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 -1.0SD and a weight of -2.5SD.

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.
  • 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 Presentation: 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 Presentation: 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 Presentation: Clinical suspicion of Fanconi anaemia and Presentation: Clinical suspicion of Bloom syndrome.
• 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.
  • See Presentation: 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 >0.555, an arm span/height ratio of <0.965 and muscular hypertrophy.
  • See Presentation: 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 Presentation: Clinical suspicion of cystic fibrosis.

• 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 of all available tests.
  • For information about how to arrange testing in Wales, Scotland or Northern Ireland, see Genomic testing in the devolved nations.
• 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 with expertise 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 do not include whole genome sequencing (WGS), including R453, R452, R26 and R52:
  • you can use your local Genomic Laboratory Hub (GLH) 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.
• For tests that are undertaken using WGS, including R27, R88 and R104, you will need to:
  • complete an NHS GMS test order form with details of the affected individual (proband) and their parents where available, 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 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).
• R27 is an amalgamation of over 10 panels of genes known to be associated with a broad range of paediatric developmental disorders. It may now be ordered directly by paediatricians, though a discussion with clinical genetics services may be beneficial.
• Most 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). For more information, see Samples for genomic testing in rare disease.
• If you are discussing genomics concepts with your patients, you may find it helpful to use the visual communication aids for genomics conversations.
• 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 Shur N. ‘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
• Cystic Fibrosis Trust
• Noonan Syndrome Association
• Silver Russell Syndrome
• Turner Syndrome Support Society