Presentation: Child with suspected skeletal dysplasia

You are asked to see a three-year-old child with disproportionate short stature with height at 3.2 standard deviations (SD) below the mean (<0.4th centile), patellar dislocations and dysmorphic facies. His birth parameters were:

• weight: 0.67SD below the mean (25th centile);
• length: 2.01SD below the mean (2nd centile); and
• occipital frontal circumference (OFC): 1.05SD below the mean (15th centile).

His parents are both of average stature. On examination, he has frontal bossing, mesomelic (middle-segment) limb shortening, misaligned patellae and brachydactyly of the fingers and toes.

• The clinical and radiological features of skeletal dysplasia disorders are wide and varied, with significant overlap. For an overview of the key features suggestive of a skeletal dysplasia, see When to suspect a skeletal dysplasia as a cause of short stature.
• Specific terminology is used to classify skeletal dysplasia disorders. For further details, see ​Key terminology for skeletal dysplasia conditions.
• Radiological imaging is an important first line of investigation to aid clinical diagnosis. Often, a skeletal survey is warranted (see How to request a skeletal survey for support). However, where there is a strong suspicion of a particular diagnosis, radiological imaging may be deferred or targeted, and genomic investigation may be considered first – for example, if achondroplasia is suspected.
• If there is high suspicion of a specific skeletal dysplasia (such as achondroplasia, hypochondroplasia, cleidocranial dysplasia, apert syndrome, multiple exostoses or Leri-Weill dyschondrosteosis), single gene testing may be available.
• If a heterogeneous condition is suspected (such as osteogenesis imperfecta), a small panel of genes may be appropriate.
• If the differential diagnosis covers a broad group of conditions that do not have a panel test, or is non-specific, then the skeletal dysplasia panel (R104 Skeletal dysplasia) via whole genome sequencing (WGS) may be appropriate.

In some cases, when a patient presents with features suggestive of a skeletal dysplasia, there may be a suspicion of a specific clinical syndrome. Some of these syndromes are listed below.

• Achondroplasia: Consider achondroplasia in presentations of short stature (pre- and postnatal) with bowed legs, macrocephaly, frontal bossing, midface retrusion, depressed nasal bridge, trident hand configuration, rhizomelia, narrowing of the interpedicular distance of the caudal spine, horizontal acetabula, proximal fibula elongation and/or mild, generalised metaphyseal changes. R24 Achondroplasia testing would be indicated.
  • See Presentation: Clinical suspicion of achondroplasia (postnatal).
• Hypochondroplasia: Consider hypochondroplasia in presentations of short stature with minimal clinico-radiological findings of achondroplasia. R382 Hypochondroplasia testing would be indicated.
  • See Presentation: Clinical suspicion of hypochondroplasia.
• Leri-Weill dyschondrosteosis (LWD) and/or SHOX-related conditions: Consider LWD and/or SHOX-related conditions in presentations of short stature with mesomelia and or Madelung deformity (a dinner fork‐like deformity of the wrist). Additional features include forearm bowing and cubitus valgus. R52 Short stature – SHOX deficiency testing would be indicated (the test includes dosage analysis, looking for small deletions or duplications of genetic material, which is a common genetic mechanism in SHOX-related conditions).
  • See Presentation: Clinical suspicion of SHOX deficiency.
• Osteogenesis imperfecta (OI): Consider OI in the context of fractures associated with minimal or no trauma and short stature. Additional features include bowing of long bones, blue sclera, atypical dentition (dentinogenesis imperfecta), hypermobility and hearing loss (post-pubertal). Radiological features include fractures, wormian bones, ‘codfish’ vertebrae, low bone mass and protrusio acetabuli. If OI is suspected, R102 Osteogenesis imperfecta testing may be indicated.
  • See Presentation: Clinical suspicion of osteogenesis imperfecta.
• Hereditary multiple exostoses (HME), also known as hereditary multiple osteochondromatosis (HMO): Consider HME if the presentation includes multiple bony growths (exostoses) with or without short stature, or a family history. R390 Multiple exostoses testing would be indicated.
  • See Presentation: Clinical suspicion of hereditary multiple exostoses.

• 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 tests best suit the needs of your patient or family.
  • For skeletal dysplasia conditions there are a number of available options.
  • For further details about testing for specific syndromes, please see the condition-specific resources detailed above.
• If the differential diagnosis covers a broad group of conditions that do not have a panel test, or is non-specific, consider:
  • R104 Skeletal dysplasia: This involves WGS. Requesting R104 currently requires clinical genetics approval.
  • Some specific skeletal dysplasia conditions are caused by one or a handful of genes but are only accessible through the R104 panel.
• If height is over 3SD below the mean at the age of two years or older in the absence of microcephaly, consider:
  • R453 Monogenic short stature. This involves whole exome sequencing or medium panel sequencing. See Presentation: Child with proportionate short stature and no learning difficulties.
• For tests that do not include WGS, including R453:
  • 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. Consent is not required for DNA storage alone, only to initiate testing.
• For tests that are undertaken using WGS, including 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); and
  • complete an NHS GMS 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 RoD 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).
• 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

• Genomics England: NHS Genomic Medicine Service (GMS) Signed Off Panels Resource
• NICE: Human growth hormone (somatropin) for the treatment of growth failure in children
• NHS England: National Genomic Test Directory
• Skeletal Dysplasia Group (promotes teaching and research)
• Skeletal Dysplasia Management Consortium: Publications

For patients

• Brittle Bone Society
• Child Growth Foundation
• 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