Presentation: Male child with recurrent infections, eczema and a low platelet count

A one-year-old boy is referred to hospital for evaluation of a petechial rash. He has a history of eczema from two weeks of age. He has had multiple infections, including two recent episodes of otitis media with perforated tympanum on both occasions. A blood film shows microthrombocytopaenia (characteristic low platelet number, volume and size).

• Genomic testing should be considered if the clinical presentation in a male patient is suggestive of Wiskott-Aldrich syndrome. Female carriers are typically unaffected.
• The classic triad of eczema, immunodeficiency and microthrombocytopenia is not always present, and some patients may present with more limited features.
• The diagnosis should be considered in any male with small platelets.
• Limited or absent expression of Wiskott-Aldrich syndrome protein (WASp) supports this diagnosis.

• 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.
• The right test to choose depends on the presenting features, and the degree of diagnostic certainty.
• The gene associated with Wiskott-Aldrich syndrome, WAS, is present on several tests available in the National Genomic Test Directory.
• For male patients with classical features of Wiskott-Aldrich syndrome, consider:
  • R20 Wiskott-Aldrich syndrome (single gene sequencing of WAS).
• For presentations with immunodeficiency with a broader differential diagnosis, consider:
  • R15 Primary immunodeficiency. This will investigate causes of severe combined immunodeficiency. The test includes a whole genome sequencing (WGS) panel of many genes known to cause immune disorders, including WAS.
• For presentations with bleeding/bruising and thrombocytopenia with a broader differential diagnosis, consider:
  • R90 Bleeding and platelet disorders.
• R20, R15 and R90 should typically be requested by immunology, clinical genetics, haematology or gastroenterology teams.
• For tests that do not include WGS, including R20 and R90:
  • 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: WAS-related disorders
• 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 1508–1520. DOI: 10.1007/s10875-022-01352-z

For patients

• Immunodeficiency UK
• Jeffrey Modell Foundation
• PID UK: Patient information sheet (PDF, 6 pages)