Precocious pubarche (PP) is most often a benign condition secondary to
the early appearance of adrenarche. However, PP may be a manifestatio
n of nonclassical adrenal hyperplasia. The incidence of nonclassical a
drenal hyperplasia in patients with PP ranges from about 0-40% of case
s. Controversy exists as to whether all children with PP should underg
o an ACTH stimulation test. The aim of this study was 1) to determine
the frequency of mild adrenal enzyme defects in a very large and ethni
cally homogeneous group of children with isolated PP (typical pubarche
); 2) to determine whether clinical data, in particular bone age, and
basal hormonal values can help to distinguish patients who are at risk
for having adrenal enzymatic defects and thus should have an ACTH tes
t; and 3) to determine which patients diagnosed as having a mild adren
al enzyme defect might require treatment. We studied 171 subjects (135
girls and 36 boys), aged 7 +/- 1.2 (SD) yr, with isolated PP. Thirty-
eight normal subjects (18 age-matched and 20 pubertal) were studied as
controls. An ACTH stimulation test (Synacthen, 0.25-mg iv bolus) was
performed. Blood samples were drawn at baseline and 1 h postinjection.
17 alpha-Hydroxyprogesterone (17OHP), 17 alpha-hydroxypregnenolone (1
7PGN), dehydroepiandrosterone, androstenedione, testosterone, 11-deoxy
cortisol, and cortisol were evaluated. Haplotype (HLA) typing was perf
ormed in the patients who were diagnosed with nonclassical 21-hydroxyl
ase deficiency (NC21OHD). Using published nomogram standards for the s
erum 17OHP response to ACTH, 10 patients (5.8%) were diagnosed as havi
ng NC21OHD. Seven of 112 patients (6.2%) were diagnosed as having nonc
lassical 3 beta-hydroxysteroid dehydrogenase deficiency (NC3HSD) on th
e basis of the following three criteria: stimulated 17PGN levels and s
timulated 17PGN/17OHP and 17PGN/cortisol ratios higher than 2 SD above
the mean for pubertal controls. None of the patients had stimulated 1
1-deoxycortisol values greater than 2 so above the mean of pubertal co
ntrols. Nineteen patients (11%) had a stimulated 170HP response charac
teristic of the heterozygotes for 21-hydroxylase deficiency. One hundr
ed and thirty-five of 171 patients with no biochemical evidence of an
adrenal biosynthetic defect were diagnosed as having precocious adrena
rche. Bone age was advanced (>2 SD for chronological age) in 80% of th
e patients with NC21OHD, in 71.4% of the patients with NC3HSD, in 58%
of the patients classified as heterozygotes, and in 32.6% of the patie
nts with precocious adrenarche. Basal hormone levels were helpful in d
etecting NC21OHD, but not NC3HSD. All patients with NC21OHD and only 1
with NC3HSD underwent glucocorticoid suppression treatment. Among the
10 patients with nonclassical al-hydroxylase deficiency, 9 had B14, a
nd 8 had DR1 haplotypes. In summary, mild errors of steroidogenesis ar
e present in 12% of patients with typical PP. The haplotypes B14 and D
R1 are closely associated with NC21OHD in our sample population. The b
one age in typical pubarche does not indicate patients with mild enzym
atic defects. Among mild enzymatic defects, the one that is clinically
important is NC21OHD. In these cases, basal plasma 170HP levels are o
ften already diagnostic, in that they are always higher than pubertal
control values. Thus, from a clinical point of view, the ACTH test in
patients with typical pubarche must be reserved for subjects with high
basal plasma 170HP levels to diagnose NC21OHD and for subjects in who
m a progressive and rapid bone maturation is observed to diagnose the
form of NC3HSD that requires treatment.