Abstract
Newborn screening for 21-hydroxylase deficiency (21OHD), the most common form of congenital adrenal hyperplasia, has been performed routinely in the United States and other countries for over 20 years. Screening provides the opportunity for early detection and treatment of patients with 21OHD, preventing salt-wasting crisis during the first weeks of life. However, current first-tier screening methodologies lack specificity, leading to a large number of false positive cases, and adequate sensitivity to detect all cases of classic 21OHD that would benefit from treatment. This review summarizes the pathology of 21OHD and also the key stages of fetal hypothalamic-pituitary-adrenal axis development and adrenal steroidogenesis that contribute to limitations in screening accuracy. Factors leading to both false positive and false negative results are highlighted, along with specimen collection best practices used by laboratories in the United States and worldwide. This comprehensive review provides context and insight into the limitations of newborn screening for 21OHD for laboratorians, primary care physicians, and endocrinologists.
Highlights
Congenital adrenal hyperplasia (CAH) refers to a group of inherited genetic disorders caused by specific enzyme defects within the biosynthetic pathway of glucocorticoids. 21-hydroxylase deficiency (21OHD) is the most common cause of CAH, accounting for over 95% of all cases [1]
Recent studies published by programs in the United States who routinely perform two newborn screens, have documented cases of both classic CAH (SW-CAH and SV-CAH) and NC-CAH identified on the second screen, due to late rising 17OHP concentrations [55,56,57]
Detection of 21OHD through newborn screening allows for treatment of most individuals prior to the onset of symptoms, preventing devastating outcomes from severe salt-wasting crises
Summary
Congenital adrenal hyperplasia (CAH) refers to a group of inherited genetic disorders caused by specific enzyme defects within the biosynthetic pathway of glucocorticoids. 21-hydroxylase deficiency (21OHD) is the most common cause of CAH, accounting for over 95% of all cases [1]. Newborns with untreated severe 21OHD, referred to as salt-wasting CAH (SW-CAH), develop progressive salt-wasting crisis during the first weeks of life, resulting in significant morbidity and mortality [2]. Newborn screening for SW-CAH provides the opportunity for early detection and treatment and has been implemented in the United States and more than 35 countries [3]. At present, first-tier screening methodologies lack specificity and adequate sensitivity to identify all newborns with 21OHD that would benefit from early treatment [1]. We provide an overview of CAH due to 21OHD, focusing on disease presentation, pathology, genetics, diagnosis, and treatment. We will summarize different screening algorithms and approaches to specimen collection used by laboratories in the United States and worldwide to enhance detection of newborns with 21OHD
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