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Paediatrics

Presentation: Child with proportionate short stature and no learning difficulties

Most cases of short stature are due to inadequate food intake and/or acquired disease, but a minority will have a genetic cause.

Example clinical scenario

An 18-month-old girl is referred to the paediatric clinic by her health visitor, who is concerned that she has crossed growth chart centiles. She has no learning difficulties and no other medical problems. Her endocrine and faltering growth (baseline investigations) workup was normal. She is proportionally small, with a height of 3.2 standard deviations below the mean (-3.2SD), a head circumference of -1SD and a weight of -2.5SD.

When to consider genomic testing

Genomic testing should be considered if the presentation is non-specific but the child’s height is at least 3SD below the mean (or 2SD bellow the mean and more than 3 centiles below the mid-parental centile).

The above clinical example looked at a child with proportionate short stature and no learning difficulties in whom there is no clinical suspicion of a specific genetic condition. However, it is important to note that in many presentations of short stature there may be a suspicion of a specific condition. Genetic conditions and families of conditions that can present with proportionate short stature and no learning difficulties are listed below.

Genomic testing should be considered for any patient in whom there is a clinical suspicion of one of these conditions.

  • Pituitary causes: Isolated growth hormone deficiency or multiple pituitary hormone deficiency can result in growth retardation and/or multiple endocrine effects.
  • Turner syndrome: This is caused by monosomy X (45,X) karyotype. It can present with short stature in early childhood, or may become apparent later on – for example, a girl may present when she does not enter puberty.
  • Silver-Russell syndrome (SRS): This is caused by disruption of imprinting at the 11p15 chromosome locus. Children with SRS usually have intrauterine growth restriction with relative macrocephaly and may have body asymmetry.
  • Chromosome breakage disorders: These include Fanconi anaemia and Bloom syndrome. Clinical features of these conditions include microcephaly, café-au-lait macules and sun sensitivity. It is particularly important to exclude them if growth hormone therapy is being considered.
  • RASopathies (including Noonan syndrome): Clinical features of this family of diagnoses include facial dysmorphism, normal or high birth weight, early feeding difficulties and cryptorchidism in boys. Intellectual disability can be a feature.
  • Inborn error of metabolism: This is characterised by faltering growth with additional suggestive features such as encephalopathy, metabolic acidosis, hepatomegaly, hypotonia, resistant hypoglycaemia, cataracts, cardiomyopathy, unusual odours, decompensation triggered by illness or fasting and/or positive family history.
  • SHOX deficiency: This is characterised by faltering growth with additional suggestive features such as Madelung deformity (a dinner fork‐like deformity of the wrist), bowing of the forearm, cubitus valgus, dislocation of the ulna at the elbow, a sitting height/height ratio of >0.555, an arm span/height ratio of <0.965 and muscular hypertrophy.
  • Cystic fibrosis: This is characterised by faltering growth with additional suggestive features such as recurrent chest infections, fat malabsorption and a neonatal history of meconium ileus.

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.
    • R453 Monogenic short stature: Should be considered if a child is presenting with non-specific proportionate short stature (<-3SD, or <2SD and 3 centiles bellow mid-parental height) and normal learning. Note that a short stature screen should be completed first to identify non-genetic causes.
    • R88 Severe microcephaly: Should be considered if the presentation includes severe microcephaly.
    • R452 Silver Russell Syndrome and Temple Syndrome: Should be considered if the patient has suggestive features of either condition.
    • R26 Likely common aneuploidy: Should be considered if the patient has features suggestive of Turner syndrome. This test includes the common aneuploidies (trisomy 13, trisomy 18, trisomy 21 and Turner syndrome) but does not include gene sequencing.
    • R52 Short stature – SHOX deficiency: Can be used to specifically test for this in patients with relatively mild disproportionate short stature, particularly affecting the forearms and lower legs. A Madelung deformity may or may not be present.
    • R104 Skeletal dysplasia: Should be considered if there is skeletal disproportion or a skeletal survey suggestive of primary bone pathology. This would typically be ordered with the involvement of a clinical geneticist or radiologist expert in skeletal dysplasias.
    • R27 Paediatric disorders: Should be considered if the short stature is part of a wider syndrome (for example learning difficulties, dysmorphism and/or congenital malformations)
  • For tests that are undertaken using whole genome sequencing (WGS), including R27 and R104, you will need to:
  • For tests that do not include WGS (including R453, R88, R452, R26, R52):
    • you can use your local Genomic Laboratory Hub test order and consent (record of discussion) 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.

Resources

For clinicians

References:

For patients

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  • Last reviewed: 13/09/2024
  • Next review due: 13/09/2025
  • Authors: Dr Benjamin Fisher
  • Reviewers: Dr Amy Frost, Dr Ellie Hay, Dr Emile Hendriks, Dr Joanna Kennedy, Professor Kate Tatton-Brown

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