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.

• If you suspect achondroplasia, the correct test to order is R24 Achondroplasia.
  • It is worth noting that 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 (hypochondroplasia hotspot testing), as some cases of severe hypochondroplasia can overlap with milder cases of achondroplasia.
• If R382 is also 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.
• 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 mutation(s)) can be arranged.
• For tests that are undertaken using WGS, including R104 and R27, you will need to:
  • complete an NHS Genomic Medicine Service (GMS) test order form with details of the affected child (proband) and their parents, 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);
  • 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 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).
• For tests that do not include WGS, including R24, R382 and R28:
  • you can use your local Genomic Laboratory Hub test order and consent (RoD) 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.
• Both R104 and R27 are large WGS ‘super panels’ (panels comprised of several different constituent panels forming one large panel), and requesting them currently requires authorisation from clinical genetics.
• The majority of tests, including those listed above, are DNA based, so 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 those working within NHS Wales, please consult the All Wales Medical Genomics Service website for information on how to arrange testing.

For clinicians

• Achondroplasia.expert
• 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