Abstract
Congenital adrenal hyperplasia (CAH), an autosomal recessive disease, is characterized by impairment of metabolic cortisol synthesis, with or without insufficient aldosterone production. It is caused by mutations in the CYP21A2 gene in approximately 90% of all cases, leading to 21-hydroxylase deficiency and androgen precursors elevation. The main disease marker is 17-hydroxyprogesterone (17-OHP). Early diagnosis through neonatal screening (NS) allows proper treatment and reduces mortality. In Brazil, the average incidence of the classic form of CAH ranges from 1: 7,500 to 1: 18,000 live births.
Objective: To determine the 17-OHP cutoffs for newborn screening to diagnose Congenital Adrenal Hyperplasia (CAH) in a Public Neonatal Screening Program in Southern Brazil.
Materials and Methods: A retrospective, descriptive, cross-sectional study was carried out for analysis of dried blood test results on the 17-OHP paper filter of 317,745 newborns screened by a public neonatal screening center from May 2014 to April 2017. CAH-C was defined as NB with elevation of 17-OHP confirmed by retest and/or clinical evaluation, followed by genotype study. False positive cases (FP) were characterized by absence of genital alterations and/or loss of salt, with normalization of 17-OHP levels on retest. For the determination of the cutoffs according to the four weight groups (WG) (WG1 ≤1,500 g, WG2 1,501 to 2,000 g, WG3 2,001 to 2,500 g and WG4 ≥ 2,501 g), the percentiles 97.5, 98.5, 99.5 and 99.8 were calculated. Sensitivity, specificity, positive predictive values (PPV), negative predictive values (NPV) were performed for the four WG.
Results: Based on the descriptive analysis of the data, the incidence of CAH for the state of Rio Grande do Sul was 1:15,887 live births, with 20 cases of classic CAH being diagnosed during this period, and 17-OHP values ranged from 32.50 ng/mL to 733.00 ng/mL in WG 2,000 g to 2,500 g and WG ≥ 2,501 g. No confirmed cases of CAH were detected for WG ≤ 1,500 g and 1,501 g at 2,000 g until the time of analysis of this study. Most (80.73%) newborns were caucasian and prematurity rate was 9.8% of the study population. The median and average (days) of first sample collection was 5 and 5.83, while for retest was 21 and 25.97 respectively. The cutoffs change from the 99th percentile to the 98.5 for the weight group between 2,001 g and 2,500 g and to the 99.8 for the other weight groups, decreasing false positive results and increasing specificity compared to current reference values to identify classic CAH cases.
Conclusion: The new 17-OHP cutoffs specified were, for all weight groups, higher than currently used by this screening program. The calculation of reference values from local population data and the combination of percentages prove to be an important tool for proper diagnosis of CAH cases and reduction of the number of FP newborns.
High Reliability of Neonatal Screening for Congenital Adrenal Hyperplasia in Switzerland
