Presentation: Clinical suspicion of SHOX deficiency

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.

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.

• 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.
• For information about the genes that 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 multidisciplinary team (MDT) meeting.
  • 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 Presentation: 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 R28 where possible, the chromosomal disorder suspected should be specified on the test request form.
• For tests that do not include whole genome sequencing (WGS), including R52, R240, R159 and R28:
  • 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 R104 and R27, you will need to:
  • complete an NHS Genomic Medicine Service 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 Whole Genome Sequencing for support in completing WGS-specific forms); and
  • complete an NHS Genomic Medicine Service record of discussion (RoD) form for each person being tested – for example, if you are undertaking trio testing of an affected individual 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 more than 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. Requesting R104 currently requires clinical genetics approval.
• Most tests are DNA based, and an EDTA sample (typically a purple-topped tube) is required. There are a few tests for which a different type of tube is used; 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

• GeneReviews: SHOX deficiency disorders
• Genomics England: NHS Genomic Medicine Service (GMS) Signed Off Panels Resource
• NHS England: National Genomic Test Directory
• Skeletal Dysplasia Group
• Skeletal Dysplasia Management Consortium: Publications

References:

• Binder G. ‘Short stature due to SHOX deficiency: Genotype, phenotype and therapy’. Hormone Research in Paediatrics 2011: volume 75, issue 2, pages 81–89. DOI: 10.1159/000324105

For patients

• Child Growth Foundation: SHOX deficiency
• Dwarf Sports Association UK
• Level Water (UK charity that promotes swimming for disabled children)
• Little People UK
• Remap (UK charity that custom-makes equipment for disabled people)
• Restricted Growth Association