Journal Article

Improved Performance of Newborn Screening for Congenital Adrenal Hyperplasia Using 21-deoxycortisol Measurement

Chakraborty, Pranesh, Bariciak, Erika, Saleh, David S, Henderson, Matthew P A, McIntosh, Nathan, Wherrett, Diane K, Marr, Alexa, Marcadier, Janet, Kowalski, Michael, Lawrence, Sarah E, Chambers, Amy, Eagle, Susanne, Auger, Sheila, Sinclair, Graham, Santander, Emeril

2026

Overview

Abstract Purpose Newborn screening for 21-hydroxylase deficiency congenital adrenal hyperplasia (CAH) has a high false-positive rate. A second-tier steroid profile using liquid chromatography mass spectrometry can improve specificity. Multiple screening algorithms were evaluated to optimize the performance of screening for salt-wasting CAH (SW-CAH). Methods Principal components analysis guided potential combinations of steroid biomarkers for evaluation in a study population of 1710 immunoassay-positive samples proceeding to the second-tier steroid profile in the Newborn Screening Ontario program between August 2020 and April 2023. A Monte Carlo simulation was used to evaluate the performance of algorithms and cutoffs. Results Optimal performance for the identification of SW-CAH used a 3-component second-tier algorithm: detectable 21-deoxycortisol (≥ 2.1 nmol/L); 17-hydroxyprogesterone + 21-deoxycortisol ≥ 40 nmol/L; and ratio of (17-hydroxyprogesterone + 21-deoxycortisol)/cortisol ≥ 0.3. All 8 cases of SW-CAH were accurately identified with a positive predictive value of 70% and 100% sensitivity for SW-CAH, whereas 1 known case of simple virilizing (SV) CAH screened negative. When applied to 26 historical cases, the algorithm identified all 13 cases of SW-CAH and all 6 SV-CAH cases, whereas other forms of CAH were filtered out because of low 21-deoxycortisol. Conclusion Using 21-deoxycortisol for second-tier screening and applying a 3-component algorithm can improve performance of newborn screening for SW-CAH, reducing burden on patients and the health care system. Although cases of SV-CAH may be identified, the thresholds were set to identify life-threatening SW-CAH with a high positive predictive value and 100% sensitivity.

• Publisher: Oxford University Press,The Endocrine Society
• Subject: Adrenogenital syndrome / Algorithms / Clinical / Corticosteroids / Genetic disorders / Hydroxyprogesterone / Hyperplasia / Infants (Newborn) / Liquid chromatography / Mass spectrometry / Measurement / Medical screening / Monte Carlo method / Monte Carlo simulation / Performance evaluation / Steroids