Presentation: Child with suspected autoimmune polyendocrine syndrome

A two-year-old girl is referred to paediatrics from primary care. She has a history of a hypocalcaemic seizures and now presents with abdominal pain, vomiting and hypotension. She is diagnosed with Addison disease and is also noted to have pitting in her nails, patchy hair loss affecting her eyebrows and oral candidiasis. There is a past medical history of chronic diarrhoea with failure to thrive (her height and weight have crossed two centile lines since birth).

Genomic testing with R155 should be considered if the patient has:

• Addison disease;
• hypoparathyroidism;
• candidiasis;
• ectodermal dysplasia; and/or
• a diagnosis of autoimmune polyendocrine syndrome is clinically suspected (patients usually have two of the features listed above).

Currently, R155 testing can only be requested by immunology, endocrinology 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.
• Decide which of the panels best suits the needs of your patient and/or family.
• For multiple organ-specific autoimmune conditions with or without candidiasis, consider:
  • R155 Autoimmune polyendocrine syndrome (single gene sequencing of AIRE).
• For conditions in which chronic mucosal candidiasis is predominant, or where immunodysregulation and/or monogenic inflammatory bowel disease are suspected, consider:
  • R15 Primary immunodeficiency. This will investigate causes of immunodeficiency, autoinflammation and/or suspected monogenic inflammatory bowel disease. The test includes a whole genome sequencing (WGS) panel of all genes known to cause immune conditions.
• For tests that do not include WGS, including R155:
  • you can use your local Genomic Laboratory Hub 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 in completing WGS-specific forms);
  • complete an NHS GMS 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

• Genomics England: NHS Genomic Medicine Service (GMS) Signed Off Panels Resource
• NHS England: National Genomic Test Directory

References:

• Ferre EMN, Rose SR, Rosenzweig SD and others. ‘Redefined clinical features and diagnostic criteria in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy‘. The Journal of Clinical Investigation Insight 2016: volume 1, issue 13. DOI: 10.1172/jci.insight.88782

For patients

• Immune Deficiency Foundation: APECED/APS-1
• National Organization for Rare Diseases: Autoimmune polyglandular syndrome type 1