The use of liquid chromatography-tandem mass spectrometry in newborn screening for congenital adrenal hyperplasia: improvements and future perspectives

Abstract

Newborn screening for congenital adrenal hyperplasia using 17-hydroxyprogesterone by immunoassay remains controversial despite screening been available for almost 40 years. Screening is confounded by poor immunoassay specificity, fetal adrenal physiology, stress, and illness which can result in a large number of false positive screening tests. Screening programmes apply higher screening thresholds based on co-variates such as birthweight or gestational age but the false positive rate using immunoassay remains high. Mass spectrometry was first applied to newborn screening for congenital adrenal hyperplasia over 15 years ago. Elevated 17-hydroxprogesterone by immunoassay can be retested with a specific liquid chromatography tandem mass spectrometry assay that may include additional steroid markers. Laboratories register with quality assurance programme providers to ensure accurate steroid measurements. This has led to improvements in screening but there are additional costs and added laboratory workload. The search for novel steroid markers may inform further improvements to screening. Studies have shown that 11-oxygenated androgens are elevated in untreated patients and that the adrenal steroidogenesis backdoor pathway is more active in babies with congenital adrenal hyperplasia. There is continual interest in 21-deoxycortisol, a specific marker of 21-hydroxylase deficiency. The measurement of androgenic steroids and their precursors by liquid chromatography tandem mass spectrometry in bloodspots may inform improvements for screening, diagnosis, and treatment monitoring. In this review, we describe how liquid chromatography tandem mass spectrometry has improved newborn screening for congenital adrenal hyperplasia and explore how future developments may inform further improvements to screening and diagnosis.

Current Status of Newborn Bloodspot Screening Worldwide 2024: A Comprehensive Review of Recent Activities (2020–2023)

“…In addition to reviewing the factors affecting screening accuracy for CAH in NZ [ 125 ], considerable attention also has been given to improving the detection of CAH by including LC-MS/MS second-tier testing [ 599 , 600 , 601 , 602 , 603 ]. Similarly, attention to NBS system improvements in CH screening has been documented: adjustments in the TSH laboratory protocol improving case detection and PPV [ 604 ]; examination of the effect that demographic variables (e.g., ethnicity and age at time specimen collection) have on newborn TSH levels [ 605 ]; review of the actions to take when obtaining discordant results (case study) [ 606 ]; and caution against reducing TSH screening cutoffs to levels at which the diagnosis may not offer long-term benefit for those detected (TSH values less than 15 mIU/L (whole blood) found not to be associated with long-term hypothyroidism or cognitive impairment in NZ) [ 607 ].…”