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

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).

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.

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.

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.