From the Guidelines
Yes, congenital adrenal hyperplasia (CAH) can sometimes be missed on newborn screening despite screening programs being in place in all 50 U.S. states. The most common form of CAH, 21-hydroxylase deficiency, is typically detected by measuring 17-hydroxyprogesterone (17-OHP) levels in dried blood spots. However, false negatives can occur for several reasons, including premature infants having lower 17-OHP levels, making detection more difficult 1. Some milder forms of CAH, particularly non-classical CAH, may not produce sufficiently elevated hormone levels during the first few days of life when screening typically occurs. Additionally, technical factors such as sample collection timing, storage conditions, or laboratory errors can affect results. Some rarer forms of CAH involving other enzyme deficiencies may not be detected by standard 17-OHP screening.
For these reasons, clinicians should maintain a high index of suspicion for CAH even with negative screening results, especially in infants presenting with ambiguous genitalia, salt-wasting crisis, or family history of CAH 1. Follow-up testing with serum electrolytes, 17-OHP levels, and other adrenal steroids may be necessary when clinical suspicion exists despite negative screening. It is also crucial to consider CAH in the differential diagnosis of disorders of sex development, as failure to diagnose can result in serious harm, including electrolyte imbalances and shock 1.
Key considerations for clinicians include:
- Maintaining a high index of suspicion for CAH in infants with ambiguous genitalia or other signs suggestive of the condition
- Being aware of the limitations of newborn screening for CAH, including false negatives in premature infants or those with milder forms of the disease
- Considering follow-up testing when clinical suspicion exists despite negative screening results
- Recognizing the importance of early diagnosis and treatment to prevent serious complications and improve outcomes for affected individuals.
From the Research
Congenital Adrenal Hyperplasia and Newborn Screening
- Congenital adrenal hyperplasia (CAH) is a primary adrenal insufficiency in children and adolescents, characterized by androgen excess secondary to impaired steroidogenesis in the adrenal glands 2.
- Newborn screening for CAH has been in place in the USA for over 20 years, measuring 17-hydroxyprogesterone (17OHP) levels 3, 4.
- However, not all patients with classic CAH are diagnosed as neonates, and some may be missed on the newborn screen (NBS) 3.
Characteristics of Patients Missed on Newborn Screen
- A study found that nearly one-fifth of patients with classic CAH were missed on the NBS, with a mean age at diagnosis of 21.7 months 3.
- Patients who were missed on the NBS presented with clinical evidence of hyperandrogenism, including clitoromegaly, posterior labial fusion, and pubic hair 3.
- A positive family history of CAH was present in 42% of the missed patients, highlighting the importance of maintaining a high index of suspicion for CAH 3.
Limitations of Newborn Screening for CAH
- Newborn screening for CAH is plagued by false positives, with 17OHP levels above cutoff values in the first 24 hours of life, in premature infants, and in term infants with physiologic stress from unrelated diseases 4.
- The use of 17OHP as a screening marker may not be specific enough, and alternative markers such as 21-deoxycortisol may be more effective 4.
- Differences in protocols among US state laboratories may also contribute to variations in sensitivity and specificity of CAH screening 5.
Importance of Early Detection and Treatment
- Early identification and treatment of CAH are crucial to avoid adverse effects and potential life-threatening adrenal crises 2, 6.
- Newborn screening must be performed soon after birth, and results must be available quickly to avert early salt-wasting crises 6.
- Standardization of newborn screening protocols and the use of more specific markers may improve the positive predictive value and reduce false positives 4, 5.