Presentation: Child with lymphoedema

A baby girl is born with bilateral swelling of the dorsum of the feet. The pregnancy was uncomplicated and she is otherwise clinically well, with no significant congenital malformations. On subsequent review, when the child is six months old, the bilateral oedema has progressed.

• You should consider genomic testing if the patient has features consistent with lymphoedema with no known explanation or secondary cause, with or without syndromic manifestations.
• Testing should be carried out in parallel with expert phenotypic assessment – for example, in the specialist lymphoedema services in Derby or at St George’s Hospital in London.

• 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 containing details of all available tests.
• To find out which genes are included on different gene panels, see the NHS Genomic Medicine Service (GMS) Signed Off Panels Resource.
• If the relevant eligibility criteria are met, discuss the case with or refer it to your local specialist lymphoedema service for further investigations (such as lymphoscintigraphy) and management, and to discuss genomic testing. You will need to provide details confirming that the patient fulfils the eligibility criteria.
• Genomic investigations for primary lymphoedema include:
  • R136 Primary lymphoedema: This indication is used when patients present with primary lymphoedema of unknown aetiology, with or without syndromic features. It includes whole exome sequencing or gene panel sequencing (medium panel) to detect small variants, plus multiplex ligation-dependent probe amplification (MLPA) or equivalent to detect copy number variants.
• In patients presenting with asymmetric or localised involvement suggestive of somatic mosaicism, genomic testing of a biopsy of affected tissue may be appropriate following discussion with a specialist lymphoedema service.
  • R26 Likely common aneuploidy: This indication should be used for patients presenting with features that are consistent with Turner syndrome. This test is performed by QF-PCR, with confirmation of results by karyotype if atypical.
• Where lymphoedema is one of multiple features of a complex multi-system condition, consider discussing with clinical genetics whether broader testing may be indicated. For example:
  • R27 Paediatric disorders: This indication involves whole genome sequencing (WGS) and microarray.
• The majority of genomic tests for primary lymphoedema are currently undertaken on a singleton basis, although samples may be needed from additional family members in order to interpret results.
• For WGS testing, parental samples would ideally be submitted alongside the patient sample (this is trio testing). Where this is not possible (for example, because the child is in care or a parent is unavailable for testing), the proband may be tested as a singleton.
• It may be helpful to take blood samples and store DNA pending referral to a specialist lymphoedema or clinical genetics service. Forms for DNA storage are available from your local clinical genetics service or Genomic Laboratory Hub (GLH).
• For tests that are undertaken using WGS:
  • complete an NHS GMS test order form with details of the 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); and
  • complete an NHS GMS record of discussion 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 of these forms (see How to complete a record of discussion form for support).
• For tests that do not include WGS, you will need to:
  • complete a test order form and consent (record of discussion) form, available from your local GLH; and
  • include details of the phenotype in the test order form (refer to HPO terms or the clinical summary) as well as the appropriate panel name(s) with associated R number.
• The majority of the above tests (including DNA storage) are DNA based, and an EDTA sample (purple-topped tube) is required.
• In patients with features suggestive of Turner syndrome, consider sending an additional sample in lithium heparin (green-topped tube) in parallel, in case confirmation of diagnosis by karyotype is required.
• 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

• Lymphatic Education & Research Network: St George’s University Hospitals national lymphoedema clinic
• Lymphatic Education & Research Network: Royal Derby Hospital lymphoedema service
• NHS England: National Genomic Test Directory

For patients

• The Lymphoedema Support Network
• NHS Health A to Z: Lymphoedema