Presentation: Child with suspected haemophagocytic syndrome with absent XIAP expression (X-linked lymphoproliferative disease type 2)

A two-year-old boy is referred to paediatric immunology with a history of recurrent fever. He recently presented acutely with fever, splenomegaly and pancytopenia and fulfilled criteria for haemophagocytic lymphohistiocytosis (HLH). He was found to have hypogammaglobulinaemia and was positive for Epstein-Barr virus (EBV) infection. XIAP expression studies demonstrated low levels of the protein (<5%) compared to controls.

R18 should be undertaken in male patients with HLH consistent with XIAP-related disease, with low or absent XIAP expression. Typical features include inflammatory bowel disease or colitis, hypogammaglobulinaemia and/or other lymphoproliferative conditions.

R15 Primary immunodeficiency or monogenic inflammatory bowel disease should be used if the broader diagnosis of a lymphoproliferative condition and/or immunodysregulation are suspected.

Note that the related condition X-linked lymphoproliferative disease type 1, which is distinguished by low/absent SAP instead of XIAP, should be tested via R17 Lymphoproliferative syndrome with absent SAP expression. If there is uncertainty, the R15 indication will test for both conditions, along with many other monogenic causes of immunodeficiency, inflammatory bowel disease and autoimmunity.

R18 and R15 testing should typically be requested by immunology, haematology 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.
• To find out which genes are included on different gene panels, see the NHS Genomic Medicine Service (GMS) Signed Off Panels Resource.
• For haemophagocytic syndrome with XIAP deficiency, consider:
  • R18 Haemophagocytic syndrome with low/absent XIAP expression (single gene sequencing of XIAP).
• For conditions in which the broader diagnosis of combined immunodeficiency or immunodysregulation is suspected, consider:
  • R15 Primary immunodeficiency and monogenic inflammatory bowel disease. This will investigate causes of severe combined immunodeficiency. 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 R18:
  • 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

• European Society for Immunodeficiencies: Diagnostic criteria PID
• GeneReviews: X-linked lymphoproliferative disease
• Jeffrey Modell Foundation: 10 warning signs of primary immunodeficiency

References:

• Bousfiha A, Moundir A, Tangye SG and others. ‘The 2022 update of IUIS phenotypical classification for human inborn errors of immunity‘. Journal of Clinical Immunology 2022: volume 42, issue 7, pages 1,508–1,520. DOI: 10.1007/s10875-022-01352-z
• Mudde ACA, Booth C and Marsh RA. ‘Evolution of our understanding of XIAP deficiency‘. Frontiers Pediatrics 2021: volume 9. doi:10.3389/fped.2021.660520

For patients

• Immunodeficiency UK
• Jeffrey Modell Foundation