Interpretive Handbook

Congenital adrenal hyperplasia (CAH) is a group of disorders caused by inherited defects in steroid biosynthesis, in particular, 21-hydroxylase deficiency (approximately 90% of cases) and 11-beta hydroxylase deficiency (approximately 5% of cases). The overall incidence of the classic form of 21-hydroxylase deficiency is approximately 1 in 15,000 live births. Individuals with CAH may present with life-threatening, salt-wasting crises in the newborn period and incorrect gender assignment of virilized females as a result of reduced glucocorticoids and mineralocorticoids and elevated 17-hydroxyprogesterone (17-OHP) and androgens. Hormone replacement therapy, when initiated early, enables a significant reduction in morbidity and mortality. Therefore, newborn screening for CAH is desirable and has been implemented in all 50 states.

Immunoassays are typically used to quantify 17-OHP as a marker for CAH. However, these immunoassays are hampered by cross-reactivity of the antibodies with other steroids, yielding a high rate of false-positive results. Tandem mass spectrometry allows for the simultaneous specific determination of 17-OHP and other steroids, such as androstenedione, cortisol, 11-deoxycortisol, and 21-deoxycortisol. Application of this technology to the determination of steroids in newborn screening blood spots significantly enhances the correct identification of patients with CAH and reduces the number of false-positive screening results.

Second-tier testing of newborns with abnormal screening result for congenital adrenal hyperplasia

Findings of a 17-hydroxyprogesterone (17-OHP) value >7.0 ng/mL in males or >4.0 ng/mL in females, and a high (17-OHP + androstenedione)/cortisol ratio (controls: < or =2.5) are supportive of the initial abnormal newborn screening result. Findings of an 11-deoxycortisol value >10.0 ng/mL or 21-deoxycortisol >1.6 ng/mL with elevated 17-OHP further support the abnormal newborn screening result and increase the diagnostic specificity. Clinical and laboratory follow-up is strongly recommended.

This is a screening test and, while it's positive predictive value is significantly higher than that of immunoassays (9.0% versus 0.5%), false-positive results can occur. Follow-up of abnormal results is necessary; perform OHPG/9231 17-Hydroxyprogesterone, Serum and DOC/8547 Deoxycortisol, Plasma on a serum specimen.

17-HYDROXYPROGESTERONE

Males: <7.1 ng/mL

Females: <4.1 ng/Ml

ANDROSTENEDIONE

<3.1 ng/mL

CORTISOL

>2.5 ng/Ml

11-DEOXYCORTISOL

<10.1 ng/mL

21-DEOXYCORTISOL

<1.7 ng/Ml

(17 OHP + ANDROSTENEDIONE)/ CORTISOL RATIO

<2.51

Note: Abnormal (17 OHP + Androstenedione)/Cortisol Ratio: >2.5 is only applicable when 17-OHP is elevated

11-DEOXYCORTISOL/CORTISOL RATIO

<1.1

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2. Minutti CZ, Lacey JM, Magera MJ, et al: Steroid profiling by tandem mass spectrometry improves the positive predictive value of newborn screening for congenital adrenal hyperplasia. J Clin Endo Met 2004;89:3687-3693

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4. Witchel SF, Azziz R: Congenital adrenal hyperplasia. Pediatri Adolesc Gynecol 2011;24:116-126