Hereditary angioedema (HAE) type 3 stems from mutations in Hageman factor XII, unlike types 1 and 2, in which either deficiency or impaired function of C1 esterase inhibitor (C1-INH) is the principal cause of angioedema, profound abdominal pain, and erythema marginatum.
The recurrent, unpredictable, and abrupt onset of edema involving the face, tongue and less commonly the extremities is the hallmark of HAE . In addition, severe abdominal pain as a result of gastrointestinal edema is seen in virtually all patients and may be followed by cramping, vomiting and disturbed peristalsis, mimicking acute abdomen . Although erythema marginatum is considered to be a constitutive feature of HAE types 1 and 2, it is rarely observed in type 3 . The swelling usually subsides within 12-72 hours after its onset, but treatment is frequently necessary .
The presence of similar symptoms in other family members is highly suggestive of HAE regardless of the type, which is why a thorough patient history should be performed, as it may provide vital information. To support the diagnosis, however, serum levels of C1-INH and C4 (a complement cascade protein involved in the pathogenesis of types 1 and 2) must be evaluated to discern between different HAE type . If both parameters are within physiological ranges, a valid suspicion toward HAE type 3 can be made. Ideally, demonstration of factor XII mutations will confirm the diagnosis, but this test is available only at highly specialized centers  .
Treatment approaches are similar across all types and focus on prompt alleviation of acute symptoms and long-term prophylaxis as a mode of prevention  . Bradykinin-receptor antagonists (icatibant) and kallikrein inhibitors (ecallantide) are recommended in the setting of acute attacks, while the use of C1-INH concentrate has also shown beneficial effects in the therapy of HAE type 3 patients through still unexplained mechanisms  . According to isolated reports, resolution of symptoms should occur within 1-2 hours after administration of therapy . Because HAE possesses an unpredictable course, instructions for home-based therapy should be provided to patients and self-treatment should be performed in order to reduce the risk for complications .
Unlike HAE types 1 and 2, in which genetic mutations cause either insufficient production (type 1) or synthesis of a dysfunctional C1-INH (type 2) , type 3 is most likely caused by aberrations in Hageman factor XII, without C1-INH involvement . Genes coding for factor XII are located on chromosome 5, but the mode of inheritance is still a matter of debate, as both autosomal dominant and X-linked modes have been proposed . In a small number of cases, however, the cause remains unknown, and the term HAE with an unknown cause (HAE-U) is sometimes used .
HAE type 3 is very rare in clinical practice and the vast majority of patients are women, the most probable reason being a strong association of estrogen with this type . Moreover, oral contraceptives and use of hormone replacement therapies containing estrogens, but also pregnancy were described as symptom triggers  . Across numerous reports, the mean age when symptoms start is estimated as 26.8 years .
Factor XII considered as the key element in the coagulation cascade. However, the conversion of prekallikrein to kallikrein, which is essential for the production of bradykinin, is the principal mediator of angioedema in HAE of all types  . Presumably, gain-of-function mutations cause increased activity of Factor XII and subsequent acceleration of bradykinin production, ultimately leading to symptom development . Angiotensin-converting enzyme (ACE), aminopeptidase P, estrogen and several other molecules are also involved in the pathogenesis in some form, but their clear roles are not yet confirmed  .
In addition to treatment of acute attacks, their frequency can be significantly reduced through long-term prophylaxis. Danazol, stanozolol, and oxandrolone are very effective prophylactic drugs  , but they should be contraindicated in pregnancy, as they can cross the placenta and potentially harm the fetus . Antifibrinolytics (aminocaproic acid or tranexamic acid) have been suggested as alternatives . Apart from the long-term use of drugs, short-term prophylaxis is also recommended, like prior to surgical or dental procedures that are known as potential triggers, as well as stressful situations and the use of androgens several days priorly or recombinant C1-INH 1-6 hours before the procedure is indicated  .
Hereditary angioedema (HAE), firstly described more than 50 years ago, is a genetic disease that was initially divided into two types based on mutations that influenced the level or the function of C1-esterase inhibitor (C1-INH), but a third type was recently described and seems to develop irrespective of the C1-INH activity . In fact, HAE type 3 results from autosomal dominant mutations in genes coding for the Hageman factor (XII) of coagulation  . Virtually all patients suffering from HAE type 3 are women, as a strong but yet undefined connection between estrogen and the onset of symptoms has been observed  . Moreover, emotional stress, trauma, and hormonal replacement therapy are established triggers . The clinical presentation includes recurrent and unpredictable attacks of edema of the face and extremities accompanied by abdominal pain and cramping . In rare cases, laryngeal edema with potentially life-threatening asphyxiation can occur without immediate therapy  . The diagnosis rests on determining C1-INH and C4 levels in serum, for the differential diagnosis and genetic tests can be done for confirmation of factor XII mutations, however, they are still not readily available . Attacks may resolve spontaneously, but treatment frequently mandates the use of bradykinin receptor antagonists, kallikrein inhibitors and fresh frozen plasma (FFP), as corticosteroids, antihistamines and adrenaline are ineffective . Long-term prophylaxis with androgens is necessary.
Hereditary angioedema (HAE) is a rare genetic disease characterized by recurrent, unpredicted, and abrupt attacks of facial and extremity edema accompanied by abdominal pain and cramping. There are three types and type 3 stems from mutations in one of the molecules involved in coagulation (the Hageman factor, or factor XII), which is also one of the key mediators of vascular permeability and edema in these patients. HAE type 3 is almost exclusively diagnosed in women and risk factors such as estrogen therapy, stress and pregnancy have been documented. The diagnosis is made by combining data from patient history, the appearance of typical symptoms and laboratory tests, whereas therapy includes management of attacks and long-term prophylaxis. In rare cases, edema may lead to life-threatening obstruction of the airways and death if not treated immediately. For this reason, patients are often trained for self-administration of drugs at home when symptoms appear.