Presentation: Neonate with ambiguous genitalia

A newborn baby presents with ambiguous genitalia and no other evident health issues.

All newborn babies presenting with ambiguous genitalia need genomic testing to establish genetic sex and possible genetic cause, in parallel with biochemical investigations.

There are two types of genomic testing that are required in this scenario:

• a rapid common aneuploidy test or karyotype (chromosome test) to establish the genetic sex; and
• additional genomic testing to determine the cause of the ambiguous genitalia.

• 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 in different gene panels, see the NHS Genomic Medicine Service (GMS) Signed Off Panels Resource.
• Decide which of the panels best suits the needs of your patient or family. It may be appropriate to select more than one. To establish the genetic sex, the appropriate test is:
  • R314 Ambiguous genitalia presenting neonatally (including common aneuploidy testing and, if necessary, karyotype).
• If this test does not identify aneuploidy and biochemical investigations suggest that congenital adrenal hyperplasia (CAH) is the likely diagnosis then proceed to:
• • R180 CAH diagnostic test (including single gene sequencing and multiplex ligation-dependent probe amplification (MLPA) of CYP21A2); and/or
• • R388 Linkage testing for congenital adrenal hyperplasia. This should be considered for families with a confirmed diagnosis of 21-hydroxylase congenital adrenal hyperplasia with no detectable variant in CYP21A2 who require linkage testing to guide management or advice.
• If the underlying diagnosis is still unclear after aneuploidy testing, biochemical investigations and a CAH diagnostic test (where relevant), proceed to:
• • R146 Differences in sex development. This includes microarray, gene panel sequencing and MLPA.
• For tests that do not include whole genome sequencing, including R314, R180, R388 and R146:
• • you can use your local Genomic Laboratory Hub test order and consent (record of discussion) 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.
• The majority of tests are DNA-based, and 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

• British Medical Journal Best Practice: Atypical genitalia in neonates
• Genomics England: NHS Genomic Medicine Service (GMS) Signed Off Panels Resource
• NHS England: National Genomic Test Directory

For patients

• DSD Families (support for families of children with differences of sex development)
• Living with CAH
• NHS Health A to Z: Differences in sex development