Presentation: Clinical suspicion of tuberous sclerosis complex

During a third-trimester growth scan, multiple rhabdomyomas are detected in a fetus. Subsequent examination of the clinically unaffected mother identifies multiple hypomelanotic macules (‘ash leaf’ spots), and an abdominal ultrasound reveals an angiomyolipoma.

Typically, testing for tuberous sclerosis complex (TSC) should be targeted to patients with one or more major clinical features, or two or more minor clinical features, from the list below.

Major features:

• hypomelanotic macules, at least three of at least five millimetres in diameter (a Wood’s light may help to visualise these);
• angiofibromas (at least three) or fibrous cephalic plaque;
• ungual fibromas (at least two);
• shagreen patch;
• multiple retinal hamartomas;
• cortical dysplasias such as multiple cortical tubers and/or cerebral white matter radial migration lines;
• subependymal nodules;
• subependymal giant cell astrocytoma;
• cardiac rhabdomyoma(s);
• lymphangioleiomyomatosis (LAM); and
• angiomyolipomas (AML) (at least two).
  • Note that LAM and AML cannot be used in isolation in making a clinical diagnosis of TSC, because they may arise as isolated findings without systemic features.

Minor features:

• confetti skin lesions;
• dental enamel pits (at least three);
• intraoral fibromas (at least two);
• retinal achromic patch;
• multiple renal cysts;
• non-renal hamartomas; and
• sclerotic bone lesions.

• 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. If TSC is strongly suspected, the following panel should be considered:
  • R228 Tuberous sclerosis: This includes TSC1 and TSC2 testing via a small panel and multiplex ligation-dependent probe amplification (MLPA) as standard.
    • Note that in around 15% of those with a clinical diagnosis, no pathogenic variants are identified in either TSC1 or TSC2.
    • As some of these individuals may be mosaic, deep sequencing of blood (R228.3) is subsequently performed. Alternatively, another (ideally affected) tissue (such as a facial angiofibroma or skin biopsy) may be considered for testing.
  • Depending on the features of the child, wider testing may be considered, including:
    • R29 Intellectual disability: This should be considered if there is developmental delay or intellectual disability and you would like to investigate chromosomal and single-gene causes. The test includes microarray and a whole genome sequencing (WGS) panel of all genes known to cause intellectual disability.
      • You may wish to consult: Presentation: A child with developmental delay or intellectual disability.
  • Alternative testing options (listed below) may need to be requested via a paediatric subspecialist (such as paediatric neurology or dermatology) or through discussion with clinical genetics.
    • R27 Paediatric disorders: This should be considered if there is developmental delay or intellectual disability in association with congenital malformation or overgrowth, and you would like to investigate chromosomal and single-gene causes. The test includes microarray and a WGS ‘super panel’ (a panel comprised of several different constituent panels forming one large panel), and requesting it currently requires authorisation from clinical genetics.
    • R59 Early onset or syndromic epilepsy: This investigates unexplained epilepsy where there is clinical suspicion of a monogenic cause. The test includes microarray and a WGS panel of genes.
    • R236 Pigmentary skin disorders: This investigates a range of skin pigmentation. The test includes whole exome sequencing or a large panel of genes and may include MLPA.
  • For tests that do not include WGS, including R228 and R236:
    • 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.
  • For tests that are undertaken using WGS, including R29, R27 and R59, 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).
  • 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).
• 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

• DermNet: Tuberous sclerosis
• GeneReviews: Tuberous sclerosis complex
• Genomics England: NHS Genomic Medicine Service (GMS) Signed Off Panels Resource
• NHS England: National Genomic Test Directory
• Tuberous Sclerosis Association: UK clinical guidelines for TSC
• UpToDate: Tuberous sclerosis complex: Genetics, clinical features, and diagnosis

References:

• Amin S, Kingswood JC, Bolton PF and others. ‘The UK guidelines for management and surveillance of tuberous sclerosis complex’. Quarterly Journal of Medicine 2018: volume 112, issue 3, pages 171–182. DOI: 1093/qjmed/hcy215
• Firth HV and Hurst JA. ‘Oxford Desk Reference: Clinical Genetics and Genomics, second edition’. Oxford University Press 2017: pages 534–537. DOI: 10.1093/med/9780199557509.003.0003
• Northrup H, Aronow ME, Bebin EM and others. ‘Updated international tuberous sclerosis complex diagnostic criteria and surveillance and management recommendations’. Pediatric Neurology 2021: volume 123, pages 50–66. DOI: 10.1016/j.pediatrneurol.2021.07.011

For patients

• NHS Health A to Z: Tuberous sclerosis
• Tuberous Sclerosis Association