Presentation: Child with suspected congenital adrenal hyperplasia

A 10-day-old baby boy presents unwell with poor feeding, vomiting and failure to regain his birth weight. Biochemical investigations reveal hyponatraemia, hyperkalaemia, metabolic acidosis and elevated 17-hydroxyprogesterone (17-OHP).

Children with suspected congenital adrenal hyperplasia (CAH) need genomic testing to establish the possible genetic cause and, in cases of ambiguous genitalia, their genetic sex. Genomic tests should be conducted in parallel with biochemical investigations.

Consider genomic testing in the following circumstances:

• neonate with ambiguous genitalia; and
• biochemically diagnosed CAH with at least one of the following:
• • ambiguous genitalia or virilisation in a female infant at birth;
  • precocious puberty;
  • accelerated pre-pubertal growth with advanced bone age and evidence of adrenal steroid anomaly;
  • salt-losing crisis in the neonatal period; and/or
  • infant electrolyte disturbance.

• 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 information about how to arrange testing in Wales, Scotland or Northern Ireland, see our dedicated Knowledge Hub resource.
• To find out which genes are included on 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.
  • If the patient has ambiguous genitalia, follow the testing approach in Neonate with ambiguous genitalia.
  • For other presentations of biochemically diagnosed CAH, the suggested panel is:
    • R180 Congenital adrenal hyperplasia diagnostic test. This includes CYP21A2 gene sequencing and multiplex ligation-dependent probe amplification (MLPA). Variants in CYP21A2 are the most common cause of CAH.
• • For families with a confirmed diagnosis of 21-hydroxylase CAH with no detectable causative variant in CYP21A2 who require linkage testing (a method which attempts to locate the familial disease-causing gene using genetic markers) to guide management or advice, the test to request is:
• • • R388 Linkage testing for congenital adrenal hyperplasia.
• • If the underlying diagnosis is still unclear after determination of genetic sex, biochemical investigations and a CAH diagnostic test, the test to request is:
• • • R146 Differences in sex development.
• • For tests that do not include whole genome sequencing, including 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 (proband’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

• GeneReviews: 21-hydroxylase-deficient congenital adrenal hyperplasia
• Genomics England: NHS Genomic Medicine Service (GMS) Signed Off Panels Resource
• National Organization for Rare Disorders: Congenital adrenal hyperplasia
• NHS England: National Genomic Test Directory

References:

• Ahmed F, Acherman J, Alderson J and others. ‘Society for Endocrinology UK guidance on the initial evaluation of a suspected difference or disorder of sex development (revised 2021)‘. Clinical Endocrinology 2021: volume 95, issue 6, pages 809–919. DOI: 1111/cen.14528
• Speiser PW, Arlt W, Auchus RJ and others. ‘Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: An Endocrine Society clinical practice guideline’. The Journal of Clinical Endocrinology & Metabolism 2018: volume 103, issue 11, pages 4,043–4,08 DOI: 10.1210/jc.2018-01865

For patients

• CAH Is Us (patient information)
• Great Ormond Street Hospital for Children NHS Foundation Trust: Information for families: Congenital adrenal hyperplasia (CAH) (PDF, three pages)
• Living with CAH (information and support group)