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Hereditary Angioedema Type 3

HAE

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.


Presentation

The recurrent, unpredictable, and abrupt onset of edema involving the face, tongue and less commonly the extremities is the hallmark of HAE [2]. 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 [4]. Although erythema marginatum is considered to be a constitutive feature of HAE types 1 and 2, it is rarely observed in type 3 [2]. The swelling usually subsides within 12-72 hours after its onset, but treatment is frequently necessary [4].

Swelling
  • It causes swelling, particularly of the face and airways, and abdominal cramping. Angioedema is swelling that is similar to hives , but the swelling is under the skin instead of on the surface.[medlineplus.gov]
  • In addition to abdominal swelling and pain, people often experience nausea, which can be accompanied by vomiting. Attacks of HAE in the throat are the most dangerous because swelling that closes off the airway may be life threatening.[berinert.com]
  • Causes of Swollen Lips Swelling of the lips can be caused by a variety of different conditions.[medicinenet.com]
  • We herein describe a case of 25-year-old male who presented with swelling over face since one day. There was history of similar episodes since two years with gradual subsidence of swelling without any treatment.[e-ijd.org]
Pain
  • The clinical presentation includes recurrent and unpredictable attacks of edema of the face and extremities accompanied by abdominal pain and cramping.[symptoma.com]
  • "The first symptoms I feel are usually sharp abdominal pains." –BERINERT patient[berinert.com]
  • The horrific abdominal pain started when I was twelve. Attacks of acute pain, nausea, and diarrhea were accompanied by severe, mysterious swelling. It was excruciating and unrelenting. At times, my abdomen would be so distended I appeared pregnant.[globalgenes.org]
  • The affected area may become painful and red. You may also experience skin tingling or tightness.[health.ucsd.edu]
  • (HAE) is a rare, autosomal dominant disorder of C1 inhibitor (C1-INH) deficiency manifested with any combination of cutaneous angioedema (painless, nonpruritic, nonpitting swelling of the submucosal, dermal, or subcutaneous tissue), severe abdominal pain[ijdvl.com]
Fatigue
  • Common warning signs that can signal the onset of an HAE attack include: Sudden mood changes Irritability or aggressiveness Anxiety Extreme fatigue Rash or tingling sensation of the skin where the swelling begins Nausea Understanding what triggers your[berinert.com]
  • […] possibly associated with an increased incidence of autoimmune disease Prognosis variable after the attack occurs, they may recur throughout the patient's life attack frequency can be reduced with appropriate therapy Presentation Symptoms prodromal symptoms fatigue[medbullets.com]
  • Dagen & Craig (2010) documented that “the most common identifiable prodromal symptoms include unusual fatigue, rash on arms or legs and muscle aches” (p. 3).[haecanada.org]
  • Some symptoms of hereditary angioedema include: Swelling of the skin (most common symptom) Swelling of the hands and feet Fatigue Headache Muscle aches Skin tingling Abdominal pain (sometimes severe) Nausea and vomiting Hoarseness Shortness of breath[medicinenet.com]
  • Fatigue, malaise, irritability, hyperactivity, mood changes, and nausea are other preceding factors [ 21 , 24 ]. The severity of HAE is variable and usually unpredictable.[intechopen.com]
Malaise
  • Fatigue, malaise, irritability, hyperactivity, mood changes, and nausea are other preceding factors [ 21 , 24 ]. The severity of HAE is variable and usually unpredictable.[intechopen.com]
Stridor
  • In case of laryngeal edema, which initially manifests as dysphonia or difficulty in swallowing followed by dyspnoea and stridor, the treatment of choice is the administration of C1 inhibitor concentrates.[isithereditary.com]
  • […] swelling of the lips, tongue, uvula, soft palate, and larynx gastrointestinal bowel wall edema resulting in gastrointestinal colic, nausea, vomiting, and/or diarrhea Physical exam skin erythema marginatum may be seen upper airway voice changes or horseness stridor[medbullets.com]
  • Pruritus, urticaria, and bronchospasm do not occur, but laryngeal edema may be present, causing stridor (and sometimes death). Swelling resolves within about 1 to 3 days of onset.[merckmanuals.com]
  • Symptoms/signs of respiratory distress - eg, stridor, dyspnoea, fear of suffocation, anxiety/agitation; the patient may grasp his/her throat with the thumb and index fingers (the universal choking sign).[patient.info]
Hoarseness
  • A 34-year-old female patient presented to the hospital complained of swollen and painful legs, flatulence, palpebral and labial edema, dyspnea, dysuria, frequent herpetic infections of mouth and nose, subfebrile body temperature and was hoarse.[signavitae.com]
  • Symptoms include: Airway blockage -- involves throat swelling and sudden hoarseness Repeat episodes of abdominal cramping without obvious cause Swelling in the hands, arms, legs, lips, eyes, tongue, throat, or genitals Swelling of the intestines -- can[medlineplus.gov]
  • Some symptoms of hereditary angioedema include: Swelling of the skin (most common symptom) Swelling of the hands and feet Fatigue Headache Muscle aches Skin tingling Abdominal pain (sometimes severe) Nausea and vomiting Hoarseness Shortness of breath[medicinenet.com]
  • Voice changes - high-pitched, hoarse, rough or with a resonant, 'barky' cough or unable to speak.[patient.info]
Dyspnea
  • A 34-year-old female patient presented to the hospital complained of swollen and painful legs, flatulence, palpebral and labial edema, dyspnea, dysuria, frequent herpetic infections of mouth and nose, subfebrile body temperature and was hoarse.[signavitae.com]
  • Her medical history showed sudden onsets of facial swelling, vomiting, abdominal pain and dyspnea several times a year since infancy.[omicsonline.org]
Abdominal Pain
  • The clinical presentation includes recurrent and unpredictable attacks of edema of the face and extremities accompanied by abdominal pain and cramping.[symptoma.com]
  • pain, or acute airway obstruction.[ijdvl.com]
  • General pathology Blood and immunity Dysimmune diseases hereditary angioedema type 3 Hereditary angioedema (HAE) is characterized clinically by recurrent acute skin swelling, abdominal pain, and potentially life-threatening laryngeal edema.[humpath.com]
  • Affiliated tissues include skin and bone , and related phenotypes are facial edema and vomiting OMIM : 57 Hereditary angioedema type III is a rare disorder characterized clinically by recurrent skin swelling, abdominal pain attacks, and potentially life-threatening[malacards.org]
  • Swelling of the intestines may also occur, which can cause debilitating abdominal pain. Swelling of mucous membranes of the mouth, tongue, or throat from HAE can be life-threatening due to obstruction of the airway.[health.ucsd.edu]
Nausea
  • […] urticaria or pruritus affecting the skin swelling of the extremities, face, and genitals can affect any area upper airway swelling of the lips, tongue, uvula, soft palate, and larynx gastrointestinal bowel wall edema resulting in gastrointestinal colic, nausea[medbullets.com]
  • Although they have few side effects involving most commonly nausea, vomiting, and diarrhea, which are dose‐dependent, they are not as effective as androgens.[intechopen.com]
  • […] tissues occur throughout the body without the presence of urticaria Typically involves arms, legs, hands, trunk, face, mouth, larynx, airway, genitals, and tongue Gastrointestinal tract often involved, with recurrent episodes of cramping, abdominal pain, nausea[arupconsult.com]
  • Attacks of acute pain, nausea, and diarrhea were accompanied by severe, mysterious swelling. It was excruciating and unrelenting. At times, my abdomen would be so distended I appeared pregnant.[globalgenes.org]
Vomiting
  • Affiliated tissues include skin and bone , and related phenotypes are facial edema and vomiting OMIM : 57 Hereditary angioedema type III is a rare disorder characterized clinically by recurrent skin swelling, abdominal pain attacks, and potentially life-threatening[malacards.org]
  • Her medical history showed sudden onsets of facial swelling, vomiting, abdominal pain and dyspnea several times a year since infancy.[omicsonline.org]
  • 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.[symptoma.com]
  • […] throat swelling and sudden hoarseness Repeat episodes of abdominal cramping without obvious cause Swelling in the hands, arms, legs, lips, eyes, tongue, throat, or genitals Swelling of the intestines -- can be severe and lead to abdominal cramping, vomiting[medlineplus.gov]
Diarrhea
  • […] sudden hoarseness Repeat episodes of abdominal cramping without obvious cause Swelling in the hands, arms, legs, lips, eyes, tongue, throat, or genitals Swelling of the intestines -- can be severe and lead to abdominal cramping, vomiting, dehydration, diarrhea[medlineplus.gov]
  • […] affecting the skin swelling of the extremities, face, and genitals can affect any area upper airway swelling of the lips, tongue, uvula, soft palate, and larynx gastrointestinal bowel wall edema resulting in gastrointestinal colic, nausea, vomiting, and/or diarrhea[medbullets.com]
  • Attacks of acute pain, nausea, and diarrhea were accompanied by severe, mysterious swelling. It was excruciating and unrelenting. At times, my abdomen would be so distended I appeared pregnant.[globalgenes.org]
  • Swelling of the skin (note that above symptoms may occur before swelling begins) Extreme fatigue or tiredness Headache Muscle aches Tingling in the skin Abdominal or belly pain (may be extreme enough to lead to surgical exploration) Nausea and vomiting Diarrhea[medicinenet.com]
Constipation
  • Attacks may be accompanied by vomiting and less commonly diarrhea or constipation. Although attacks are sporadic and often occur without a clear trigger, precipitating factors include pressure or trauma and emotional stress.[clinicaladvisor.com]
  • […] usual, range) Recommended dosage for children (usual, range) FDA approved/HAE indication Adverse effects 17‐α alkylated androgens Common: weight gain, virilization, acne, altered libido, muscle pains, and cramps, headaches, depression, fatigue, nausea, constipation[intechopen.com]
  • Symptoms include abdominal pain (can be severe or sudden in onset), nausea and vomiting, diarrhoea, constipation and abdominal distention. Large fluid shifts with ascites or hypovolaemic shock may occur.[patient.info]
Lip Swelling
  • Causes of Swollen Lips Swelling of the lips can be caused by a variety of different conditions.[medicinenet.com]
Hypotension
  • It leads to an increase in vascular permeability by binding to the B2 receptor on the vascular endothelial cells, and this in turn causes the development of edema, ascites, and hypotension [ 25 , 26 ].[intechopen.com]
  • Allergy attacks are rapid in onset, there is generally a recognisable allergen, and will be associated with a superficial itch, a generalised rash with raised wheals, respiratory wheeze, abdominal pain and possibly hypotension.[rcemlearning.co.uk]
  • Antifibrinolytics also may have efficacy for HAE, but these agents have been associated with a variety of adverse effects, including nausea and diarrhea, postural hypotension, fatigue, enhanced thrombosis, retinal changes, and teratogenicity. 8, 22, 23[the-hospitalist.org]
  • Recombinant human C1-inhibitor for treatment of acute angioedema attacks Adverse events In C1 INH Headache, vertigo colitis In placebo Headache, injection site swelling, epistaxis, hypotension J Allergy ClinImmunol 2010;126:821-7. 52.[slideshare.net]
  • Stanozolol (Winstrol) Usual doses Adults: 2 mg/day Children 6–12 yr: 0.5–2 mg/day Children 0.5–1 mg/day Yes Yes Yes Yes No Antifibrinolytics Epsilon aminocaprioic acid (EACA) or Amicar 1–2 g by mouth 3x daily Hypercoagulability Muscle cramps Postural hypotension[clevelandclinicmeded.com]
Myalgia
  • Antifibrinolytic agents are reserved for patients who cannot tolerate anabolic steroids or other forms of prophylactic therapy. 12,13 Side effects associated with these agents include myalgias, fatigue, and coagulation disorders.[clevelandclinicmeded.com]
  • The most frequent adverse effects of the 17α‐alkylated androgens are menstrual irregularities, changes in libido, hirsutism, acne, changes in mood, weight gain, myalgia, erythrocytosis, increased blood pressure, and abnormalities in lipid profiles [ 51[intechopen.com]
Swelling of Hand
  • Figure 1: Hand swelling (left hand). She was referred to our obstetric outpatient ward for the care of pregnancy. At 18 weeks of pregnancy, she had an episode of abdominal pain and GI tract edema was suspected.[omicsonline.org]
Facial Edema
  • Affiliated tissues include skin and bone , and related phenotypes are facial edema and vomiting OMIM : 57 Hereditary angioedema type III is a rare disorder characterized clinically by recurrent skin swelling, abdominal pain attacks, and potentially life-threatening[malacards.org]
  • Facial edema and oral mucuous membrane swelling may be present. The abdomen may be distended and tender to palpation, and bowel sounds are often diminished. Abdominal attacks often lead to unnecessary imaging and surgical exploration.[clinicaladvisor.com]
Facial Swelling
  • Her medical history showed sudden onsets of facial swelling, vomiting, abdominal pain and dyspnea several times a year since infancy.[omicsonline.org]
Tingling
  • Common warning signs that can signal the onset of an HAE attack include: Sudden mood changes Irritability or aggressiveness Anxiety Extreme fatigue Rash or tingling sensation of the skin where the swelling begins Nausea Understanding what triggers your[berinert.com]
  • […] children) Most frequent cause of death is airway obstruction secondary to laryngeal edema Presence of autoimmune diseases (especially glomerulonephritis ) is higher in these patients Typical and predictable course Many attacks, preceded by prodrome (tingling[arupconsult.com]
  • You may also experience skin tingling or tightness.[health.ucsd.edu]
  • Some symptoms of hereditary angioedema include: Swelling of the skin (most common symptom) Swelling of the hands and feet Fatigue Headache Muscle aches Skin tingling Abdominal pain (sometimes severe) Nausea and vomiting Hoarseness Shortness of breath[medicinenet.com]
  • Tingling in the area that is about to swell is also another commonly noted prodrome (Frank, 2008; Gower et al., 2011).[haecanada.org]
Headache
  • Some symptoms of hereditary angioedema include: Swelling of the skin (most common symptom) Swelling of the hands and feet Fatigue Headache Muscle aches Skin tingling Abdominal pain (sometimes severe) Nausea and vomiting Hoarseness Shortness of breath[medicinenet.com]
  • According to the product prescribing information, the most common adverse reactions observed by at least 5% of subjects are upper respiratory tract infection, sinusitis, rash, and headache.[clevelandclinicmeded.com]
  • Recombinant human C1-inhibitor for treatment of acute angioedema attacks Adverse events In C1 INH Headache, vertigo colitis In placebo Headache, injection site swelling, epistaxis, hypotension J Allergy ClinImmunol 2010;126:821-7. 52.[slideshare.net]
  • All impeded androgens have many potentially important side effects, including masculinization, headaches, lack of libido or increased libido, hair gain or loss, liver function abnormalities, myopathy, and lipid abnormalities.[clinicaladvisor.com]
Irritability
  • Common warning signs that can signal the onset of an HAE attack include: Sudden mood changes Irritability or aggressiveness Anxiety Extreme fatigue Rash or tingling sensation of the skin where the swelling begins Nausea Understanding what triggers your[berinert.com]
  • Due to the nature of the disease, swelling can also occur in the intestines, causing various types of episodic and unpredictable abdominal pain, which may be confused with irritable bowel syndrome, inflammatory bowel disease, gynecological conditions[health.ucsd.edu]
  • In addition, they become pale and swollen if irritated. The deep swelling of angioedema can also be painful. If you have difficulty breathing, seek medical advice immediately.[isithereditary.com]
  • Firazyy is a 10 amino acid peptide which causes local irritation, but otherwise has not been associated with serious side effects thus far. It is approved for self-administration subcutaneously.[clinicaladvisor.com]
Urinary Retention
  • The genitourinary tract may also be involved, causing acute urinary retention, often with hematuria. Patients also often experience headaches, although the reason for this remains unclear. Angioedema itself is not known to cause a febrile illness.[mdmag.com]

Workup

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 [4]. 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 [2] [5].

Treatment

Treatment approaches are similar across all types and focus on prompt alleviation of acute symptoms and long-term prophylaxis as a mode of prevention [2] [4]. 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 [2] [4]. According to isolated reports, resolution of symptoms should occur within 1-2 hours after administration of therapy [2]. 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 [6].

Prognosis

Although recurrent attacks may significantly impair the quality of life, their spontaneous resolution is rather common, but in rare cases, laryngeal edema may cause asphyxiation and even death due to upper airway obstruction [2]. For this reason, HAE must be diagnosed early on.

Etiology

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) [1], type 3 is most likely caused by aberrations in Hageman factor XII, without C1-INH involvement [6]. 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 [4]. In a small number of cases, however, the cause remains unknown, and the term HAE with an unknown cause (HAE-U) is sometimes used [2].

Epidemiology

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 [2]. Moreover, oral contraceptives and use of hormone replacement therapies containing estrogens, but also pregnancy were described as symptom triggers [2] [4]. Across numerous reports, the mean age when symptoms start is estimated as 26.8 years [2].

Sex distribution
Age distribution

Pathophysiology

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 [1] [5]. Presumably, gain-of-function mutations cause increased activity of Factor XII and subsequent acceleration of bradykinin production, ultimately leading to symptom development [2]. 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 [2] [5].

Prevention

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 [2] [4], but they should be contraindicated in pregnancy, as they can cross the placenta and potentially harm the fetus [3]. Antifibrinolytics (aminocaproic acid or tranexamic acid) have been suggested as alternatives [3]. 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 [3] [6].

Summary

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 [1]. In fact, HAE type 3 results from autosomal dominant mutations in genes coding for the Hageman factor (XII) of coagulation [2] [3]. 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 [4] [5]. Moreover, emotional stress, trauma, and hormonal replacement therapy are established triggers [4]. The clinical presentation includes recurrent and unpredictable attacks of edema of the face and extremities accompanied by abdominal pain and cramping [2]. In rare cases, laryngeal edema with potentially life-threatening asphyxiation can occur without immediate therapy [2] [4]. 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 [5]. 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 [4]. Long-term prophylaxis with androgens is necessary.

Patient Information

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.

References

Article

  1. Zuraw BL, Christiansen SC. Pathogenesis and laboratory diagnosis of hereditary angioedema. Allergy Asthma Proc. 2009;30(5):487-492.
  2. Bork K. Diagnosis and treatment of hereditary angioedema with normal C1 inhibitor. Allergy Asthma Clin Immunol. 2010;6(1):15.
  3. Henao MP, Kraschnewski JL, Kelbel T, Craig TJ. Diagnosis and screening of patients with hereditary angioedema in primary care. Ther Clin Risk Manag. 2016;12:701-711.
  4. Miranda AR, de Ue APF, Sabbag DV, Furlani W de J, de Souza PK, Rotta O. Hereditary angioedema type III (estrogen-dependent) report of three cases An Bras Dermatol. 2013;88(4):578-584.
  5. Binkley KE. Factor XII mutations, estrogen-dependent inherited angioedema, and related conditions. Allergy Asthma Clin Immunol. 2010;6(1):16.
  6. Caballero T, Canabal J, Rivero-Paparoni D, Cabañas R. Management of hereditary angioedema in pregnant women: a review. Int J Womens Health. 2014;6:839-848.

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Last updated: 2018-06-21 19:50