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Hereditary Angioedema Type 2

HAE-II

Hereditary angioedema type II is a genetic disorder in which synthesis of dysfunctional C1-esterase inhibitor results in angioedema, abdominal pain, and erythema marginatum.


Presentation

The clinical presentation is identical to HAE type 1. Angioedema, defined as sudden onset of edema involving the subcutaneous tissues of the extremities and face, but also the respiratory and gastrointestinal tract, is the main feature of HAE type 2. GI edema manifests as severe abdominal pain and cramping (mimicking acute abdomen), while laryngeal edema may cause breathing difficulties and even asphyxiation [3]. An erythematous, nonpruritic, nonpitting rash known as erythema marginatum is frequently noted in HAE patients and should be easily distinguished from urticaria. Symptoms usually resolve in 12-72 hours, but their frequent occurrence often mandates adequate therapy.

Swelling
  • On physical examination, the peripheral swelling during an acute attack is typically asymmetric and not well circumscribed. Facial edema and oral mucuous membrane swelling may be present.[clinicaladvisor.com]
  • Abstract Hereditary angioedema (HAE) is rare autosomal dominant disease, characterised by spontaneous and recurrent swellings in various parts of the body.[signavitae.com]
  • Her medical history showed sudden onsets of facial swelling, vomiting, abdominal pain and dyspnea several times a year since infancy.[omicsonline.org]
  • Related reading 35 years ago: “We probably will never know why you swell, but it’s called Angioneurotic Edema” - things have changed a lot since then. HAEA.org. Published: 02/26/2009 Updated: 06/26/2012[allergycases.blogspot.com]
Pain
  • GI edema manifests as severe abdominal pain and cramping (mimicking acute abdomen), while laryngeal edema may cause breathing difficulties and even asphyxiation.[symptoma.com]
  • The disease presents with orbital pain, edema on the eyelids, erythema, and fever. In this case, a child with hereditary angioedema type 2 who presented as mimicking a complication of acute sinusitis is discussed.[ncbi.nlm.nih.gov]
  • The patient had no symptoms until 3 months ago when she started to have daily abdominal pain below the umbilicus. The pain lasts a whole day and she has night symptoms as well. There is no consistent relief provided by pain medications.[allergycases.blogspot.com]
  • HAE is a potentially lethal disease and should be considered if repeating edema of various body parts, painful swelling and tightening of the skin are present.[signavitae.com]
  • Extremity swelling tends to be asymmetric and is rarely painful. Swelling may also involve the genitalia, trunk, face, tongue or larynx. Most debilitating are attacks of abdominal pain due to swelling of the bowel wall.[clinicaladvisor.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]
  • 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[rxlist.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]
Swelling of Limb
  • It is characterized by swelling of limbs, face, airway and abdominal pains caused by trauma, cold and stress.The mortality rate is up to 35% due to laryngeal oedema therefore spinal anesthesia was preferred.[journals.lww.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]
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]
  • 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[rxlist.com]
  • These may include: Extreme fatigue Muscle ache Tingling Headache Belly pain Hoarseness Mood changes Triggers Although you may not be able to tell what your triggers are, common ones include: Stress or anxiety Minor injury or surgery Illnesses such as[webmd.com]
  • Voice changes - high-pitched, hoarse, rough or with a resonant, 'barky' cough or unable to speak.[patient.info]
Stridor
  • […] 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]
  • Edema of the throat (pharynx) or voice-box (larynx) can result in pain, difficulty swallowing (dysphagia), difficulty speaking (dysphonia), noisy respiration (stridor), and potentially life-threatening asphyxiation.[rarediseases.org]
  • 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]
  • Ominous signs suggesting airway involvement include dysphagia, voice change, and stridor. There will generally be a family history of angio-oedema. However, 5% of adults carry the mutation for the C1-INH gene while remaining asymptomatic.[academic.oup.com]
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
  • A 12-year-old Caucasian female is seen as a new patient by the allergy and immunology clinic for abdominal pain for 3 months. She has a family history of hereditary angioedema (HAE) diagnosed in her maternal grandfather, mother, and brother.[allergycases.blogspot.com]
  • Her medical history showed sudden onsets of facial swelling, vomiting, abdominal pain and dyspnea several times a year since infancy.[omicsonline.org]
  • Abdominal associated with angioedema may manifest as severe acute-onset abdominal pain or as moderately severe chronic recurrent abdominal pain. Two medications are currently FDA-approved for the treatment of these patients.[ncbi.nlm.nih.gov]
  • It is characterized by swelling of limbs, face, airway and abdominal pains caused by trauma, cold and stress.The mortality rate is up to 35% due to laryngeal oedema therefore spinal anesthesia was preferred.[journals.lww.com]
Vomiting
  • Her medical history showed sudden onsets of facial swelling, vomiting, abdominal pain and dyspnea several times a year since infancy.[omicsonline.org]
  • Pain irradiated to the right lower quadrant and was associated with five episodes of vomiting. Computed tomography showed thickening of the duodenal wall with liquid in the subphrenic space.[ncbi.nlm.nih.gov]
  • 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]
  • […] 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, vomiting[medbullets.com]
Nausea
  • At 29 weeks of gestation, she was admitted to our emergency ward mainly complaining of nausea and vomiting; she received an injection of hC1- INH and her symptoms were resolved.[omicsonline.org]
  • […] 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]
Diarrhea
  • Swelling in your belly can cause: Extreme pain Nausea Vomiting Diarrhea You may notice warning signs before swelling begins.[webmd.com]
  • 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]
  • […] 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]
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]
  • 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]
  • Constipation and intestinal obstruction may also occur[ 6 , 12 ]. Abdominal pain may occur for many years in the absence of cutaneous symptoms, but this is a rare occurrence[ 16 ].[link.springer.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]
Lip Swelling
  • Six months after the accident he developed acute onset bilateral facial swelling, lip swelling, and difficulty breathing.[hoajonline.com]
  • Causes of Swollen Lips Swelling of the lips can be caused by a variety of different conditions.[medicinenet.com]
Hypotension
  • If hypotension is present, elevation of the legs, commencement of basic life support, if indicated, and administration of i.v. crystalloid at rapid infusion rates are the first steps in treatment.[academic.oup.com]
  • 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]
  • When urticaria, generalized pruritus, or hypotension is present, the mast cell system is usually involved. In these cases, internal and external triggers (ie, foods, drugs, insects) should be sought.[mdmag.com]
  • 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]
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]
  • Adverse events were reported by nearly 80% of patients on danazol therapy and included weight gain, menstrual irregularities, female virilization, acne, headache, depression, and myalgia.[link.springer.com]
  • Side-effects include myalgia, muscle weakness, hypotension, fatigue, and elevation of serum creatine kinase (CK). Liver and renal function, serum CK, and ocular pressures (risk of glaucoma) need to be monitored on treatment (Table 2 ).[academic.oup.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 Swelling
  • Her medical history showed sudden onsets of facial swelling, vomiting, abdominal pain and dyspnea several times a year since infancy.[omicsonline.org]
  • Six months after the accident he developed acute onset bilateral facial swelling, lip swelling, and difficulty breathing.[hoajonline.com]
  • In 2009, FDA approved Berinert, to treat acute abdominal attacks and facial swelling associated with HAE in adults and adolescents. It is a protein product derived from human plasma, and is manufactured by CSL Behring, Inc.[rarediseases.org]
Facial Edema
  • 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]
Hunger
  • Attacks are frequently accompanied by prodromal symptoms, including nonspecific complaints of irritability, aggressiveness, fatigue, or hunger[ 15 ].[link.springer.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]
Tingling
  • The rash is characterized by red rings that appear on the trunk and appendages as part of a prodrome that may also include a tingling sensation in the area where swelling will occur. 7 Reproduced with permission from the US Hereditary Angioedema Association[jaoa.org]
  • 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]
  • Some patients note a prodrome consisting of a tingling sensation in the area where an attack will start. A subset of patients also note erythema marginatum at the onset of an attack. True urticaria and pruritis are typically absent.[clinicaladvisor.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]
Headache
  • 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]
  • Upper respiratory infection, sinusitis, rash, and headache were the most commonly reported adverse reactions[ 34 ].[link.springer.com]
  • 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[rxlist.com]
  • These may include: Extreme fatigue Muscle ache Tingling Headache Belly pain Hoarseness Mood changes Triggers Although you may not be able to tell what your triggers are, common ones include: Stress or anxiety Minor injury or surgery Illnesses such as[webmd.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]
  • 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]
  • 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]
  • Attacks are frequently accompanied by prodromal symptoms, including nonspecific complaints of irritability, aggressiveness, fatigue, or hunger[ 15 ].[link.springer.com]
Ataxia
  • 遺伝性運動失調症 hereditary central nervous system demyelinating disease 遺伝性中枢神経系脱髄疾患 hereditary cerebellar ataxia 遺伝性小脳性運動失調 hereditary chorea 遺伝性舞踏病 hereditary coproporphyria 遺伝性コプロポルフィリン症 hereditary corneal dystrophy 遺伝性角膜ジストロフィー hereditary deafness 遺伝性難聴[jpeds.or.jp]

Workup

A properly obtained patient history including the frequency of attacks and data regarding the familial presence of symptoms may be the key in making an initial diagnosis. Laboratory studies are necessary to confirm HAE, however, and serum levels of C1-INH and its function, as well as C4 (which is consumed during acute attacks), should be evaluated [2]. Patients in whom functional activity of C1-INH is reduced, but with normal serum concentration, are diagnostic of HAE type 2.

C4 Decreased
  • […] the absence of urticaria of Subcutaneous tissues Systemic organs Mouth, larynx, or pharynx Family history of angioedema Unexplained episode of laryngeal edema Laboratory Testing Initial testing Complement 1 esterase inhibitor (C1-INH), complement 4 (C4[arupconsult.com]

Treatment

HAE attacks do not respond to corticosteroids, antihistamines, or adrenaline and the use of other agents is necessary. Icatibant (a competitive bradykinin receptor antagonist), ecallantide (inhibitor of kallikrein) and either recombinant or human C1-INH are drugs of choice for relieving acute symptoms [1]. On the other hand, attenuated androgens are used for long-term prophylaxis, with danazol, stanozolol, and oxandrolone being most frequently used [4] [5]. It must be emphasized, however, that androgens are strongly contraindicated in pregnant women due to their teratogenic effects, particularly in the first trimester [4]. Patients (especially pregnant women) should be trained for self-administration of therapy at home, the primary reason being the associated morbidity and mortality from delayed treatment [4].

Prognosis

Management of symptoms with proper therapy is very good, but approximately 50% of patients develop at least one episode of laryngeal edema, which may be life-threatening in some cases [1]. Other studies have shown that untreated HAE can cause at least 1 acute attack per month and individuals may experience a severe reduction in their quality of life for 20-100 days on an annual basis [2]. For this reason, an early diagnosis is detrimental.

Etiology

HAE type II stems from impaired function of a normally synthesized C1-INH, the primary reason being mutations in genes that code for this protein [3]. Point mutations, most frequently missense, of SERPING1 genes located on chromosome 11, are responsible for production of a dysfunctional C1-INH [3].

Epidemiology

An estimated global prevalence of HAE ranges between 1:10,000 and 1:50,000, with 15% of cases attributed to type 2 [1]. Several provoking factors of HAE have been described, including trauma, emotional stress (eg. weddings, Christmas, etc.), use of oral contraceptives and angiotensin-converting-enzyme inhibitor (ACE inhibitor), as well as infections [1]. A predilection of HAE type 2 toward female gender was observed in some studies, with the most probable reason being a strong association between the onset of symptoms and estrogen, but the exact connection remains to be elucidated [4].

Sex distribution
Age distribution

Pathophysiology

Under physiological conditions, C1-INH inhibits the production of kallikrein and factor XII-mediated complement stimulation [2]. In the setting of its improper activity, abnormal production of kallikrein, and bradykinin as the end-product leads to a profound onset of edema due to markedly increased vascular permeability in tissues [2] [3]. It must be emphasized that histamine is not the principal mediator of symptoms in HAE of all types, which is why the presence of urticaria (hives) can immediately exclude HAE from the differential diagnosis [3].

Prevention

Fortunately, drugs that are used for management of acute attacks may also be used as prophylaxis. Plasma-derived C1-INH is given 1-6 hours prior to surgical or dental procedures as a preventive measure, whereas long-term use of androgens has shown very good results in reducing the number of acute exacerbations down to a minimum [4].

Summary

Hereditary angioedema (HAE) is a rare genetic disease divided into three types and type 2, encompassing approximately 15% of all HAE cases, is characterized by a poor functional activity of C1-esterase inhibitor (C1-INH) [1] [2]. Mutations in the C1-INH protein, coded by C1-INH genes on chromosome 11, is the underlying cause and approximately 20-25% of mutations arise de novo [2]. The remaining patients, however, inherit these mutations through an autosomal dominant pattern, suggesting a strong familial component in HAE [2]. Symptoms stem from excessive generation of bradykinin due to the inability of dysfunctional C1-INH to suppress its production and include an abrupt onset of erythema marginatum (non-pruritic and non-pitting rash), edema on the extremities and face and severe abdominal pain [3]. The clinical presentation is indistinguishable from hereditary angioedema type 1 (caused by a deficiency of C1-INH), which is why laboratory tests to determine the levels of C1-INH should be performed. Bradykinin receptor antagonists (icatibant), recombinant or human C1-INH, antifibrinolytics (tranexamic acid), and kallikrein inhibitors (ecallantide) are recommended for treatment of acute attacks [1] [4], while attenuated androgens - danazol, stanozolol, or oxandrolone are used for long-term prophylaxis [1] [5]. Androgens are contraindicated in pregnancy, however, as they can cross the placenta and exert teratogenic effects [4].

Patient Information

Hereditary angioedema (HAE) is a rare genetic disorder demarcated by an acute and abrupt onset of edema of the face and extremities, severe abdominal pain and a rash (known as erythema marginatum) due to mutations of an enzyme responsible for various functions in the immune system. There are three distinct types and in type 2, production of this enzyme (C1-esterase inhibitor, or C1-INH) is normal, but the synthesized protein is dysfunctional and is unable to perform its function. As a result, typical symptoms appear and are often related to triggering events such as infections, pregnancy (in which more frequent attacks are observed), use of oral contraceptives and ACE inhibitors, but also emotional stress. The diagnosis is made after conducting blood tests to assess the levels of C1-INH and its functional activity. Management of acute attacks and long-term use of drugs to prevent their occurrence is the mainstay of treatment and patients should be trained for self-treatment at home, in order to prevent life-threatening edema of the larynx that can cause cessation of breathing if treatment is delayed. HAE can be a debilitating disease in the absence of appropriate therapy, which is why an early diagnosis carries a very good prognosis and minimal impairment of daily life.

References

Article

  1. Kargarsharif F, Mehranmehr N, Zahedi Fard S, Fazlollahi MR, Ayazi M, Mohammadzadeh I, et al. Type I and Type II Hereditary Angioedema: Clinical and Laboratory Findings in Iranian Patients. Arch Iran Med. 2015;18(7):425-429.
  2. Nzeako UC, Frigas E, Tremaine WJ. Hereditary angioedema: a broad review for clinicians. Arch Intern Med. 2001;161(20):2417-2429.
  3. Cichon S, Martin L, Hennies HC, et al. Increased Activity of Coagulation Factor XII (Hageman Factor) Causes Hereditary Angioedema Type III. Am J Hum Genet. 2006;79(6):1098-1104.
  4. 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.
  5. Floccard B, Hautin E, Bouillet L, Coppere B, Allaouchiche B. An evidence-based review of the potential role of icatibant in the treatment of acute attacks in hereditary angioedema type I and II. Core Evid. 2012;7:105–114.

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Last updated: 2019-07-11 20:19