Romy de Kroon1, Renée de Mutsert2, Raymond Noordam2, Dineke Westra3, Wjera Wickenhagen1, Jacquelien Hillebrand1, Martin Den Heijer4, Annemieke Heijboer1
(1) Endocrine Laboratory, department of Laboratory Medicine, Amsterdam University Medical Center, location University of Amsterdam and location Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
(2) Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
(3) Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
(4) Department of Internal Medicine, division of Endocrinology, Amsterdam University Medical Center, location Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
Background
21-deoxycortisol (21-DOCL) is a highly specific neonatal screening marker for congenital adrenal hyperplasia due to 21-hydroxylase deficiency, but its relevance in adults remains unclear.Objectives: To determine the prevalence of detectable serum 21-DOCL in the general adult population, and to assess associations with androgen concentrations and CYP21A2 mutations.
Methods
Data from 3,416 women and 3,096 men in the Netherlands Epidemiology of Obesity (NEO) study were analyzed. Steroid hormones, including 21-DOCL (LoD=0.18 nmol/L), testosterone and androstenedione, were measured by mass spectrometry. Genetic testing was performed in all individuals with detectable 21-DOCL using Sanger sequencing and multiplex ligation-dependent probe amplification.
Results
Detectable 21-DOCL concentrations were observed in 1.45% (95% CI 1.07-1.97%) of participants, with concentrations ranging from 0.2 to 16.5 nmol/L. Women with detectable 21-DOCL had higher testosterone and androstenedione concentrations, while men showed increased androstenedione concentrations compared to those without detectable 21-DOCL. Among those with detectable 21-DOCL, 27.3% were carriers of non-classical variants, 10.8% of classical variants, 6.0% had two variants, and 48.2% showed no CYP21A2 variants. Sensitivity analyses estimated that the prevalence of heterozygosity for non-classical and classical variants, and of two variants, were respectively 2.85-, 7.94-, and 94-fold higher than those without detectable 21-DOCL.
Conclusions
Our results demonstrate that detectable concentrations are present in 1.45% of adults and are associated with elevated androgen concentrations and an increased likelihood of CYP21A2 mutations. Further research is needed to clarify the clinical relevance of detectable 21-DOCL concentrations and its potential as a screening marker for CYP21A2 mutations.