Presentation: Child with pancytopenia

A family attends the emergency department with their six-year-old daughter. They have been urgently referred by an out-of-hours GP service because a full blood count (undertaken due to the child’s easy bruising) has revealed 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 her patient history, you note that she had a ventricular septal defect as a neonate. On examination, you find that her head circumference is on the 0.4th centile, that she has widely spaced eyes and that she has seven café-au-lait spots on her trunk.

Children with pancytopenia should be referred to a paediatric haematologist for further investigation and management. Genomic testing should be requested 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, which provides 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 our dedicated Knowledge Hub resource.
• To find out which genes 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;
  • R258 Cytopenia – Fanconi breakage testing indicated, and R260 Fanconi anaemia or Bloom syndrome – chromosome breakage testing;
  • R229 Confirmed Fanconi anaemia or Bloom syndrome – variant testing;
  • R259 Nijmegen breakage syndrome;
  • R294 Ataxia telangiectasia – DNA repair testing;
  • R227 Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome; and
  • R27 Paediatric disorders or R89 Ultra-rare and atypical monogenic disorders: These tests should be requested for patients with congenital malformations, dysmorphism or other complex or syndromic presentations.
• For tests that are undertaken using whole genome sequencing (WGS), including R27 and R89, you will need to:
  • complete an NHS GMS test order form with details of the affected child (proband) and 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 record of discussion (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 (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 and R227:
  • you can use your local Genomic Laboratory Hub test order and consent (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.
• The majority of 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).
• R27 is a large WGS ‘super panel’ (a panel comprised of several different constituent panels forming one large panel), and requesting it currently requires authorisation from clinical genetics.
• 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

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