Presentation: Clinical suspicion of Bloom syndrome

An 18-month-old girl is referred to the paediatric clinic by her GP because of short stature, slow weight gain, recurrent ear infections, sun sensitivity and a facial rash. She was monitored in pregnancy for poor growth. Development to date has been normal.

You should consider investigating for Bloom syndrome if a child presents with the following:

• Growth deficiency:
  • prenatal onset and symmetrical (height, weight, head circumference); and
  • over two standard deviations (2SD) below the mean in infancy, childhood and adulthood.
• Suggestive skin changes:
  • sun sensitivity resulting in erythematous rash over the face (butterfly distribution) and, in some, the hands, arms and neck; and
  • areas of skin hyperpigmentation and hypopigmentation in no specific distribution.
• Recurrent infections:
  • upper respiratory tract infections;
  • ear infections; and
  • lung infections.
• Early-onset cancers:
  • leukaemia;
  • lymphoma;
  • skin cancer; and
  • gastrointestinal tract cancers.
• Other:
  • insulin resistance;
  • diabetes;
  • chronic obstructive pulmonary disease; and
  • subtly distinctive facial appearance:
    • malar/mandibular underdevelopment;
    • micrognathia; and
    • paucity of subcutaneous fat;
• Ashkanazi Jewish heritage:
  • The incidence is higher in this population due to a founder mutation. In 2020, one third of those on the Bloom syndrome registry were of Ashkanazi Jewish descent.

• 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 those working within NHS Wales, please consult the All Wales Medical Genomics Service website for information on how to arrange testing.
• 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. This will be determined in part by your confidence in the clinical diagnosis and presenting features.
  • R260 Fanconi anaemia or Bloom syndrome (chromosome breakage testing): This should be undertaken if there is a strong suspicion of Bloom syndrome or Fanconi anaemia. It is not a genomic sequencing test but instead looks for DNA repair defects . The test cannot currently be requested directly by paediatrics, and should therefore be discussed with clinical genetics or haematology.
  • R229 Confirmed Fanconi anaemia or Bloom syndrome (mutation testing): This should be undertaken if chromosome breakage analysis supports the diagnosis of Bloom syndrome and molecular confirmation is required. The test comprises gene panel sequencing and multiplex ligation-dependent probe amplification (MLPA) for a small number of genes known to cause Fanconi anaemia and Bloom syndrome.
  • R258 Cytopenia (Fanconi breakage testing indicated): This should be considered if the main findings are recurrent infections with persistent or recurrent bicytopenia or pancytopenia. Analysis includes both DNA repair defect testing and sequencing and copy number variant analysis of a panel of associated genes.
  • R27 Paediatric disorders: This throws the net much more widely and investigates chromosomal and single gene causes of congenital malformations and dysmorphism syndromes. You should consider R27 if you are less certain of the clinical diagnosis of Bloom syndrome. Analysis is through whole genome sequencing (WGS), ideally with samples from both parents and child (trio testing).
• For tests that are undertaken using WGS, including R27, 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 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 R260, R229 and R258:
  • 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 (purple-topped tube) is required. Exceptions include karyotype testing and DNA repair defect testing (for chromosome breakage), which require lithium heparin (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

• GeneReviews: Bloom syndrome
• Genomics England: NHS Genomic Medicine Service (GMS) Signed Off Panels Resource
• NHS England: National Genomic Test Directory
• Weill Cornell Medicine (Pediatrics): Bloom syndrome registry

For patients

• Bloom Syndrome Association
• Child Growth Foundation