Advances in Congenital Adrenal Hyperplasia newborn screening: 11-ketotestosterone and 21-deoxycortisone as additional discriminatory biomarkers.

Background A major limitation of newborn screening (NBS) for congenital adrenal hyperplasia (CAH) is the lack of specificity of the fluoroimmunoassay (FIA) currently used for 17-hydroxyprogesterone (17OHP) determination. This issue is more pronounced in newborns, due to elevated levels of interfering compounds. FIA at our NBS centre in Ile-de-France has a false positive rate of around 80%, and a predictive positive value (PPV) of 16% for first- and second-tier measurements from dried blood spots (DBS). Recently, tandem mass spectrometry (LC-MS/MS) has gained international recognition as a complementary tool to FIA testing. Currently, the most frequently used biomarkers are 17OHP and 21-deoxycortisol, used either alone or in combination with steroid ratios such as cortisol or 4-androstenedione. Concurrently, the class of 11-oxygenate-androgens—such as 11-ketotestosterone—and more recently 11-oxygenate pregnanes—such as 21-deoxycortisone—have attracted growing interest in the diagnosis of 21-hydroxylase deficiency. These derivatives result from the combined action of 11-beta hydroxysteroid dehydrogenase and 11-beta hydroxylase. Methods We propose a revisited LC-MS/MS steroid profile, enriched with these classes of biomarkers, to be included in the CAH NBS algorithm. This combination could be used as a multi-steroid approach implemented using a machine learning model. Results Our preliminary results suggest that these oxygenated androgen/pregnane steroids are significantly discriminative to streamline the NBS process for CAH. We have demonstrated this in two different NBS centres, in the greater Paris region and in Brittany, France. Conclusion This new algorithm could have an important impact on reducing the number of recall and family stress related to NBS.