High Incidence of Molecular Defects of the CYP21 Gene in Patients with Premature Adrenarche

Abstract

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 i.v., and 17-hydroxyprogesterone and cortisol were determined at 0 and 60 min. At baseline, delta4-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 delta4-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.

Molecular defects of the CYP21 gene in Spanish girls with isolated precocious pubarche

“…Previous reports have shown higher (15) or similar frequencies (17,33,34) of heterozygosity in both PP children and hyperandrogenic women. However, some of these studies included patients with NCAH (15), were performed in unselected groups of hirsute women (34), or included different racial groups (17).…”

Sex determination and disorders of sex development according to the revised nomenclature and classification in 46,XX individuals

“…Most girls are asymptomatic at birth and may present later on with premature pubarche during childhood, hirsutism and/or menstrual irregularities during adolescence, subfertility in later life or a phenotype resembling polycystic ovary syndrome. 71,73,74 Several mutations in the CYP21A2 gene have been described with a broad overlap with regard to the degree of virilization and a variable genotype-phenotype correlation.The concordance between phenotype and genotype varies in the different forms, being 100% in the salt-losing variety. 70,75 11β-hydroxylase deficiency (CYP11Β1) represents about 5-8% of CAH cases and occurs in 1 out of 200,000 live births.…”

The Prevalence of Non-classical Congenital Adrenal Hyperplasia Due to 21-hydroxylase Deficiency in Greek Women with Hirsutism and Polycystic Ovary Syndrome

“…In our previous two papers in Greek hyperandrogenic women, it was estimated that the frequency of NC-CAH was about 5%; however, a great number of women that reached the 11% had hormonal levels compatible with a possible heterozygosity of 21-OHdef [38,39]. Dacou Voutetakis et al in a substantial sample of children from Greece with premature adrenarche reported a high incidence of molecular defects of CYP 21 gene that reached to 33% [40]. The genetic linkage disequilibrium between 21-OHdef and HLA phenotypes B 14, DR 1 , B 35 , B 7 and B 44 has been reported in many studies in the Caucasian populations and the Jewish Ashkenazi as well as in the populations around the Mediterranean.…”