Presentation: Child with a suspected autoinflammatory condition

A five-year-old girl is referred to paediatrics from primary care following a third presentation of painful joints. She has been reluctant to take part in school activities due to fatigue and joint pain. She has a long history of frequent febrile episodes, thought to be due to recurrent colds. She has an erythematous patchy rash over her back and legs.

Genomic testing with R413 should be considered when individuals have the following features:

• evidence of recurrent or continuous inflammation (localised or systemic) of otherwise undetermined cause, which fluctuate apparently randomly, either periodically or irregularly; and
• infectious and autoimmune testing have been non-diagnostic.

Attacks typically start during childhood, but symptoms can also begin during adolescence or even in later adulthood. The main symptom is fever; other symptoms include:

• serositis (peritonitis, pleuritis and pericarditis);
• recurrent stroke-like episodes;
• myalgia, arthralgia and rash; and
• central nervous system, gastrointestinal and respiratory symptoms.

R413 testing should typically be requested by immunology, rheumatology, dermatology, gastroenterology, paediatrics 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.
• Depending on the presenting signs and symptoms, in addition to R413 you may wish to consider R15 Primary immunodeficiency or monogenic inflammatory bowel disease. R15 includes many more genes than R413; however, there are a few genes on R413 that are not included in R15. If relevant, both test indications may be requested.
  • R15 uses whole genome sequencing (WGS) with subsequent analysis of panel of many genes currently known to cause immune disorders.
• For tests that do not include WGS, including R413:
  • you can use your local Genomic Laboratory Hub (GLH) test order and consent (record of discussion (RoD)) forms; and
  • 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.
• For tests that are undertaken using WGS, including R15, you will need to:
  • complete an NHS GMS test order form with details of the affected child (proband) and their parents, including details of the phenotype (using human phenotype ontology (HPO) terms) and the appropriate panel name(s) with associated R number (see How to complete a test order form for WGS for support);
  • complete an NHS GMS record of discussion (RoD) form for each person being tested – for example, if you are undertaking trio testing of an affected child and their parents, you will need three RoD forms (see How to complete a record of discussion form for support); and
  • submit parental samples alongside the child’s sample to aid interpretation, especially for the larger WGS panels (where this is not possible, for example because the child is in care or the parents are unavailable for testing, the child may be submitted as a singleton).
• 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

References:

• Rood JE and Behrens EM. ‘Inherited Autoinflammatory Syndromes‘. Annual Review of Pathology: Mechanisms of Disease 2022: volume 17, pages 227–249. DOI: 10.1146/annurev-pathmechdis-030121-041528

For patients

• Autoinflammatory Alliance
• Autoinflammatory UK