Presentation: Child with suspected autoimmune lymphoproliferative syndrome

A 10-year-old boy is referred to paediatrics with haemolytic anaemia and splenomegaly. He has a history of cervical lymphadenopathy lasting several months. Further blood tests are undertaken, including analysis of T cell subsets. These find an elevated percentage of double-negative alpha-beta T cells (greater than 1.8%).

Genomic testing with R19 should only be undertaken if autoimmune lymphoproliferative syndrome (ALPS) is suspected, with the presence of FAS-related diagnostic features.

A definitive diagnosis of ALPS is based on the presence of both required criteria (see below) plus one primary accessory criterion. A probable diagnosis is based on the presence of both required criteria plus one secondary accessory criterion.

The required diagnostic features are:

• chronic (>6 months) non-malignant, non-infectious lymphadenopathy and/or splenomegaly; and
• elevated CD3+ alpha-beta+ CD4- CD8- double-negative T cells (>1.8% of total lymphocytes or >2.5% of CD3+ lymphocytes).

The primary accessory criteria are:

• abnormal FAS-mediated apoptosis; and
• confirmed constitutional (germline) or somatic (tumour) pathogenic genetic variant in FAS, FASLG, FADD or CASP8.

The secondary accessory criteria are:

• elevated plasma sFAS-ligand levels (>200pg/ml);
• elevated plasma IL-10 levels (>20 pg/ml);
• elevated serum or plasma vitamin B12 levels (>1500 pg/ml);
• autoimmune cytopaenia with elevated polyclonal IgG levels;
• positive family history of ALPS; and
• typical immunohistologic features, such as lymph node pathology.

R15 should be used where the broader diagnosis of a lymphoproliferative condition and/or immunodysregulation is suspected.

R19 and R15 testing is typically 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.
• For information about the genes that are included on different gene panels, see the NHS Genomic Medicine Service (GMS) Signed Off Panels Resource.
• For ALPS with suspected FAS-related defective apoptosis, consider:
  • R19 Autoimmune lymphoproliferative syndrome with defective apoptosis (single gene sequencing of FAS).
• For conditions in which the broader diagnosis of autoimmune lymphoproliferation and/or immunodysregulation is suspected, consider:
  • R15 Primary immunodeficiency. 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 R19:
  • 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

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
• Rieux-Laucat F, Magérus-Chatinet A and Neven B. ‘The autoimmune lymphoproliferative syndrome with defective FAS or FAS-ligand functions‘. Journal of Clinical Immunology 2018: volume 38, issue 5, pages 558–568. DOI: 10.1007/s10875-018-0523-x

For patients

• Immunodeficiency UK
• Jeffrey Modell Foundation