Abstract
The positive predictive value of newborn screening for congenital adrenal hyperplasia due to 21-hydroxylase deficiency was <2% in New Zealand. This is despite a bloodspot second-tier immunoassay method for 17-hydroxyprogesterone measurement with an additional solvent extract step to reduce the number of false positive screening tests. We developed a liquid chromatography tandem mass spectrometry (LCMSMS) method to measure 17-hydroxyprogesterone in bloodspots to replace our current second-tier immunoassay method. The method was assessed using reference material and residual samples with a positive newborn screening result. Correlation with the second-tier immunoassay was determined and the method was implemented. Newborn screening performance was assessed by comparing screening metrics 2 years before and 2 years after LCMSMS implementation. Screening data analysis demonstrated the number of false positive screening tests was reduced from 172 to 40 in the 2 years after LCMSMS implementation. The positive predictive value of screening significantly increased from 1.71% to 11.1% (X2 test, p < 0.0001). LCMSMS analysis of 17OHP as a second-tier test significantly improves screening specificity for CAH due to 21-hydroxylase deficiency in New Zealand.
Highlights
Congenital adrenal hyperplasia (CAH) represents a group of inherited disorders characterised by absent or reduced adrenal cortisol synthesis
90% of CAH is caused by mutations in the CYP21A2 gene resulting in reduced activity of adrenal steroid 21-hydroxylase. 21-Hydroxylase catalyses the conversion of 17α-hydroxyprogesterone (17OHP) to 11-deoxycortisol and progesterone to 11-deoxycorticosterone, the respective precursors to cortisol and aldosterone [1]
Screening is sensitive for the severe salt-wasting form of CAH but can be confounded by high concentrations of cross reactive 17OHP steroid precursors and their sulphated conjugates, which are present in the first 48 h after birth and longer in pre-term neonates [3]. 17OHP levels may be elevated due to illness, stress and biological variation [4,5]
Summary
Congenital adrenal hyperplasia (CAH) represents a group of inherited disorders characterised by absent or reduced adrenal cortisol synthesis. 90% of CAH is caused by mutations in the CYP21A2 gene resulting in reduced activity of adrenal steroid 21-hydroxylase. Reduced synthesis of aldosterone can lead to life threatening salt wasting, vascular collapse and an Addisonian crisis in the neonatal period. Increased ACTH levels cause adrenal hyperplasia with increased androgen synthesis and the concomitant rise in intermediate metabolites in the steroidogenesis pathway. Many countries perform newborn screening for CAH due to 21-hydroxylase deficiency to prevent life threatening salt-wasting crises and hypoglycaemia in early infancy. Screening is sensitive for the severe salt-wasting form of CAH but can be confounded by high concentrations of cross reactive 17OHP steroid precursors and their sulphated conjugates, which are present in the first 48 h after birth and longer in pre-term neonates [3]. Screening is sensitive for the severe salt-wasting form of CAH but can be confounded by high concentrations of cross reactive 17OHP steroid precursors and their sulphated conjugates, which are present in the first 48 h after birth and longer in pre-term neonates [3]. 17OHP levels may be elevated due to illness, stress and biological variation [4,5]
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