Presentation: Fetus with an isolated short femur

A primigravid (first-time pregnant) woman is referred to fetal medicine because she has just had her fetal anomaly ultrasound at 20 weeks’ gestation and, although the head circumference and the abdominal circumference plot onto the 50th centile, the femur length is on the first centile.

Genomic testing should be considered when:

• the femur length in the second or third trimester is less than the first centile for gestational age;
• the femur length is disproportionately small compared with the head circumference and abdominal circumference;
• there are other anomalies noted on ultrasound other than short femur length;
• there are other bony anomalies seen on a scan (unusual head shape, small chest size, signs of bowing or fractures in the long bones – see Pregnancy with suspicion of a skeletal dysplasia);
• there is no evidence of placental insufficiency;
• there is a higher-chance first- or second trimester screening result, or when the parents have previously declined screening but now wish to receive it; and/or
• there is a family history of skeletal anomalies or significant short stature (three standard deviations above the mean (>3SD)).

• 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.
• Take a detailed history from the pregnant woman, which should include:
  • family history of short stature; and
  • family history of skeletal problems.
• Look carefully at both parents for height and disproportion.
• Refer to local guidance regarding fetal medicine referral. Further review in a fetal medicine unit is usually warranted.
• A fetal medicine review will determine whether genomic testing is appropriate and referral to clinical genetics will be considered.
• Depending on the clinical scenario, a range of different genomic tests may be considered.
  • R22 Fetus with a likely chromosomal abnormality. Unless clinical information and/or initial results indicate otherwise, R22 requests will process both:
  • • R22.1 Genome-wide common aneuploidy testing; and
  • • R22.2 Chromosomal microarray.
  • R21 Fetal anomalies with a likely genetic cause may be considered following a multidisciplinary team discussion, including clinical genetics, and in the following circumstances:
  • • isolated short long bones all <3rd percentile with abdominal circumference and head circumference >3rd percentile (estimated due date confirmed with early ultrasound scan, no evidence of placental insufficiency, no previous fetal growth restriction, no previous stillbirth, no maternal history of systemic lupus erythematosus and so on); and
  • • where there are multiple or complex anomalies and/or the above testing is non-diagnostic.
• 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) form.
• 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 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.
• All of the above tests are DNA based and require an amniocentesis or chorionic villus sample, or a fetal blood sample in an EDTA (typically purple-topped) tube. For more information about different sample types, 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

• 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)

References:

• Benacerraf BR, Gelman R and Frigoletto Jr FD. ‘Sonographic identification of second-trimester fetuses with Down’s syndrome‘. The New England Journal of Medicine 1987: volume 317, issue 22, pages 1,371–1,376. DOI: 10.1056/NEJM198711263172203
• Liu J, Huang L, He Z and others. ‘Clinical value of genetic analysis in prenatal diagnosis of short femur‘. Molecular Genetics & Genomic Medicine 2019: volume 7, issue 11, page 978. DOI: 10.1002/mgg3.978
• Nyberg DA, Resta RG, Hickok DE and others. Femur length shortening in the detection of Down syndrome: Is prenatal screening feasible? The American Journal of Obstetrics and Gynecology 1990: volume 162, issue 5, pages 1,247–1,252. DOI: 1016/0002-9378(90)90028-6
• Nyberg DA, Souter VL, El-Bastawissi A and others. Isolated sonographic markers for detection of fetal Down syndrome in the second trimester of pregnancy. Journal of Ultrasound in Medicine 2001: volume 20, issue 10, pages 1,053–1,063. DOI: 10.7863/jum.2001.20.10.1053

For patients

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