Presentation: Pregnancy at risk of congenital adrenal hyperplasia

A woman in her third pregnancy presents at the booking appointment with her partner. They inform the midwife that their second pregnancy was complicated by fetal anomalies and that postnatal genomic testing confirmed a diagnosis of congenital adrenal hyperplasia (CAH). Both parents were subsequently diagnosed as carriers of the genetic variant causing this disease.

• Genomic testing should be considered when:
• • there is a confirmed history of a previous pregnancy or child diagnosed with CAH;
  • there is a family history of CAH (maternal, paternal or both);
  • either or both parents are known to be carriers of CAH; and/or
  • clinical features in the fetus are suggestive of CAH.

• Collect a detailed family and personal history from the couple.
• Refer to clinical genetics for review by a clinical geneticist or genetic counsellor.
• The clinical genetics team will review the National Genomic Test Directory rare and inherited disease eligibility criteria, which identifies the tests for which patients are eligible. The directory itself provides 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.
• Testing options may include the following.
  • Carrier screening of the parent(s).
  • • R242 Predictive testing for known familial variant(s): This may be offered when one or both parents have a family history of CAH but have not yet had carrier testing themselves. It can only be requested by clinical genetics services. If only one parent is tested, and is found to be a carrier, testing for their partner is recommended.
  • • R181 CAH carrier testing: This is for partners of known carriers, in whom there is no personal or family history of CAH. Testing can only be requested by clinical genetics services. R181 confirms whether the partner is a carrier of the condition, with a known variant, and will provide information about the chance of a pregnancy being affected.
  • Prenatal testing in a pregnancy with a known familial disease-causing variant.
  • • R251 Non-invasive fetal sexing: This is conducted via non-invasive prenatal diagnosis (NIPD). Females affected by CAH are at risk of developing virilisation of the genitalia with clitoromegaly. If the fetus is female, consider invasive testing for diagnostic purposes. NIPD can be performed after seven weeks of pregnancy. Contact your local Genomic Laboratory Hub in advance to determine the local process.
  • • R250 NIPD for CAH – CYP21A2 haplotype testing: Clinical genetics and fetal medicine services can offer this test from 8 to 10 weeks’ gestation for pregnancies at risk of CAH in which:
  • • • both parents have been confirmed as carriers;
  • • • the parents have a previous child diagnosed with CAH; and
  • • • the pregnancy is confirmed as female.
  • • Control samples are required for R250, including maternal and paternal DNA samples and DNA samples from a previous affected pregnancy.
  • • R448 Prenatal testing: This is conducted via amniocentesis or chorionic villus sampling, and may be offered to test a pregnancy for CAH where NIPD is not appropriate or available, or where it is a patient’s preference.
  • If a pregnant woman does not wish to receive testing for CAH prior to or during pregnancy, the infant can be tested after birth.
  • • R242 Predictive testing for known familial variant(s) may be offered if the infant does not show any clinical signs of CAH. Testing can only be requested by clinical genetics services.
  • • R180 CAH diagnostic test can be arranged if the infant (or child) shows clinical signs of CAH. Testing can be requested by clinical genetics, endocrinology, neonatology or paediatrics services.
  • If an individual or couple presents prior to conception, preimplantation genomic testing may be available. Referral via clinical genetics 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) form.
• Parental samples may be needed for interpretation of the proband’s result. Parental samples can be taken alongside that of the proband, and their DNA stored, or can be requested at a later date if needed.
• 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 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

• National Organisation for Rare Disorders: Congenital adrenal hyperplasia
• NHS England: National Genomic Test Directory
• West Midlands Regional Genetics Laboratory: NIPD for congenital adrenal hyperplasia (CAH) (PDF, one page)

For patients

• Great Ormond Street Hospital for Children NHS Foundation Trust: Congenital adrenal hyperplasia (CAH)
• Living with CAH