ISOLATED PRECOCIOUS PUBARCHE - AN APPROACH

Precocious pubarche (PP) is most often a benign condition secondary to the early appearance of adrenarche. However, PP may be a manifestation of nonclassical adrenal hyperplasia. The incidence of nonclassical adrenal hyperplasia in patients with PP ranges from about 0-40% of cases. Controversy exists as to whether all children with PP should undergo 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 ethnically 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 test; and 3) to determine which patients diagnosed as having a mild adrenal 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 (17PGN), dehydroepiandrosterone, androstenedione, testosterone, 11-deoxycortisol, and cortisol were evaluated. Haplotype (HLA) typing was performed in the patients who were diagnosed with nonclassical 21-hydroxylase deficiency (NC21OHD). Using published nomogram standards for the serum 17OHP response to ACTH, 10 patients (5.8%) were diagnosed as having NC21OHD. Seven of 112 patients (6.2%) were diagnosed as having nonclassical 3 beta-hydroxysteroid dehydrogenase deficiency (NC3HSD) on the basis of the following three criteria: stimulated 17PGN levels and stimulated 17PGN/17OHP and 17PGN/cortisol ratios higher than 2 SD above the mean for pubertal controls. None of the patients had stimulated 11-deoxycortisol values greater than 2 so above the mean of pubertal controls. Nineteen patients (11%) had a stimulated 170HP response characteristic of the heterozygotes for 21-hydroxylase deficiency. One hundred and thirty-five of 171 patients with no biochemical evidence of an adrenal biosynthetic defect were diagnosed as having precocious adrenarche. Bone age was advanced (>2 SD for chronological age) in 80% of the 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 patients with precocious adrenarche. Basal hormone levels were helpful in detecting 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, and 8 had DR1 haplotypes. In summary, mild errors of steroidogenesis are present in 12% of patients with typical PP. The haplotypes B14 and DR1 are closely associated with NC21OHD in our sample population. The bone age in typical pubarche does not indicate patients with mild enzymatic defects. Among mild enzymatic defects, the one that is clinically important is NC21OHD. In these cases, basal plasma 170HP levels are often 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 whom a progressive and rapid bone maturation is observed to diagnose the form of NC3HSD that requires treatment.