High incidence of molecular defects of the CYP21 gene in patients with premature adrenarche

On the basis of hormonal studies, the incidence of defective steroidogenesi s in children with premature adrenarche (PA) in the various reports ranges from 0-54%. Molecular studies have not been reported to date. The aim of th e present study was to search for defects in the CYP21 gene in children wit h PA and to detect possible correlations of the molecular defect to pertine nt hormonal and clinical data. In 48 children with PA (40 females and 8 mal es) and without signs of virilization, a Synachten test and molecular studi es were carried out. DNA analysis was performed using the Southern blot tec hnique and allele-specific PCR. Synachten (0.25 mg) was given iv, and 17-hy droxyprogesterone and cortisol were determined at 0 and 60 min. At baseline , Delta(4)-androstenedione, dehydroepiandrosterone sulfate, and 11-deoxycor tisol were also determined. Bone age was evaluated using the Greulich and P yle atlas. Abnormal genotype was detected in 45.8% of the studied subjects; 8.3% were homozygotes, with genotypes concordant with the nonclassical phe notype of 21 hydroxylase deficiency, and 37.5% were heterozygotes for 9 dif ferent molecular defects of the CYP21 gene. The children with no detectable molecular defect were designated normal. The 60 min post-Synachten values in homozygotes(17.9 +/- 7.1 ng/mL) and heterozygotes (7.1 +/- 3.6 ng/mL) we re significantly higher than that in normal subjects (3.3 +/- 1.5 ng/mL,), but with significant overlapping of values. The mean difference between bon e age and chronological age differed in the three groups with overlapping v alues. The basal Delta(4)-androstenedione level was lower in the normal sub jects (0.65 +/- 0.3 ng/mL) than in those with abnormal genotype (1.1 +/- 0. 8 ng/mL). The data indicate that the incidence of molecular defects in PA i s quite high. The CYP21 heterozygocity is clinically expressed in some subj ects prepubertally. In a significant number of cases the genotype cannot be predicted by the age of onset of PA, the mean difference between bone age and chronological age, or the results of a Synachten test. Follow-up of the se children through puberty is imperative and may reveal the clinical signi ficance of the molecular defect, namely more hypertrichosis, intense acne, early puberty, possible abnormal menses, and/or fertility problems in the a ffected.