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 Jonge; Annemieke C Heijboer; Hedi L Claahsen-van der Grinten; Anita Boelen

doi:10.1210/clinem/dgab464

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 journal › Article › Academic › peer-review

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Abstract

BACKGROUND: Newborn screening (NBS) for classic congenital adrenal hyperplasia (CAH) consists of 17-hydroxyprogesterone (17-OHP) measurement with gestational age-adjusted cut-off values. A second heel puncture (HP) is performed in newborns with inconclusive results to reduce false-positives. We assessed the accuracy and turnaround time of the current CAH NBS-algorithm and compared this to 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 liquid chromatography-tandem mass spectrometry, in parallel with routine NBS. Diagnoses were confirmed by mutation analysis.

RESULTS: 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. In the second-tier, all 37 confirmed CAH had elevated 21-DF concentrations, all 33 false-positives and 253/258 second HP negatives had undetectable 21-DF concentrations. The elevated 21-DF of the other five newborns may be NBS false-negatives or second-tier false-positives. Adding the second-tier 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 at the cost of 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 language	English
Pages (from-to)	e4487-e4996
Number of pages	10
Journal	Journal of Clinical Endocrinology and Metabolism
Volume	106
Issue number	11
Early online date	25-Jun-2021
DOIs	https://doi.org/10.1210/clinem/dgab464
Publication status	Published - Nov-2021

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10.1210/clinem/dgab464

Second-tier testing for 21-hydroxylase deficiency in the Netherlands; a newborn screening pilot studyFinal publisher's version, 930 KBLicence: Taverne

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Stroek, K., Ruiter, A., van der Linde, A., Ackermans, M., Bouva, M. J., Engel, H., Jakobs, B., Kemper, E. A., van den Akker, E. L. T., van Albada, M. E., Bocca, G., Finken, M. J. J., Hannema, S. E., Houdijk, E. C. A. M., van der Kamp, H. J., van Tellingen, V., van Trotsenburg, A. S. P., Zwaveling-Soonawala, N., Bosch, A. M., ... Boelen, A. (2021). Second-tier testing for 21-hydroxylase deficiency in the Netherlands; a newborn screening pilot study. Journal of Clinical Endocrinology and Metabolism, 106(11), e4487-e4996. https://doi.org/10.1210/clinem/dgab464

Stroek, Kevin ; Ruiter, An ; van der Linde, Annelieke ; Ackermans, Mariette ; Bouva, Marelle J ; Engel, Henk ; Jakobs, Bernadette ; Kemper, Evelien A ; van den Akker, Erica L T ; van Albada, Mirjam E ; Bocca, Gianni ; Finken, Martijn J J ; Hannema, Sabine E ; Houdijk, E C A Mieke ; van der Kamp, Hetty J ; van Tellingen, Vera ; van Trotsenburg, A S Paul ; Zwaveling-Soonawala, Nitash ; Bosch, Annet M ; de Jonge, Robert ; Heijboer, Annemieke C ; Claahsen-van der Grinten, Hedi L ; Boelen, Anita. / Second-tier testing for 21-hydroxylase deficiency in the Netherlands; a newborn screening pilot study. In: Journal of Clinical Endocrinology and Metabolism. 2021 ; Vol. 106, No. 11. pp. e4487-e4996.

@article{fb7c5d947cd04ac08252bf6e74788490,

title = "Second-tier testing for 21-hydroxylase deficiency in the Netherlands; a newborn screening pilot study",

abstract = "BACKGROUND: Newborn screening (NBS) for classic congenital adrenal hyperplasia (CAH) consists of 17-hydroxyprogesterone (17-OHP) measurement with gestational age-adjusted cut-off values. A second heel puncture (HP) is performed in newborns with inconclusive results to reduce false-positives. We assessed the accuracy and turnaround time of the current CAH NBS-algorithm and compared this to 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 liquid chromatography-tandem mass spectrometry, in parallel with routine NBS. Diagnoses were confirmed by mutation analysis.RESULTS: 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. In the second-tier, all 37 confirmed CAH had elevated 21-DF concentrations, all 33 false-positives and 253/258 second HP negatives had undetectable 21-DF concentrations. The elevated 21-DF of the other five newborns may be NBS false-negatives or second-tier false-positives. Adding the second-tier 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 at the cost of 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.",

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

note = "{\textcopyright} The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.",

year = "2021",

month = nov,

doi = "10.1210/clinem/dgab464",

language = "English",

volume = "106",

pages = "e4487--e4996",

journal = "Journal of Clinical Endocrinology and Metabolism",

issn = "0021-972X",

publisher = "ENDOCRINE SOC",

number = "11",

}

Stroek, K, Ruiter, A, van der Linde, A, Ackermans, M, Bouva, MJ, Engel, H, Jakobs, B, Kemper, EA, van den Akker, ELT, van Albada, ME , Bocca, G, Finken, MJJ, Hannema, SE, Houdijk, ECAM, van der Kamp, HJ, van Tellingen, V, van Trotsenburg, ASP, Zwaveling-Soonawala, N, Bosch, AM, de Jonge, R, Heijboer, AC, Claahsen-van der Grinten, HL & Boelen, A 2021, 'Second-tier testing for 21-hydroxylase deficiency in the Netherlands; a newborn screening pilot study', Journal of Clinical Endocrinology and Metabolism, vol. 106, no. 11, pp. e4487-e4996. https://doi.org/10.1210/clinem/dgab464

Second-tier testing for 21-hydroxylase deficiency in the Netherlands; a newborn screening pilot study. / Stroek, Kevin; Ruiter, An; van der Linde, Annelieke; Ackermans, Mariette; Bouva, Marelle J; Engel, Henk; Jakobs, Bernadette; Kemper, Evelien A; van den Akker, Erica L T; van Albada, Mirjam E ; Bocca, Gianni; Finken, Martijn J J; Hannema, Sabine E; Houdijk, E C A Mieke; van der Kamp, Hetty J; van Tellingen, Vera; van Trotsenburg, A S Paul; Zwaveling-Soonawala, Nitash; Bosch, Annet M; de Jonge, Robert; Heijboer, Annemieke C; Claahsen-van der Grinten, Hedi L; Boelen, Anita.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 106, No. 11, 11.2021, p. e4487-e4996.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - Second-tier testing for 21-hydroxylase deficiency in the Netherlands; a newborn screening pilot study

AU - Stroek, Kevin

AU - Ruiter, An

AU - van der Linde, Annelieke

AU - Ackermans, Mariette

AU - Bouva, Marelle J

AU - Engel, Henk

AU - Jakobs, Bernadette

AU - Kemper, Evelien A

AU - van den Akker, Erica L T

AU - van Albada, Mirjam E

AU - Bocca, Gianni

AU - Finken, Martijn J J

AU - Hannema, Sabine E

AU - Houdijk, E C A Mieke

AU - van der Kamp, Hetty J

AU - van Tellingen, Vera

AU - van Trotsenburg, A S Paul

AU - Zwaveling-Soonawala, Nitash

AU - Bosch, Annet M

AU - de Jonge, Robert

AU - Heijboer, Annemieke C

AU - Claahsen-van der Grinten, Hedi L

AU - Boelen, Anita

PY - 2021/11

Y1 - 2021/11

N2 - BACKGROUND: Newborn screening (NBS) for classic congenital adrenal hyperplasia (CAH) consists of 17-hydroxyprogesterone (17-OHP) measurement with gestational age-adjusted cut-off values. A second heel puncture (HP) is performed in newborns with inconclusive results to reduce false-positives. We assessed the accuracy and turnaround time of the current CAH NBS-algorithm and compared this to 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 liquid chromatography-tandem mass spectrometry, in parallel with routine NBS. Diagnoses were confirmed by mutation analysis.RESULTS: 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. In the second-tier, all 37 confirmed CAH had elevated 21-DF concentrations, all 33 false-positives and 253/258 second HP negatives had undetectable 21-DF concentrations. The elevated 21-DF of the other five newborns may be NBS false-negatives or second-tier false-positives. Adding the second-tier 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 at the cost of 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.

AB - BACKGROUND: Newborn screening (NBS) for classic congenital adrenal hyperplasia (CAH) consists of 17-hydroxyprogesterone (17-OHP) measurement with gestational age-adjusted cut-off values. A second heel puncture (HP) is performed in newborns with inconclusive results to reduce false-positives. We assessed the accuracy and turnaround time of the current CAH NBS-algorithm and compared this to 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 liquid chromatography-tandem mass spectrometry, in parallel with routine NBS. Diagnoses were confirmed by mutation analysis.RESULTS: 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. In the second-tier, all 37 confirmed CAH had elevated 21-DF concentrations, all 33 false-positives and 253/258 second HP negatives had undetectable 21-DF concentrations. The elevated 21-DF of the other five newborns may be NBS false-negatives or second-tier false-positives. Adding the second-tier 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 at the cost of 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.

U2 - 10.1210/clinem/dgab464

DO - 10.1210/clinem/dgab464

M3 - Article

C2 - 34171085

VL - 106

SP - e4487-e4996

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

SN - 0021-972X

IS - 11

ER -