Plasma kinetics and metabolism of labeled dexamethasone were evaluated in nine subjects before and after administration of diphenylhydantoin. Labeled dexamethasone was injected intravenously followed by frequent sampling of blood and urine. The labeled dexamethasone in plasma was isolated chromatographically. Total urine and fractional radioactivity after solvent extraction (chloroform and ethyl acetate), with and without glucuronide hydrolysis, were determined. Baseline plasma equilibrated tj4's and metabolic clearance rates (2 compartment model) ranged from 167 to 368 minutes and 222 to 456 liters/day, respectively. After diphenylhydantoin there were consistent decreases in t j^ and increases in metabolic clearance rate; mean changes -5 1 % and -f-140% respectively.Mean recovery of urinary radioactivity at 4 and 24 hours was 16 and 64 percent of dose respectively. The largest fraction was a more polar unconjugated one, 7 and 31 percent of dose at 4 and 24 hours. Following diphenylhydantoin there was a significant increase in rate of appearance of radioactivity in urine, the greatest increase being in the more polar unconjugated fraction.It is concluded that 1) the metabolic kinetics of plasma dexamethasone vary considerably among individuals and 2) diphenylhydantoin administration markedly hastens removal rate of dexamethasone from plasma mainly by increasing conversion to more polar metabolites. ( / Clin Endocr 34: 44, 1972) A LTHOUGH synthetic glucocorticoids have been employed clinically for several years little attention has been given to their metabolism. Our interest in this problem developed a few years ago when it was noted that diphenylhydantoin (DPH) inhibited the effectiveness of dexamathasone during standard plasma dexamethasone suppression tests (1). The current report describes studies of plasma disappearance and metabolic clearance rates of circulating labeled dexamethasone, of rate of appearance of radioactivity in urine fractions and of the manner in which DPH affects these measurements.Jubiz et al. have reported on certain aspects of this problem (2). It was demon-

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We present a family with 2 members who received long-term steroid treatment for presumed classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, until molecular testing revealed nonclassic CAH, not necessarily requiring treatment. A 17-year-old male presented to our clinic on glucocorticoid and mineralocorticoid treatment for classic CAH. He was diagnosed at 4 years of age based on mild-moderate elevations of 17-hydroxyprogesterone (17-OHP) and adrenocorticotropic hormone (ACTH), but without evidence of precocious adrenarche/puberty. Due to his diagnosis, his clinically asymptomatic 3-year-old sister was tested and also found to have elevated ACTH and 17-OHP levels and was started on glucocorticoids for classic CAH. Family history revealed a healthy sibling who had no biochemical evidence of CAH and consanguineous healthy parents. We questioned the diagnosis of classic CAH and performed an ACTH1-24 stimulation test, which showed a level of 17-OHP in the borderline range between classic and nonclassic CAH. Molecular testing, using sequencing and multiplex ligation-dependent probe amplification analysis of CYP21A2, revealed that both affected siblings were compound heterozygotes for a whole-gene deletion and a, likely pathogenic (nonclassical), sequence variant, p.R124C. The asymptomatic father had the same genotype, while the mother showed one deleted copy and 2 active copies, making her an asymptomatic carrier. Our report demonstrates the importance of molecular testing in atypical cases of CAH, as well as the importance of both sequencing and deletion analysis. The results of molecular testing should be interpreted in clinical context, and treatment should be prescribed according to guidelines when available.

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