Angioedema hereditary D84.1

Knowledge of rare genetic diseases such as hereditary angioedema (HAE) has evolved in parallel with the development of new molecular tools. C1 inhibitor (C1-INH) deficiency has been recognized as the major cause of HAE (HAE-C1-INH) since the 1960s. Discovery of the broad spectrum of mutations affecting the C1-INH gene (SERPING1) was not possible until the late 1980s, when Sanger sequencing became available and more readily accessible worldwide.

However, the involvement of other genes in HAE was not discovered until 2006 with the description of mutations in the F12 gene in patients with HAE and normal C1-INH. The knowledge gained through the new era of genomics has been crucial for the discovery of mutations in additional genes, improving or explaining the understanding of the complex pathogenesis of this phenotypically largely identical disease. In the last three years, advanced next-generation sequencing techniques have enabled the identification of mutations in five additional novel genes associated with hereditary angioedema variants with normal C1-INH (nC1-INH-HAE): ANGPT1 (angiopoietin-1), PLG (plasminogen), KNG1 (kininogen), MYOF (myoferlin), and HS3ST6 (heparan sulfate glucosamine 3-O-sulfotransferase 6).

Hereditary angioedema:

Type I hereditary angioedema , mutation in Serping1 (C1-INH deficiency).

Type II hereditary angioedema, mutation in Serping1 (C1-INH dysfunction)

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Type III Hereditary angioedema , mutation in factor XII (F12)

Type IV Hereditary angioedema , mutation in plasminogen (PLG)

Type V Hereditary angioedema , mutation in angiopoietin 1 (ANGPT1)

Type VI Hereditary angioedema , mutation in kininogen 1 (KNG1)

Type VII Hereditary angioedema , mutation in myoferlin (MYOF)

Type VIII Hereditary angioedema , mutation in heparan sulfate (HS)-glucosamine 3-O-sulfotransferase 6 (HS3ST6)

Type U Hereditary angioedema, genetic defect unknown

Basically, hereditary angioedema can be distinguished between:

• hereditary angioedema with mutation in the C1-esterase inhibitor gene(SERPING1): C1-INH-HAE (HAE type I/ HAE type II)

and

• hereditary angioedemawithout detectable mutation in SERPING1 gene: nC1-INH-HAE (HAE types III - VIII) with normal C1-INH (see below classification).

Note: Mutations in SERPING1, the gene encoding C1-INH (C1 esterase inhibitor), are responsible for the vast majority of cases of hereditary angioedema (85%). C1-esterase inhibitor (C1-INH) is an important regulator of critical enzymes involved in the cascades of bradykinin formation. These increase vascular permeability and allow the flow of fluids into the extracellular space. Disturbances in this cascade can lead to acute swelling conditions (angioedema).

Face, extremities (especially arms, less frequently legs), genitals; also lips, tongue, larnyx, abdomen (abdominal cramps). Laryngeal swelling is acutely life-threatening.

The therapy of hereditary angioedema should be individually tailored to the needs of the affected person.

There are several options for treatment:

Acute therapy: Depending on the age of the patient, there are several drugs approved for treatment. The drugs Berinert®, Cinryze® and Conestat alfa (Ruconest® ) replace the missing C1 inhibitor. The drugs Icatibant (Firazyr®^: blockade of the bradykinin B2 receptor) and Lanadelumab (Takhzyro®^: monoclonal antibody against plasma kallikrein) inhibit the action of bradykininin different ways. Bradykinin is responsible for the development of symptoms in HAE.

• In the neck and head region, any attack in all age groups should be treated
• Therapy should start as early as possible
• Children < 6 years: All attacks (including those of the gastrointestinal tract and arms and legs) should be treated
• Children > 6 years: Therapy should be considered for attacks outside the head/neck region (indication according to severity)
• Medication must be available at short notice at all times

Short-term prophylaxis: Short-term prophylaxis is recommended before surgery in the head/neck area. This concerns an upcoming surgical medical intervention, e.g. dental treatment. Use of Berinert® (i.v.), alternatively: Cinryze®.

• Recommended for all tissue traumatizing and surgical procedures in the head and neck region.
• If short-term prophylaxis is not used, a C1 inhibitor concentrate should be available as an emergency medication.
• Short-term prophylaxis should be administered as soon as possible before the operation.

Long-term prophylaxis: The aim of this is to prevent swelling attacks in the long term. The possibility of permanent preventive treatment may be considered in patients in life situations associated with increased disease activity (judged by frequency and severity of attacks). Disease burden as such may also be considered for prophylactic therapy. In addition, long-term prophylaxis is useful in patients who cannot be adequately treated with repeated as-needed treatments.

• Long-term prophylaxis is not standard for all patients. It depends on the age of the patient and the disease process. From the age of 12, Cinryze® or Berinert® (s.c.) or lanadelumab (Takhzyro®) is recommended. The decision to use long-term prophylaxis should take into account the frequency of attacks, the individual burden of the disease, and the interference with the usual daily routine. As a rule, long-term prophylaxis is not given for fewer than two attacks per month.

Concomitant medication: In mild ventral attacks, it may be sufficient to prescribe antispasmodic medication only.

Therapy of laryngeal edema: Patients with HAE of the head with edema of the pharynx or larynx are emergencies because of the threat of asphyxiation and should be hospitalized and monitored immediately. All affected patients must be treated with C1 inhibitor or Firazyr® medication as soon as possible. Intubation of the patient is necessary if there is threatening respiratory distress (see also Angioedema of the head and neck region).

Supportive measures: To enable rapid treatment of incipient swelling, elderly patients as well as parents, other relatives, teachers and other caregivers should be informed about the clinical picture. They should be able to recognize a life-threatening situation (e.g., laryngeal edema) and take specific action (activate emergency preparedness).

• The patient should always carry an emergency plan showing what action is to be taken. Similarly, all affected individuals should carry an emergency identification card.
• Patients with HAE due to C1-INH deficiency should always keep an emergency medication sufficient for two doses on hand at home and carry it with them when traveling. The nearest hospital should be aware of the patient and the disease.
• For school children, teachers should be informed that acute attacks may occur. Before dental surgery, including tooth extractions, and other oral and pharyngeal surgeries, patients with HAE due to C1-INH deficiency should receive 20 units per kg of body weight of C1-INH concentrate one hour before the procedure (see short-term prophylaxis).

Home self-treatment: As HAE is a lifelong disease, there is the possibility of home self-treatment. This is only possible with the consent of the treating physician and after training of the parents or the patients themselves by the physician. Through self-treatment, a swelling attack can be treated earlier and the severity of the swelling is usually less .

1. Hubiche T et al. (2005) Érythème annulaire réticulé annonciateur de crises d'œdème angioneurotique héréditaire chez un enfant. Ann Dermatol Venereol132: 249-251.

2. Rasmussen ER et al. (2016) Urticaria and Prodromal Symptoms Including Erythema Marginatum in Danish Patients with Hereditary Angioedema. Acta Derm-Venereol 96: 373-376.

3. Santacroce R et al. (2021) The Genetics of Hereditary Angioedema: A Review. J Clin Med 10: 2023.
4. Veronez CL et al. (2021) The Expanding Spectrum of Mutations in Hereditary Angioedema. J Allergy Clin Immunol Pract 9: 2229-2234.