Presentation: Child with proportionate short stature and no learning difficulties

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.

Genomic testing should be considered if the presentation is non-specific but the child’s height is over three standard deviations below the mean (less than -3SD).

In this clinical example, we are looking 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 or 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.
  • See Presentation: A child with multiple pituitary deficiency.
• 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.
  • See Clinical suspicion of Turner syndrome.
• 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.
  • See Clinical suspicion of Silver-Russell syndrome.
• 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.
  • See Clinical suspicion of Fanconi anaemia and Clinical suspicion of Bloom syndrome.
• RASopathies (including Noonan syndrome): Clinical features of this family of diagnoses include normal or high birth weight, early feeding difficulties and cryptorchidism in boys.
  • See Clinical suspicion of Noonan syndrome.
• 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 greater than 0.555, an arm span / height ratio of less than 0.965, and muscular hypertrophy.
  • See Clinical suspicion of SHOX deficiency.
• 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.
  • See Clinical suspicion of cystic fibrosis.

• 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 a child is presenting with non-specific proportionate short stature (less than -3SD) and normal learning, consider:
    • R147 Growth failure in early childhood;
    • R26.1 (Likely common aneuploidy testing) for Turner syndrome: This test includes the common aneuploidies (trisomy 13, trisomy 18, trisomy 21 and Turner syndrome) but does not include gene sequencing; and/or
    • R52.1 (short stature-SHOX deficiency): R52.1 is for microarray only, and looks for SHOX dosage abnormalities; R52.2 is for SHOX sequencing, and would not be requested unless the child had disproportionate short stature and/or a Madelung deformity.
  • Currently none of the above test indications (R147, R26.1 or R52.1) are undertaken through whole genome sequencing (WGS). For tests that do not include WGS:
    • 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 (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

• British Inherited Metabolic Diseases Group
• Genomics England: NHS Genomic Medicine Service (GMS) Signed Off Panels Resource
• NHS England: National Genomic Test Directory

References:

• Rabago J, Marra K, Allmendinger N and others. ‘The clinical geneticist and the evaluation of failure to thrive versus failure to feed’. American Journal of Medical Genetics Part C: Seminars in Medical Genetics 2015: volume 169, issue 4, pages 337–348. DOI: 10.1002/ajmg.c.31465
• Rappold G, Blum WF, Shavrikova EP and others. ‘Genotypes and phenotypes in children with short stature: Clinical indicators of SHOX haploinsufficiency’. Journal of Medical Genetics 2007: volume 44, issue 5, pages 306–313. DOI: 10.1136/jmg.2006.046581

For patients

• Child Growth Foundation
• Down’s Syndrome Association
• Turner Syndrome Support Society
• Silver Russell Syndrome
• Noonan Syndrome Association
• Cystic Fibrosis Trust