Presentation: Child with pancytopenia

A six-year-old girls is seen in the emergency department for bruising. Her full blood count reveals a total white cell count of 1.2×10⁹/L, a platelet count of 12×10⁹/L and a haemoglobin count of 80g/L. These values are corroborated by repeat testing.

On taking the history, you note she had a ventricular septal defect as a neonate. Examination findings include widely spaced eyes, seven café-au-lait spots and a head circumference on the 0.4th centile.

Children with pancytopenia should be referred to a paediatric haematologist for further investigation and management. Genomic testing is typically guided by the paediatric haematology team, prior to definitive management (such as stem cell transplantation), for the following indications:

• persistent pancytopenia with no other established cause;
• dysmorphism in keeping with an underlying genetic diagnosis;
• a family history of relevant genetic haematological problems or cancer syndromes; and
• childhood tumours, the presence of which raises the possibility of a chromosomal instability disorder such as Fanconi anaemia, Bloom syndrome, ataxia telangiectasia, xeroderma pigmentosum or Nijmegen breakage syndrome.

• Consult the National Genomic Test Directory. From here you can access the rare and inherited disease eligibility criteria for information about individual tests and their associated eligibility criteria. You can also access a spreadsheet 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 or family. For haematological disorders there are a number of available panels, including:
  • R91 Cytopenia – NOT Fanconi anaemia: Consider this where there is persistent or recurrent cytopenia or where there is pancytopenia of unknown cause and Fanconi anaemia is unlikely (for example unexplained isolated aplastic anaemia, thrombocytopenia or neutropenia);
  • R260 Fanconi anaemia or Bloom syndrome – chromosome breakage testing (or R258.1): Consider this where there are clinical features strongly suggestive of Fanconi anaemia or Bloom syndrome. This is not a genomic test and has specific sample requirements as outlined below.
  • R258 Cytopenia – Fanconi breakage testing indicated: This request includes indications for chromosome breakage (test R258.1) and genomic testing through a small panel and multiplex ligation-dependent probe amplification analysis (R258.2 and R258.3 respectively) and is for those clinically suspected to have Fanconi syndrome.
  • R229 Confirmed Fanconi anaemia or Bloom syndrome – variant testing: Consider this where chromosome breakage testing is suggestive of either diagnosis and molecular confirmation of the specific variants is required.
  • R259 Nijmegen breakage syndrome: Consider this where there are clinical features characteristic of Nijmegen breakage syndrome.
  • R294 Ataxia telangiectasia – DNA repair defect testing: Consider this where ataxia telangiectasia is suspected clinically. This is not a genomic test and has specific sample requirements as outlined below. See also: Presentation: Clinical suspicion of ataxia telangiectasia.
  • R295 Ataxia telangiectasia – variant testing: Consider this where DNA repair defect testing is suggestive of ataxia telangiectasia and molecular confirmation of the specific variants is required.
  • R227 Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome: Consider this where there is a confident clinical diagnosis of each condition. Skin biopsy for complementation testing (specialist DNA repair test) is likely to be required in many patients to confirm the results of the panel test; this can be carried out in parallel with or after the genetic panel test, usually as part of assessment in the highly specialised service for xeroderma pigmentosum.
  • R27 Paediatric disorders: This should be requested for patients with wider congenital malformations, dysmorphism or other complex or syndromic presentations. Additional panels, including those above, can be added to the trio analysis.
• For tests that are undertaken using whole genome sequencing (WGS), including R27, you will need to:
  • complete an NHS Genomic Medicine Service test order form with details of the affected individual (proband) and their parents where available, 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 whole genome sequencing for support in completing WGS-specific forms); and
  • complete an NHS Genomic Medicine Service record of discussion (RoD) form for each person being tested – for example, if you are undertaking trio testing of an affected individual 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 (this is trio testing) 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).
• For tests that do not include WGS, including R91, R258, R260, R229, R259, R294, R295 and R227:
  • you can use your local Genomic Laboratory Hub (GLH) test order and consent (record of discussion) 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.
• Most tests are DNA based, and an EDTA sample (typically a purple-topped tube) is required. Exceptions include karyotype testing and DNA repair defect testing (for chromosome breakage), which require lithium heparin (typically a green-topped tube). For more information, see Samples for genomic testing in rare disease.
• R260, R258.1 and R294 peripheral blood samples must be sent in a lithium heparin bottle and should arrive within 72 hours (preferably 24 hours) of sampling. The samples should neither be spun down nor frozen prior to sending.
• R27 is an amalgamation of more than 10 panels of genes known to be associated with a broad range of paediatric developmental disorders. It may now be ordered directly by paediatricians, though a discussion with clinical genetics services may be beneficial.
• 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
• National Organization for Rare Disorders: Fanconi anaemia
• NHS England: National Genomic Test Directory
• Patient Info: Fanconi’s anaemia

References:

• Samarasinghe S, Veys P, Vora A and Wynn R. ‘Paediatric amendment to adult BSH guidelines for aplastic anaemia’. British Journal of Haematology 2017: volume 180, issue 2, pages 201–205. DOI: 10.1111/bjh.15066

For patients

• NHS England: Whole genome sequencing patient information
• The Aplastic Anaemia Trust: Fanconi anaemia