Presentation: Fetus with ambiguous genitalia

A couple present for their anomaly scan at 21 weeks of pregnancy. The sonographer notices some concerning features in the perineal region when assessing the femur length. The couple are referred to their local fetal medicine unit, where ambiguous genitalia is identified.

Genomic testing should be considered if:

• ambiguous or discordant genitalia is identified on antenatal imaging;
• the genetic sex (as identified via invasive or non-invasive prenatal testing) conflicts with the physical appearance of the genitals on ultrasound; and/or
• there is a family history of congenital adrenal hyperplasia (CAH).
• • See ‘Pregnancy at risk of congenital adrenal hyperplasia‘.

Ambiguous genitalia has a broad differential. See ‘Differences in sex development‘ for further information about potential causes.

• 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.
• Collect a detailed family and personal history from both parents.
• Refer the family to clinical genetics for review by a clinical geneticist or genetic counsellor and/or to your local fetal medicine unit, depending on local protocol. Endocrinology involvement may also be warranted. Some regions may have specialist ‘disorder of sexual differentiation’ teams, which may include specialist psychologists.
• Testing options may include the following.
  • R251 Non-invasive prenatal sexing.
  • • The most common cause of ambiguous genitalia in fetuses with XX sex chromosomes is CAH.
  • • Females affected by CAH are at risk of developing virilisation of the genitalia with clitoromegaly.
  • • If the fetus has XX sex chromosomes, consider invasive testing for CAH.
• Invasive testing may be offered via chorionic villous sampling or amniocentesis. Testing may include the following.
  • R180 Congenital adrenal hyperplasia diagnostic test. This will target both:
  • • R180.1 CYP21A2 single gene sequencing; and
  • • R180.2 CYP21A2 multiple ligation-dependent probe amplification (MLPA) or equivalent.
  • R146 Differences in sex development. This includes microarray and single gene sequencing.
  • If ambiguous genitalia is present in combination with other structural anomalies, you may need to consider whether R21: Fetal anomalies with a likely genetic cause is indicated.
• 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.
• Postnatal testing at birth for a neonate at risk of CAH would typically include electrolyte and urine steroid profiles. The baby would need monitoring for salt-losing crisis until results are available.
• 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

• Great Ormond Street Hospital for Children NHS Foundation Trust: Congenital adrenal hyperplasia (CAH)
• National Organization for Rare Disorders: Congenital adrenal hyperplasia
• 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)

For patients

• Great Ormond Street Hospital for Children NHS Foundation Trust: Congenital adrenal hyperplasia (CAH)
• Great Ormond Street Hospital Biomedical Research Centre: Genomic medicine – Our impact
• NHS North Thames and NHS West Midlands, Oxford and Wessex Genomic Laboratory Hubs: Information on prenatal exome sequencing for parents (PDF, two pages)