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Example clinical scenario

A seven-year-old girl is referred to the paediatric clinic by her GP because of short stature. Her height is 2.68 standard deviations (2.68SD) below the mean (at the 0.4th centile), with no cause yet identified. There are no developmental concerns. Her mother, maternal uncle and maternal grandfather are also short in stature. You note that her forearms and lower legs are especially short.

When to consider genomic testing

You should consider genomic testing if your patient has disproportionate short stature with features (apparent in either the patient or their relatives) suggestive of SHOX deficiency. These may include:

  • short forearms and lower legs (mesomelic shortening);
  • Madelung deformity of the wrist (more common in women and presents in mid- to late childhood); and
  • an apparent autosomal dominant pattern of inheritance.

You can also consider testing in a child with isolated short stature without disproportion, in whom you suspect a genetic cause. Clues to a genetic cause would include an apparent autosomal dominant pattern and/or no obvious alternative cause.

What do you need to do?

  • 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.
  • 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.
    • R52 Short stature – SHOX deficiency. This is a single gene test that looks for variants affecting the SHOX gene only, and also includes multiplex ligation-dependent probe amplification (MLPA) to identify exon-level copy number variants.
    • R240 Diagnostic testing for known variant(s): This should be considered if a member of the patient’s family already has a known SHOX variant. In this situation, cascade testing should be offered to first-degree relatives and the laboratory will only test for the known familial variant.
  • If you feel that there are other likely diagnoses for short stature, or if SHOX testing is negative, you may also wish to consider the tests listed below.
    • R453 Monogenic short stature: This should be considered if a patient’s height is more than three standard deviations (3SD) below the mean at the age of at least two years in the absence of microcephaly, with a normal short-stature screen. Testing may also be considered where a patient’s height is 2SD to 3SD below the mean at the age of at least two years in the absence of microcephaly, though the child’s height should be 3SD below mid-parental-height centile and testing should be discussed at a specialist MDT.
    • R452 Silver Russell syndrome and Temple syndrome: This should be considered if clinical features are strongly indicative of Silver-Russell syndrome or Temple syndrome.
    • R159 Pituitary hormone deficiency: This should be considered if more than one pituitary hormone is deficient.
    • R104 Skeletal dysplasia: This should be considered if clinical features are indicative of a likely monogenic skeletal dysplasia. See Child with suspected skeletal dysplasia.
    • R28 Congenital malformation and dysmorphism syndromes – microarray only, or R27 Paediatric disorders: These 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. R27 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 R104 and R27, you will need to:
  • For tests that do not include WGS, including R52, R240, R147, R159 and R28:
    • 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, including those listed above, are DNA based, so an EDTA sample (typically a purple-topped tube) is required.
  • R27 is a large WGS super panel, and requesting it currently requires authorisation from clinical genetics. Requesting R104 also currently requires clinical genetics approval.
  • 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.

Resources

For clinicians

References:

For patients

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  • Last reviewed: 27/06/2024
  • Next review due: 27/06/2025
  • Authors: Dr Joanna Kennedy
  • Reviewers: Dr Danielle Bogue, Dr Amy Frost, Dr Ellie Hay, Dr Emile Hendriks, Dr Ataf Sabir