Presentation: Clinical suspicion of achondroplasia (postnatal)

You are asked to see a term neonate on the postnatal ward who is noted to have short limbs and a large head. His birth growth parameters were:

• weight: 0 standard deviations (0SD) below the mean (on the 50th centile);
• length: 2.68SD below the mean (on the 0.4th centile); and
• occipital frontal circumference (OFC): 1.92SD above the mean (on the 97th centile).

He is the first child of healthy, unrelated parents of average stature. His father is 45 years old. On examination, he has frontal bossing, a flat midface and rhizomelic (proximal segment) limb shortening with short, broad hands and feet.

You should consider genomic testing if your patient has features suggestive of achondroplasia, which may include those listed below.

• Clinical features:
  • disproportionate short stature (rhizomelic limb shortening);
  • macrocephaly;
  • characteristic facies (frontal bossing, midface retrusion, depressed nasal bridge);
  • bowed legs;
  • brachydactyly; and
  • trident hand configuration.
• There are numerous radiological features that can be suggestive of achondroplasia, including:
  • short tubular bones;
  • rhizomelia; and
  • narrowing of the interpedicular distance of the caudal spine.
• A family history of increased paternal age is often elicited. Achondroplasia is one of a select few genetic conditions in which the paternal age effect is noted.

• 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.
• If you suspect achondroplasia, the correct test to order is:
  • R24 Achondroplasia: This is ‘hotspot’ testing for common FGFR3 gene variants (not sequencing of the whole gene), as 99% of patients with achondroplasia have one of two pathogenic variants: 98% of cases have the 1138G>A (p.Gly380Arg) variant, and 1% have the c.1138G>C (p.Gly380Arg) variant.
• If R24 returns a negative result but suspicion for achondroplasia is still high, you could consider requesting:
  • R382 Hypochondroplasia: This is hypochondroplasia hotspot testing. Some cases of severe hypochondroplasia can overlap with milder cases of achondroplasia.
• If R24 and R382 are negative but achondroplasia is still suspected, discuss further testing options with your laboratory (other options, such as FGFR3 gene Sanger sequencing, may or may not be available in an NHS diagnostic setting).
• If you feel there are other likely diagnoses for the presentation, you may wish to consider the following tests:
  • R104 Skeletal dysplasia: This should be considered if clinical features are indicative of a likely monogenic skeletal dysplasia (the test includes whole genome sequencing (WGS)).
  • R28 Congenital malformation and dysmorphism syndromes – microarray only, or R27 Paediatric disorders: Consider these if your patient has short stature and congenital malformations and/or dysmorphism suggestive of an underlying monogenic disorder, and targeted genomic testing is not possible. Where possible, the chromosomal disorder suspected should be specified on the test request form.
• If a member of the patient’s family already has a known achondroplasia FGFR3 causative variant, cascade testing can be carried out to identify other affected individuals. Testing relatives when the molecular basis is confirmed in the family may not be useful unless there is a clear rationale for doing so – for example, where the clinical diagnosis in the relative is in doubt. In this situation, the laboratory would test for the known familial variant only. First-degree relatives may be eligible for genomic counselling, at which point subsequent testing (R240 Diagnostic testing for known variant(s)) can be arranged.
• For information on non-invasive prenatal testing in at-risk pregnancies due to paternal FGFR3-related skeletal disorder or a previous pregnancy with confirmed FGFR3-related skeletal disorder, see Presentation: Pregnancy in which non-invasive prenatal diagnosis is planned.
• For tests that do not include WGS, including R24, R382, R240, 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

• Genomics England: NHS Genomic Medicine Service (GMS) Signed Off Panels Resource
• National Organization for Rare Disorders: Achondroplasia
• NHS England: National Genomic Test Directory
• Patient Info: Achondroplasia
• Skeletal Dysplasia Group
• Skeletal Dysplasia Management Consortium: Publications

For patients

• 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