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Genotyping for 10 mutations in the CYP21 gene was performed in 88 families with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Southern blot analysis was used to detect CYP21 deletions or large gene conversions, and allele-specific hybridizations were performed with DNA amplified by the polymerase chain reaction to detect smaller mutations. Mutations were detected on 95% of chromosomes examined. The most common mutations were an A----G change in the second intron affecting pre-mRNA splicing (26%), large deletions (21%), Ile-172----Asn (16%), and Val-281----Leu (11%). Patients were classified into three mutation groups based on degree of predicted enzymatic compromise. Mutation groups were correlated with clinical diagnosis and specific measures of in vivo 21-hydroxylase activity, such as 17-hydroxyprogesterone, aldosterone, and sodium balance. Mutation group A (no enzymatic activity) consisted principally of salt-wasting (severely affected) patients, group B (2% activity) of simple virilizing patients, and group C (10-20% activity) of nonclassic (mildly affected) patients, but each group contained patients with phenotypes either more or less severe than predicted. These data suggest that most but not all of the phenotypic variability in 21-hydroxylase deficiency results from allelic variation in CYP21. Accurate prenatal diagnosis should be possible in most cases using the described strategy.

Exogenous glucocorticoid replacement in patients with congenital adrenal hyperplasia (CAH), who due to an adrenal 21-hydroxylase enzyme deficiency are unable to produce endogenous glucocorticoids, is aimed at normalizing hypothalamic-pituitary-adrenal function. Excess androgen production by the adrenals is thus decreased. Despite standard glucocorticoid replacement doses (12.5-40 mg, 10.5-27 mg/m2/day hydrocortisone equivalents) 4 of 7 patients ranging in age from 14 to 33 years had abnormalities of the pituitary on MRI. Three appeared to have microadenomas and 1 had an empty sella. Five (3 salt wasters, 2 simple virilizers) of these 7 patients had 60-min p.m. ovine corticotropin-releasing hormone (oCRH) stimulation studies. The mean (logarithm) area under the ACTH curve for 0-60 min after oCRH stimulation was significantly greater in patients than controls (p0.0001). Mean ACTH at each time point before and after oCRH stimulation was similarly greater in patients than controls (p0.05). Two of these patients had pituitary microadenomas, 1 had an empty sella; all 3 were salt wasters. Despite standard glucocorticoid replacement, adolescent and young adult patients with CAH tend to have high basal ACTH and ACTH hyperresponsiveness to oCRH, as well as structural abnormalities of the pituitary. The inevitable periods of under- and overexposure to glucocorticoids in CAH patients may over time cause abnormalities of the hypothalamic-pituitary-adrenal axis.

To determine whether hyperandrogenism caused by an inborn error of adrenal steroidogenesis could produce insulin resistance, we examined insulin sensitivity in females with 21-hydroxylase deficiency. Minimal modelling was used to analyze the results of tolbutamide-modified, frequently sampled, iv glucose tolerance testing. Insulin sensitivity [Si; (min-1) (microU/mL)-1] was plotted against body mass index (BMI; defined as kilograms per m2). Six patients with nonclassical 21-hydroxylase deficiency (mean age, 27 yr; mean BMI, 23.2) underwent testing. None of these patients was in active puberty, nor was any patient being treated with glucocorticoids at the time of the study. Twelve eumenorrheic nonhyperandrogenic young adult female control subjects (mean age, 27 yr; mean BMI, 22.4) were also tested. The basal 17-hydroxyprogesterone concentration, but not the total serum testosterone level, was significantly different in the two groups (mean +/- SEM, 11,987 +/- 2,761 vs. 4,059 +/- 802 pmol/L; P0.05). As a group the patients' Si values were significantly lower than those of the controls (mean +/- SEM, 4.1 +/- 0.6 vs. 9.7 +/- 1.2; P0.05). There was no correlation between Si and basal serum 17-hydroxyprogesterone, testosterone, delta 4-androstenedione, or dehydroepiandrosterone. We conclude that chronic hypersecretion of androgen precursors due to an inborn error of metabolism can induce a reduction in insulin sensitivity.