Second-tier Testing for 21-Hydroxylase Deficiency in the Netherlands: A Newborn Screening Pilot Study

Kevin Stroek, An Ruiter, Annelieke van der Linde, Mariette Ackermans, Marelle J. Bouva, Henk Engel, Bernadette Jakobs, Evelien A. Kemper, Erica L. T. van den Akker, Mirjam E. van Albada, Gianni Bocca, Martijn J. J. Finken, Sabine E. Hannema, E. C. A. Mieke Houdijk, Hetty J. van der Kamp, Vera van Tellingen, A. S. Paul van Trotsenburg, Nitash Zwaveling-Soonawala, Annet M. Bosch, Robert de JongeAnnemieke C. Heijboer, Hedi L. Claahsen-van der Grinten, Anita Boelen*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Context: Newborn screening (NBS) for classic congenital adrenal hyperplasia (CAH) consists of 17-hydroxyprogesterone (17-OHP) measurement with gestational age-adjusted cutoffs. A second heel puncture (HP) is performed in newborns with inconclusive results to reduce false positives. Objective: We assessed the accuracy and turnaround time of the current CAH NBS algorithm in comparison with alternative algorithms by performing a second-tier 21-deoxycortisol (21-DF) pilot study. Methods: Dried blood spots (DBS) of newborns with inconclusive and positive 17-OHP (immunoassay) first HP results were sent from regional NBS laboratories to the Amsterdam UMC Endocrine Laboratory. In 2017-2019, 21-DF concentrations were analyzed by LC-MS/MS in parallel with routine NBS. Diagnoses were confirmed by mutation analysis. Results: A total of 328 DBS were analyzed; 37 newborns had confirmed classic CAH, 33 were false-positive and 258 were categorized as negative in the second HP following the current algorithm. With second-tier testing, all 37 confirmed CAH had elevated 21-DF, while all 33 false positives and 253/258 second-HP negatives had undetectable 21-DF. The elevated 21-DF of the other 5 newborns may be NBS false negatives or second-tier false positives. Adding the second-tier results to inconclusive first HPs reduced the number of false positives to 11 and prevented all 286 second HPs. Adding the second tier to both positive and inconclusive first HPs eliminated all false positives but delayed referral for 31 CAH patients (1-4 days). Conclusion: Application of the second-tier 21-DF measurement to inconclusive first HPs improved our CAH NBS by reducing false positives, abolishing the second HP, and thereby shortening referral time.
Original languageEnglish
Pages (from-to)E4487-E4496
JournalThe Journal of clinical endocrinology and metabolism
Volume106
Issue number11
Early online date25 Jun 2021
DOIs
Publication statusPublished - 1 Nov 2021

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