Neonatal Screening for CAH in Sweden-Results of Implementing Second-Tier Testing

Area of Science:

• Biochemistry
• Genetics
• Pediatrics

Background:

• Newborn screening for congenital adrenal hyperplasia (CAH) effectively identifies severe cases but suffers from high false-positive rates.
• Current screening methods necessitate improvement to enhance diagnostic accuracy and reduce unnecessary follow-ups.

Purpose of the Study:

• To enhance the Swedish national neonatal screening program for CAH.
• To improve the positive predictive value (PPV) of CAH screening by implementing LC-MS/MS second-tier testing.

Main Methods:

• Implemented LC-MS/MS second-tier testing for CAH screening.
• Utilized a combination of steroid hormone ratios ((androstenedione+17-hydroxyprogesterone)/cortisol) and 21-deoxycortisol concentrations.
• Optimized cut-off levels for both full-term and preterm infants.
• Employed CYP21A2 genotyping to assess CAH severity in confirmed cases.

Main Results:

• Increased the positive predictive value (PPV) for CAH screening from 14% to 84% in full-term infants.
• Achieved an 88% reduction in false-positive screening cases.
• Successfully identified severe CAH cases while minimizing false positives through optimized testing and cut-offs.

Conclusions:

• LC-MS/MS second-tier testing significantly improves the accuracy of newborn screening for CAH.
• Optimized cut-off levels and multi-parameter analysis are crucial for enhancing PPV and reducing false positives in neonatal screening.
• The refined screening strategy ensures timely identification of true CAH cases without missing affected infants.