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. 2025 Jul;48(7):1623-1633.
doi: 10.1007/s40618-025-02581-w. Epub 2025 Apr 15.

Diagnostic cut-offs of 17-hydroxyprogesterone by LC-MS/MS in children with non-classical congenital adrenal hyperplasia

Carla Bizzarri  1   2 , Laura Chioma  3 , Giorgia Bottaro  3 , Laura Paone  3 , Tommaso Todisco  3   4 , Mariangela Chiarito  3 , Cecilia Surace  5 , Ottavia Porzio  6   7 , Annamaria D'Alessandro  6 , Lucilla Ravà  8 , Marco Cappa  9
Affiliations

Diagnostic cut-offs of 17-hydroxyprogesterone by LC-MS/MS in children with non-classical congenital adrenal hyperplasia

Carla Bizzarri et al. J Endocrinol Invest. 2025 Jul.

Abstract

Purpose: Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder, commonly caused by 21-hydroxylase mutations, that converts 17-hydroxyprogesterone (17-OHP) into 11-deoxycortisol in the adrenal cortex. Elevated morning serum levels of 17-OHP identify suspected CAH, and the diagnosis is confirmed by CYP21 A2 gene analysis. Liquid-chromatography tandem mass spectrometry (LC-MS/MS) has become the recommended method for 17-OHP measurement; however, diagnostic 17-OHP thresholds measured with LC-MS/MS are not yet defined. We aimed to identify optimal cut-offs for basal and peak 17-OHP levels after ACTH stimulation test, measured by LC-MS/MS, to distinguish non-classical CAH (NC-CAH) and heterozygous carriers (HC) from wild type subjects (WT) in children.

Methods: We retrospectively analyzed the records of 198 children referred for suspected NC-CAH.

Results: The ideal basal 17-OHP cut-off to differentiate NC-CAH from WT subjects was 0.94 ng/mL (2.82 nmol/L) with AUC 0.988 (95% CI 0.972-1.000; sensitivity 100%, specificity 90%). The optimal peak 17-OHP cut-off was 7.81 ng/mL (23.43 nmol/L) with AUC 0.998 (95% CI 0.994-1.000; sensitivity 100%, specificity 97%). The ideal basal 17-OHP cut-off to distinguish HC from WT subjects was 0.81 ng/mL (2.43 nmol/L), with AUC 0.727 (95% CI 0.645-0.809; sensitivity 54%, specificity 83%); while the optimal peak 17-OHP cut-off was 3.79 ng/mL (11.37 nmol/L) with AUC 0.932 (95% CI 0.894-0.971; sensitivity 96%, specificity 87%).

Conclusions: The ideal cut-offs of peak 17OHP able to distinguish NC-CAH and HC individuals from WT subjects were significantly lower to using LC-MS/MS. These new thresholds demonstrate high sensitivity and specificity, making them effective in distinguishing individuals with suspected NC-CAH.

Keywords: 17-Hydroxyprogesterone; 21-Hydroxylase; Child; Congenital adrenal hyperplasia; Liquid-chromatography tandem mass spectrometry.

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Conflict of interest statement

Declarations. Conflict of interest: The authors have no competing interests to declare that are relevant to the content of this article. Informed consent: Written informed consent was obtained from parents and/or legal guardians.

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