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

Abstract

Objective: To determine the frequency of mutant alleles in the CYP21 gene in Spanish girls presenting with precocious pubarche (PP) and to assess the relationships between genotype and endocrinemetabolic variables. Design: Fifty-three unrelated girls with a history of PP (14 prepubertal, 8 pubertal and 31 postmenarcheal) and 35 controls were studied. Methods: Genomic DNA was extracted from peripheral blood leukocytes. After selection against the pseudogen, an allele-specific PCR was used to identify 14 known mutations in the CYP21 gene. The mutations studied were Pro30Leu, splice intron 2, Ilel72Asn, Cluster E 6 , Glyl92Ser, Ins T, GT-CT, Gln318-stop, Arg357Trp, Trp406-stop, Pro453Ser, Arg483Pro, Arg483 frameshift and Val281Leu. A standard 2-h oral glucose tolerance test was performed in all PP girls. Ovarian 17-hydroxyprogesterone (17-OHP) responses to gonadotrophin-releasing hormone-agonist stimulation was assessed in postmenarcheal PP girls. Results: Thirteen PP girls and eight control girls were heterozygous for one of the mutations studied. The frequency of the carrier status was 25% and 23% in the PP and control groups respectively. Severe mutations were found in 33% of the carrier girls. Serum 17-OHP responses to ACTH stimulation were similar in carriers and non-carriers ð351^65 vs 334^22 ng=dlÞ: The presence of ovarian hyperandrogenism and/or hyperinsulinism was also not related to the carrier status. Conclusion: The incidence of molecular defects in the CYP21 gene in the present study was comparable in the PP and control groups. We found no relationship between the presence of carrier status and endocrine-metabolic abnormalities. Prospective studies of larger cohorts of PP girls are needed to ascertain the long-term clinical relevance of CYP21 heterozygosity.

A Favorable Metabolic and Antiatherogenic Profile in Carriers of <i>CYP21A2</i> Gene Mutations Supports the Theory of a Survival Advantage in This Population

“…These findings are in agreement with those reported by Ibanez et al [35], revealing that the presence of functional ovarian hyperandrogenism was not related to CYP21A2 carrier status. …”

Characteristics and prevalence of non-classical congenital adrenal hyperplasia with a V281l mutation in patients with premature pubarche

“…Other studies have reported an incidence of approximately 30 % based on a search for known CYP21 mutations (22,28,29) . Potau et al studied 53 unrelated girls with a history of PP and 35 controls (28) . Thirteen PP girls and eight control girls were heterozygous for one of the mutations studied.…”

“…Potau et al studied 53 unrelated girls with a history of PP and 35 controls (28) . The frequency of the carrier status was similar between 25 % in PP and 23 % in control groups (28) . The frequency of the carrier status was similar between 25 % in PP and 23 % in control groups (28) .…”

Pubarquia precoz: Experience in 173 cases

“…Esta proporción es más baja que en otras series de países como Grecia: 45,8% 39 , Brasil: 21,4% 40 , EE.UU. de Norteamérica: 30% 41 , y España; 25% 42 , pero más alta comparada con una serie italiana: 5,8% 43 . Es importante destacar que esas diferentes proporciones pueden deberse al uso de diferentes métodos y criterios para definir el diagnóstico (bioquímico, genético e incluso el estado de portador).…”