SAT-462 - When 17-OHP Fails: 21-Deoxycortisol as the Sole Diagnostic Marker in Salt-Wasting Congenital Adrenal Hyperplasia

Newborn screening (NBS) for congenital adrenal hyperplasia (CAH) relies on 17-hydroxyprogesterone (17-OHP) immunoassay, which has poor specificity. Second-tier liquid chromatography-tandem mass spectrometry (LC-MS/MS) improves accuracy, and 21-deoxycortisol (21-DOC) has emerged as a highly specific marker for 21-hydroxylase deficiency. We present a case where 21-DOC was the sole marker identifying classic salt-wasting CAH when LC-MS/MS 17-OHP was normal.
A term male neonate (40+2 weeks, 2920 g) was identified through Newborn Screening Ontario on day of life (DOL) 9 with a positive CAH screen. First-tier immunoassay 17-OHP was marginally elevated at 40.7 nmol/L (cutoff >38.0). Second-tier LC-MS/MS showed normal 17-OHP at 5.5 nmol/L (normal < 14.0) but markedly elevated 21-DOC at 24.2 nmol/L (normal < 2.1), exceeding the upper limit by 11-fold.
Despite appearing clinically well on DOL 12, laboratory evaluation revealed impending adrenal crisis: hyperkalemia (6.9 mmol/L), hyponatremia (134 mmol/L), and elevated renin (557 mU/L; normal < 40). ACTH stimulation demonstrated exaggerated 17-OHP response (132.8 to 323.0 nmol/L) with blunted cortisol (25 to 57 nmol/L). Molecular testing confirmed compound heterozygous CYP21A2 variants: c.518T>A (p.Ile173Asn) and c.1451_1452delinsC (p.Arg484Profs*58). Treatment with hydrocortisone (15 mg/m²/day) and fludrocortisone (0.1 mg BID) was initiated with excellent response. At follow-up, electrolytes normalized with appropriate weight gain.
Without 21-DOC, this infant would have been classified as screen negative based on normal LC-MS/MS 17-OHP. This case supports incorporating 21-DOC into second-tier NBS protocols worldwide.

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