Presentation: Child with recurrent swellings

A 14-year-old girl presents to paediatric allergy services with non-pitting recurrent swellings that have occurred on her left hand, arms and face. There has been no associated urticarial rash and no itching. She was prescribed antihistamines for five days at the time of each swelling, but did not notice any immediate improvement. She also has a history of sporadic episodes of abdominal pain with diarrhoea, lasting one to two days.

• Genomic testing for hereditary angioedema should be considered for patients with recurrent non-urticarial angioedema, usually of gradual onset involving the peripheries, gastrointestinal tract or larynx, typically lasting one to five days.
• There are three types of hereditary angioedema. Hereditary angioedema types 1 and 2 result from genetic variants in SERPING1, leading to a deficiency in C1 inhibitor (C1INH). Hereditary angioedema type 3 results from genetic variants in a small group of genes, including specific variants in the Factor XII gene (F12).
• R341 Hereditary angioedema types I and II should be considered if serum C1INH concentration and/or function is atypical.
• R368 Hereditary angioedema type 3 should be considered if the patient has a normal serum C1INH concentration or function.
• Exclusion of secondary and acquired causes of angioedema should be considered, such as drug-induced, autoimmune-mediated or lymphoproliferative conditions.
• Currently, testing can only be requested by immunology, dermatology or clinical genetics teams.

• Consult the National Genomic Test Directory. From here you can access the rare and inherited disease eligibility criteria, which contains information about individual tests and their associated eligibility criteria. You can also access a spreadsheet containing details of all available tests.
  • For information about how to arrange testing in Wales, Scotland or Northern Ireland, see Genomic testing in the devolved nations.
• For information about the genes that are included on different gene panels, see the NHS Genomic Medicine Service (GMS) Signed Off Panels Resource.
• For hereditary angioedema with normal C1 inhibitor esterase concentration and/or function, consider:
  • R368 Hereditary angioedema type 3 (targeted variant testing of F12 variant hotspot).
• For patients with hereditary angioedema with atypical C1 inhibitor esterase concentration and/or function, consider:
  • R341 Hereditary angioedema types I and II (single gene sequencing of SERPING1).
• None of the tests outlined above use whole genome sequencing, so you should use your local Genomic Laboratory Hub test order form and consent (record of discussion) form.
• Parental samples may be needed for interpretation of the child’s result. Parental samples can be taken alongside that of the child, and their DNA stored, or can be requested at a later date if needed.
• Most tests are DNA based, and an EDTA sample (typically a purple-topped tube) is required. There are a few tests for which a different type of tube is used; see Samples for genomic testing in rare disease.
• If you are discussing genomics concepts with your patients, you may find it helpful to use the visual communication aids for genomics conversations.
• Information about patient eligibility and test indications was correct at the time of writing. When requesting a test, please refer to the National Genomic Test Directory to confirm the right test for your patient.

For clinicians

• British Society of Immunology: Bite-sized immunology: Immune dysfunction: Hereditary angioedema
• NHS England: Clinical Commissioning Policy: Plasma-derived C1-esterase inhibitor for prophylactic treatment treatment of hereditary angioedema (HAE) types I and II (PDF, 21 pages)

References:

• Busse PJ and Christiansen SC. ‘Hereditary angioedema‘. The New England Journal of Medicine 2020: volume 382, issue 12, pages 1,136–1,148. DOI: 10.1056/NEJMra1808012
• Santacroce R, D’Andrea G, Maffione AB and others. ‘The genetics of hereditary angioedema: A review‘. Journal of Clinical Medicine 2021: volume 10, issue 9. DOI: 10.3390/jcm10092023

For patients

• British Society of Immunology: Bite-sized immunology: Immune dysfunction: Hereditary angioedema
• HAE UK