Perfil da 17OH progesterona na triagem neonatal biológica para hiperplasia adrenal congênita no Distrito Federal

Abstract

Introduction: Congenital adrenal hyperplasia (CAH) is a genetic metabolic disorder and one of the most common autosomal recessive conditions. Mutations of the CYP21A2 cause more than 95 percent of the cases attributed to the steroid 21-hydroxylase deficiency (21OHD). Neonatal screening (NBS) for classic CAH measuring neonatal 17OHP (N17OHP) on filter paper was introduced to prevent morbidity and mortality from adrenal crisis. The overall incidence of classic CAH-21OHD is approximately 1:10,000 to 1:20,000 live births. Among these cases, about 75% present with the salt-wasting (SW) form and 25% with the simple virilizing (SV) form. Despite numerous studies and modifications to improve the accuracy of newborn screening for 21OHD, there is no universally accepted N17OHP cutoff value for congenital adrenal hyperplasia newborn screening (CAH-NBS). It may be due to various enzymatic deficiencies in adrenal steroidogenesis, with a broad spectrum of severity. The most common form, which occurs in about 90 to 99% of cases, is caused by an inactivating mutation of the CYP21A2 gene, which encodes the enzyme 21-hydroxylase (21-OH), leading to a deficiency of this enzyme in varying degrees. NBS for the classic form of CAH measuring neonatal 17OHP (N17OHP) on filter paper was initiated to reduce morbidity and mortality caused by the adrenal crisis. The estimated combined incidence of the classic form is around 1 in 14,000 to 1 in 18,000 live births based on NBS data. Among these, approximately 75% are due to the salt-wasting form (SW-CAH) and 25% due to the simple virilizing form (SV-CAH). It is known that current methodologies for NS lack specificity and adequate sensitivity in identifying all newborns with the disease, resulting in a high number of false positives (FP). The challenges in performing neonatal screening for CAH remain significant. Therefore, it is necessary to implement regional measures to strengthen screening and reduce program costs while maintaining its objective, which is to achieve early diagnosis for all children and modify the natural history of the disease. Methods: A cross-sectional study using data from the Neonatal Screening for Congenital Adrenal Hyperplasia in the Federal District was conducted from January 2012 to September 2022. The study analyzed the adjustment of N17OHP for birth weight and time collection. Data were obtained retrospectively from the Federal District's Neonatal Screening Reference Service database. The study included samples from all newborns collected in the public health network of the FD on neonatal filter paper with 17OHPN measurement. Cut-off points were adjusted to the 99th percentile (P99) according to birth weight and time collection. Quantitative variables (mean and standard deviation) and metric analysis with a 95% confidence interval were calculated, with statistical significance set at P<0.05. Results: A total of 448,285 samples for CAH neonatal screening were analyzed. For Article 1, 340,291 samples were used, and for Article 2, 431,423 samples were analyzed. The disease incidence varied between the articles according to the sample, with rates of 1 in 30,935 (11 confirmed cases) in Article 1 and 1 in 23,412 (18 confirmed cases) in Article 2. The majority were diagnosed with the SW-CAH. In Article 1, the P99 of N17OHP adjusted for birth weight had a lower false positive rate than the other two criteria. Our sample showed even greater specificity (99.02%, 95% CI: 98.99-99.05%), positive likelihood ratio (102.12, 95% CI: 98.73–105.63), and accuracy (99.02%, 95% CI: 98.99-99.05%) compared to the other criteria analyzed. Article 2 compared cut-off points with birth weight and time collection and demonstrated a low false positive rate for all groups, with high specificity (98.99%, 95% IQ: 98.96-99.02%), positive likelihood ratio (99.22%, 95% IQ: 96.33-102.2%), and accuracy (98.99%, 95% IQ: 98.96-99.02%); however, the positive predictive value (PPV) remained low. Conclusion: Although the efficiency of this test was demonstrated in our study, we encountered challenges related to the quantity of false positive results, which have been associated with unnecessary costs and emotional stress for parents. The low PPV suggests that screening practices must be cheaply adjusted with more precise methodologies. This study replicates and expands upon previous Brazilian works to validate and implement cutoff values to improve CAH-NBS, using a large sample for a long time.