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Background <p>The multiplex steroid assay of liquid chromatography-tandem mass spectrometry (LC-MS/MS) has the potential to diagnose 21-hydroxylase deficiency (21OHD) directly from screening results.</p> Aim <p>To establish an endocrinological diagnostic algorithm for 21OHD from screening positive cases based on LC-MS/MS screening.</p> Methods <p>For determining the cut-off criteria of 21-deoxycortisol (21DOF), the Tokyo screening cohort (21OHD, <i>n</i> = 26; false positives(FPs), <i>n</i> = 37) was examined. For identifying the biomarker to differentiate 21OHD from P450 oxidoreductase (POR) deficiency (PORD), another condition to cause 21DOF elevation in addition to 17α-OHP, we employed two cohorts from different origins, namely, 21OHD patients from the Tokyo screening cohort and the endocrinological data of previously reported PORD cases (<i>n</i> = 42 of 17 reports).</p> Results <p>The 21DOF levels between 21OHD patients and FPs yielded 0.999 AUC. The combination of 17α-OHP &gt; 15.1 nmol/L (5.0 ng/mL) and 21DOF &gt; 2.88 nmol/L (1.0 ng/mL) yielded 1.000 and 0.949 of the positive and negative predictive values, respectively. Using both data, 21OHD and PORD can be narrowed down from other conditions in which 17α-OHP is elevated.</p> <p>To estimate 17,20-lyase activity, which is compromised only in PORD, we examined the androstenedione/cortisol (4AD/F) molar ratio, revealing a significant, non-overlapping difference (AUC, 1.000). Postnatal and gestational age dependency of the 4AD/F ratio was not apparent.</p> Conclusion <p>We propose a two-step method to endocrinologically diagnose 21OHD in screening positive newborns. After, narrowing down to 21OHD and PORD using a cut-off of 21DOF &gt; 2.88 nmol/L (1.0 ng/mL), a 4AD/F ratio &gt; 0.06 would be indicative of 21OHD.</p>

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A Two-Step LC-MS/MS method to differentiate 21OHD and PORD in Screen-Positive newborns

  • 期刊论文

  • 发表日期：

    2026年3月10日

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  • Hisae Nakatani,
  • Kazuhiro Watanabe,
  • Atsumi Tsuji-Hosokawa,
  • Akito Sutani,
  • Yoko Saito,
  • Shizuka Kirino,
  • Haruki Yamano,
  • Ryuta Orimoto,
  • Maki Gau,
  • Analia Yogi,
  • Nobuyuki Ishige,
  • Toshihiro Tajima,
  • Tomonobu Hasegawa,
  • Kei Takasawa,
  • Masatoshi Takagi,
  • Kenichi Kashimada

摘要

Background

The multiplex steroid assay of liquid chromatography-tandem mass spectrometry (LC-MS/MS) has the potential to diagnose 21-hydroxylase deficiency (21OHD) directly from screening results.

Aim

To establish an endocrinological diagnostic algorithm for 21OHD from screening positive cases based on LC-MS/MS screening.

Methods

For determining the cut-off criteria of 21-deoxycortisol (21DOF), the Tokyo screening cohort (21OHD, n = 26; false positives(FPs), n = 37) was examined. For identifying the biomarker to differentiate 21OHD from P450 oxidoreductase (POR) deficiency (PORD), another condition to cause 21DOF elevation in addition to 17α-OHP, we employed two cohorts from different origins, namely, 21OHD patients from the Tokyo screening cohort and the endocrinological data of previously reported PORD cases (n = 42 of 17 reports).

Results

The 21DOF levels between 21OHD patients and FPs yielded 0.999 AUC. The combination of 17α-OHP > 15.1 nmol/L (5.0 ng/mL) and 21DOF > 2.88 nmol/L (1.0 ng/mL) yielded 1.000 and 0.949 of the positive and negative predictive values, respectively. Using both data, 21OHD and PORD can be narrowed down from other conditions in which 17α-OHP is elevated.

To estimate 17,20-lyase activity, which is compromised only in PORD, we examined the androstenedione/cortisol (4AD/F) molar ratio, revealing a significant, non-overlapping difference (AUC, 1.000). Postnatal and gestational age dependency of the 4AD/F ratio was not apparent.

Conclusion

We propose a two-step method to endocrinologically diagnose 21OHD in screening positive newborns. After, narrowing down to 21OHD and PORD using a cut-off of 21DOF > 2.88 nmol/L (1.0 ng/mL), a 4AD/F ratio > 0.06 would be indicative of 21OHD.