Presentation: Clinical suspicion of Fanconi anaemia

A nine-month-old girl is referred to the paediatric clinic by her GP because of short stature, relatively small head size, multiple café-au-lait macules and a smaller left thumb. She was born small for gestational age. Development to date has been normal.

You should consider investigating for Fanconi anaemia if a child presents with any of the clinical features listed below.

• Physical characteristics:
• • Prenatal and/or postnatal short stature with or without microcephaly.
  • Unusual skin pigmentation (such as multiple café-au-lait macules, generalised hyperpigmentation or areas of hypopigmentation).
  • Unilateral or bilateral limb skeletal anomalies (commonly radial ray anomalies such as absent, hypoplastic or bifid thumbs and hypoplastic or absent radii).
  • Genitourinary anomalies (such as horseshoe or ectopic kidney, hypospadias or bicornuate uterus).
  • Endocrine disorders (such as hypothyroidism or impaired glucose tolerance).
  • Ophthalmic anomalies (such as microphthalmia, cataracts or strabismus).
  • Less commonly: Congenital heart disease, hearing loss, gastrointestinal anomalies, developmental delay or intellectual disability (around 10% of cases).
• Clinical or haematological suggestion of bone marrow impairment (the average age of onset is seven to eight years), including:
  • thrombocytopenia: Presenting with easy bruising, petechiae and/or nose bleeds;
  • leukopenia: Either presenting with recurrent infections or presenting incidentally on full blood count; and/or
  • anaemia: May be preceded by increased fetal haemoglobin, pallor and/or fatigue.
• Early onset malignancies (more commonly found from adolescence onwards):
  • acute myelogenous leukaemia; and/or
  • solid tumours (head and neck squamous cell carcinoma, skin, genitourinary).

• 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:
  • R260 Fanconi anaemia or Bloom syndrome – chromosome breakage testing: Should be undertaken if clinical features are suggestive of Fanconi anaemia or Bloom syndrome (this is not a genomic sequencing test but instead looks for DNA repair defects);
  • R229 Confirmed Fanconi anaemia or Bloom syndrome – variant testing: Should be undertaken if chromosome breakage analysis supports the diagnosis of Fanconi anaemia and molecular confirmation is required (this test comprises gene panel sequencing for a small number of genes known to cause Fanconi anaemia);
  • R258 Cytopenia – Fanconi breakage testing indicated: Should be considered if the main findings are haematological (persistent or recurrent bi- or pancytopenia). Analysis includes DNA repair testing, DNA sequencing and multiplex ligation-dependent probe amplification (MLPA) analysis of a panel of associated genes; or
  • R27 Paediatric disorders: Should be considered if the clinical features are less specific. For instance there could be developmental delay or intellectual disability in association with congenital malformation or overgrowth. This test is a whole genome sequencing (WGS) ‘super panel’ (a panel comprised of several different constituent panels forming one large panel).
• 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, include 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 parent is unavailable for testing, the child may be submitted as a singleton).
  • R27 is a large WGS ‘super panel’ that currently requires authorisation from clinical genetics to request.
• 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 (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).
• 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: Fanconi anaemia
• 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

For patients

• Child Growth Foundation
• Fanconi Anemia Research Fund
• Fanconi Hope
• NHS England: Whole genome sequencing patient information leaflets