Presentation: Clinical suspicion of hypochondroplasia

A three-year-old-girl presents with a large head, short limbs relative to her trunk and mildly bowed legs. Her growth parameters were:

• weight: 1.34 standard deviations (1.34SD) above the mean (on the 91st centile);
• height: 0SD (on the 50th centile); and
• occipital frontal circumference (OFC): 3SD above the mean (above the 99.6th centile).

She is the first child of healthy, unrelated parents of average stature. Her mother is 33 years old and her father is 40 years old.

You should consider genomic testing if your patient has clinical features strongly suggestive of hypochondroplasia, which may include:

• shortening of the proximal (rhizomelia) or middle (mesomelia) segments of the limbs;
• short stature (often 2–3SD below the mean, though it can be milder), or normal stature with limb-trunk disproportion;
• relative macrocephaly;
• joint laxity (often mild);
• broad hands and feet with brachydactyly (short digits); and
• less commonly:
  • lumbar lordosis;
  • scoliosis;
  • mild to moderate intellectual disability;
  • temporal lobe epilepsy;
  • adult-onset osteoarthritis; and
  • acanthosis nigricans.
• Radiological features include:
  • brachydactyly;
  • short long bones with metaphyseal flare;
  • shortened squared ilia;
  • short, broad femoral neck; and
  • narrowed inferior lumbar interpedicular distances.

Antenatal scans can show a short femur or shortened long bones in some cases.

• Consult the National Genomic Test Directory. From here you can access the rare and inherited disease eligibility criteria, which provides information about individual tests and their associated eligibility criteria. You can also access a spreadsheet containing details of all available tests.
  • For those working within NHS Wales, please consult the All Wales Medical Genomics Service website for information on how to arrange testing.
• To find out which genes are included on different gene panels, see the NHS Genomic Medicine Service (GMS) Signed Off Panels Resource.
• If you suspect hypochondroplasia, the correct test to order is:
  • R382 Hypochondroplasia: This is targeted testing for the most common FGFR3 gene causative variants (rather than sequencing of the whole gene).
• If R382 is negative but hypochondroplasia 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. See Child with suspected skeletal dysplasia and When to suspect a skeletal dysplasia as a cause of short stature.
  • 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 family member already has a known hypochondroplasia 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 will 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.
• Requesting R104 and R27 requires authorisation from clinical genetics. R27 is a large whole genome sequencing (WGS) ‘super-panel’ (a panel comprised of several different constituent panels forming one large panel). As both these tests are undertaken using WGS, you will need to:
  • complete an NHS 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 R382, R390 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.
• All the above tests 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 clinicians

• GeneReviews: Hypochondroplasia
• Genomics England: NHS Genomic Medicine Service (GMS) Signed Off Panels Resource
• National Organization for Rare Disorders: Hypochondroplasia
• NHS England: National Genomic Test Directory
• 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