On the basis of hormonal studies, the incidence of defective
steroidogenesis 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 the present study was to search for defects
in the CYP21 gene in children with PA and to detect possible
correlations of the molecular defect to pertinent hormonal and clinical
data. In 48 children with PA (40 females and 8 males) and without signs
of virilization, a Synachten test and molecular studies were carried
out. DNA analysis was performed using the Southern blot technique and
allele-specific PCR. Synachten (0.25 mg) was given iv, and
17-hydroxyprogesterone and cortisol were determined at 0 and 60 min. At
baseline, Delta(4)-androstenedione, dehydroepiandrosterone sulfate, and
11-deoxycortisol were also determined. Bone age was evaluated using the
Greulich and Pyle atlas. Abnormal genotype was detected in 45.8% of the
studied subjects; 8.3% were homozygotes, with genotypes concordant with
the nonclassical phenotype of 21 hydroxylase deficiency, and 37.5% were
heterozygotes for 9 different 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) were significantly higher than that in
normal subjects (3.3 +/- 1.5 ng/mL,), but with significant overlapping
of values. The mean difference between bone age and chronological age
differed in the three groups with overlapping values. The basal
Delta(4)-androstenedione level was lower in the normal subjects (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 is quite
high. The CYP21 heterozygocity is clinically expressed in some subjects
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 these children through puberty is imperative and may reveal the
clinical significance of the molecular defect, namely more
hypertrichosis, intense acne, early puberty, possible abnormal menses,
and/or fertility problems in the affected
