Interpretation

In untreated 21-hydroxylase (CYP21A2) deficiency, 21-deoxycortisol serum concentrations on average exceed the upper limit of the reference range 30-fold to 40-fold.

21-Hydroxycortisol measurements are particularly useful in equivocal cases of suspected 21-hydroxylase deficiency. Most untreated patients with 21-hydroxylase deficiency have serum 17-hydroxyprogesterone concentrations well in excess of 1000 ng/dL. For the few patients with levels in the range of greater than 630 ng/dL (upper limit of reference range for newborns) to 2000 ng/dL or 3000 ng/dL, it might be prudent to consider 11-hydroxylase deficiency as an alternative diagnosis. This is particularly true if serum androstenedione concentrations are also only mildly-to-modestly elevated and if the phenotype is not salt wasting but either simple virilizing (female) or normal (female or male). 11-Hydroxylase deficiency, particularly if it affects 11 beta-hydroxylase 1 (CYP11B1), can be associated with modest elevations in serum 17-hydroxyprogesterone concentrations. In these cases, testing for CYP11B1 deficiency and 11 beta-hydroxylase 2 (CYP11B2) deficiency should be considered and interpreted as described above. Alternatively, measurement of 21-deoxycortisol might be useful in such cases. This minor pathway metabolite accumulates in CYP21A2 deficiency, as it requires 21-hydroxylation to be converted to cortisol but is usually not elevated in CYP11B1 deficiency since its synthesis requires via 11-hydroxylation of 17-hydroxyprogesterone.

For genetic counseling purposes, identification of asymptomatic carriers of CYP21A2 variants and deletions is sometimes required. The gold-standard is full DNA sequencing of CYP21A2, its pseudogene CYP21A1P, and, if possible, recombinants of gene and pseudogene, along with deletion detection. Such a procedure may be costly and complex, and often has a slow turnaround time. Therefore, many laboratories perform less complex, but also less complete, variant and deletion assessments, which may miss a significant minority of heterozygote carriers. Biochemical testing using corticotropin (previously adrenocorticotropic hormone: ACTH) 1-24 adrenal stimulation represents an alternative. However, for 17-hydroxyprogesterone and androstenedione measurements, there is significant overlap between poststimulation results in normal patients and in heterozygote carriers. By contrast, poststimulation 21-deoxycortisol concentrations of 55 ng/dL identify virtually all heterozygote carriers, with minimal overlap with normal individuals.

The goal of congenital adrenal hyperplasia (CAH) treatment is normalization of cortisol levels and, ideally, sex steroid levels. Serum 17-hydroxyprogesterone, androstenedione, and testosterone should be measured and used to guide treatment modifications. Normal prepubertal androgen levels may be difficult to achieve, but if testosterone levels are within the reference range, androstenedione levels up to 100 ng/dL are usually regarded as acceptable. 17-Hydroxyprogesterone levels should not significantly exceed the normal reference range at any time of the day. However, during puberty, the changing levels of sex steroid production may make 17-hydroxyprogesterone measurements less reliable. Since 21-deoxycortisol is not a sex-steroid precursor, its levels appear more reliable during the pubertal period; again, the aim being not to exceed the reference range significantly.