Presentation: Pregnancy with suspicion of a skeletal dysplasia

A pregnant woman presents for a growth scan at 32 weeks’ gestation after an episode of reduced fetal movements. The scan identifies a short femur length, and a fetal medicine referral is made. When measured, all the long bones are below the first centile. Her fetal anomaly scan at 20 weeks was unremarkable.

Genomic testing should be considered if:

• the long bones are over two standard deviations below the mean (<2SD) in the second or third trimester;
• there are signs of bowing or fractures in the long bones;
• there are short long bones associated with:
  • an unusual head shape;
  • a small chest size;
  • hand or foot anomalies;
  • widened proximal femoral metaphyseal angle (achondroplasia); and/or
  • atypical bone mineralisation;
• abdominal circumference is normal and there is no evidence of placental insufficiency; and/or
• there is a family history of a skeletal dysplasia or another skeletal anomaly.

• 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.
• Look carefully at both parents for height and disproportion.
• Refer to local guidance regarding a fetal medicine and/or clinical genetics referral.
• A fetal medicine review will determine whether genomic testing is appropriate, and referral to clinical genetics will be considered in certain circumstances.
• The fetal medicine team will decide which of the panels best suits the needs of the family and/or will discuss the case with a multidisciplinary team, depending on the specific clinical scenario and the family’s wishes. For skeletal dysplasias, the available panels include the following.
• • R22 Fetus with a likely chromosomal abnormality. This will process both:
• • • R22.1 Genome-wide common aneuploidy testing; and
• • • R22.2 Chromosomal microarray.
• • Many skeletal dysplasias are monogenic, so consideration of R21 Fetal anomalies with a likely genetic cause (which involves rapid fetal exome sequencing) is key and is often performed in parallel with R22. R21 can be considered under the following circumstances:
• • • an estimated date of delivery confirmed via early ultrasound scan;
• • • no evidence of placental insufficiency, including normal fetal and maternal dopplers;
• • • no history of previous fetal growth restriction or stillbirth;
• • • normal PAPP-A (if measured); and
• • • no maternal history of systemic lupus erythematosus or similar.
• • R309 NIPD for FGFR3-related skeletal dysplasias – variant testing: This can be requested in isolation if scan findings are suggestive of achondroplasia or thanatophoric dysplasia. The test can be conducted via non-invasive prenatal diagnosis (NIPD). A blood sample in a Streck tube is required.
• None of the tests outlined above use whole genome sequencing, so you should use your local Genomic Laboratory Hub test order form and consent (record of discussion, or RoD forms.
• For NIPD, a blood sample in a Streck tube is required. For invasive tests, an amniocentesis or chorionic villus sample or fetal blood sample (in an EDTA tube) is required as well as a sample from the mother to test for maternal cell contamination. For many tests, parental samples are also needed or are helpful. For more information about different sample types, see Samples for genomic testing in rare disease.
• For R21 Fetal anomalies with a likely genetic cause, you will need to:
• • ensure that the required multidisciplinary discussions have taken place, including fetal medicine, clinical genetics and the regional specialist R21 laboratory, and that there is an agreement that R21 can be offered;
• • inform your local laboratory of the plan for R21 testing, so that they can arrange the necessary exports to the specialist R21 laboratories in a timely fashion;
• • fill in the R21-specific test order form;
• • take informed consent for both parents, documented on R21-specific RoD forms;
• • send blood samples for both parents to the local laboratory (if only one parent is available, let the lab know – testing can still proceed, but there will be a small reduction in diagnostic yield); and
• • arrange and send a chorionic villus sample or amniocentesis sample for the fetus.
• Note that, in Scotland, referral to clinical genetics is required for consideration of rapid prenatal exome testing.
• 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

• NHS England: National Genomic Test Directory
• NHS North Thames and NHS West Midlands, Oxford and Wessex Genomic Laboratory Hubs: National Genomic Test Directory Clinical Indication R21 Rapid prenatal exome sequencing test request (PDF, two pages)
• NHS North Thames and NHS West Midlands, Oxford and Wessex Genomic Laboratory Hubs: Record of discussion regarding prenatal exome sequencing (PDF, two pages)
• The Fetal Medicine Foundation: Skeletal dysplasia
• UpToDate: Skeletal dysplasias: Approach to evaluation

References:

• Krakow D: ‘Skeletal dysplasias‘. Clinics in Perinatology 2015: volume 42, issue 2, pages 301–319. DOI: 10.1016/j.clp.2015.03.003

For patients

• Antenatal Choices & Results
• Gov.uk Guidance: Severe skeletal dysplasia: Information for parents
• NHS North Thames and NHS West Midlands, Oxford and Wessex Genomic Laboratory Hubs: Information on prenatal exome sequencing for parents (PDF, two pages)