Wisconsin's Screening Algorithm for the Identification of Newborns with Congenital Adrenal Hyperplasia.

Eric R Bialk,Patrice K Held,Michael R Lasarev

doi:10.3390/ijns5030033

Abstract

Newborn screening for congenital adrenal hyperplasia (CAH) has one of the highest false positive rates of any of the diseases on the Wisconsin panel. This is largely due to the first-tier immune assay cross-reactivity and physiological changes in the concentration of 17-hydroxyprogesterone during the first few days of life. To improve screening for CAH, Wisconsin developed a second-tier assay to quantify four different steroids (17-hydroxyprogesterone, 21-deoxycortisol, androstenedione, and cortisol) by liquid chromatography–tandem mass spectrometry (LC–MSMS) in dried blood spots. From validation studies which included the testing of confirmed CAH patients, Wisconsin established its own reporting algorithm that incorporates steroid concentrations as well as two different ratios—the birth weight and the collection time—to identify babies at risk for CAH. Using the newly developed method and algorithm, the false positive rate for the CAH screening was reduced by 95%. Patients with both classical forms of CAH, salt-wasting and simple virilizing, were identified. This study replicates and expands upon previous work to develop a second-tier LC–MSMS steroid profiling screening assay for CAH. The validation and prospective study results provide evidence for an extensive reporting algorithm that incorporates multiple steroids, birth weight, and collection times.

Highlights

Congenital Adrenal Hyperplasia (CAH) is a group of autosomal recessive disorders caused by enzymatic defects within the biosynthetic pathways of mineralocorticoids, glucocorticoids, and sex hormones
A protocol (2019-0118) for the use of residual dried blood spot (DBS) newborn screening (NBS) specimens was approved by the Health Sciences Institutional Review Board (IRB) at the University of Wisconsin (3/28/2019)
A complete clinical assay laboratory validation was performed for four steroids quantified within the second-tier assay (F, 17-OHP, 21, and 4-A)

Summary

Introduction

Congenital Adrenal Hyperplasia (CAH) is a group of autosomal recessive disorders caused by enzymatic defects within the biosynthetic pathways of mineralocorticoids, glucocorticoids, and sex hormones. Screening for CAH using 17-OHP is effective at identifying severely affected patients at risk for salt-wasting crisis, there is a high false positive rate associated with the assay [7]. Assay limitations, such as cross-reactivity with other steroid sulfatides [8], and physiological differences between newborns within the premature infant population, contribute to the high false positive rate [9,10]. 9 states mandate a second screen on all newborns at 9–14 days of life [14] This additional screen can impact the positive predictive value of CAH testing, the logistical and financial burden is large

Methods

Results

Conclusion