients (85%) and is distinguished by the deficiency of C1 esterase inhibitor (C1-INH) due to genetic mutations of C1-INH producing gene located on chromosome 11 . HAE type 1 is transmitted by an autosomal dominant pattern of inheritance , and numerous risk factors have been proposed, including stress (eg. weddings, Christmas, etc.), trauma, infection and menstruation . The clinical presentation includes the appearance of erythema marginatum (non-pitting and non-pruritic rash), recurrent attacks of angioedema that may involve any part of the body and severe abdominal pain and cramping . The diagnosis is made by determining very low levels of C4 and C1-INH in serum . Treatment with androgens, antifibrinolytics, bradykinin receptor antagonists or C1-INH concentrate has shown good results and their prophylactic use (both short-term and long-term) is one of the key measures in preventing attacks .
Hereditary angioedema (HAE) is a familial disorder in which genetic mutations cause a rash, generalized swelling of the face and the extremities and profound abdominal pain accompanied by cramping. There are three distinct types and type 1 is distinguished by the deficiency of C1-esterase inhibitor (C1-INH), an enzyme responsible for regulation of numerous functions in the immune and coagulation system. It is by far the most common subtype, but the cause of mutations responsible for its development remains unknown. Various precipitating events have been established, including emotional stress, trauma, pregnancy and use of estrogen and angiotensin-converting enzyme drugs. The clinical presentation involves a sudden onset of marked swelling of the subcutaneous tissue preceded by a rash that does not itch and remains at the level of the skin (erythema marginatum), while profound abdominal pain, cramping, and tenderness on palpation are constitutive symptoms as well. In rare cases, swelling of the larynx may cause life-threatening asphyxiation, which is why early diagnosis through laboratory detection of low C1-INH in serum and prompt use of recombinant C1-INH and several other drugs are vital. Prevention of attack can be achieved through the use of androgen drugs - danazol, stanozolol or oxandrolone, prior to potentially stressful events.