title: Relationship of CYP21A2 genotype and serum 17-hydroxyprogesterone and cortisol levels in a large cohort of Italian children with premature pubarche.
abstract: OBJECTIVE
  Premature pubarche (PP) is the most frequent sign of nonclassic congenital adrenal hyperplasia (NCCAH) due to 21-hydroxylase deficiency in childhood. The aim of this study was to assess the relationship between the CYP21A2 genotype and baseline and ACTH-stimulated 17-hydroxyprogesterone (17-OHP) and cortisol serum levels in patients presenting with PP.
  
  
  METHODS
  A total of 152 Italian children with PP were studied. Baseline and ACTH-stimulated 17-OHP and cortisol serum levels were measured and CYP21A2 gene was genotyped in all subjects.
  
  
  RESULTS
  Baseline and ACTH-stimulated serum 17-OHP levels were significantly higher in NCCAH patients than in both heterozygotes and children with idiopathic PP (IPP). Of the patient population, four NCCAH patients (7.3%) exhibited baseline 17-OHP values <2 ng/ml (6 nmol/l). An ACTH-stimulated 17-OHP cutoff level of 14 ng/ml (42 nmol/l) identified by the receiver-operating characteristics curves showed the best sensitivity (90.9%) and specificity (100%) in distinguishing NCCAH patients. This value, while correctly identifying all unaffected children, missed 9% of affected individuals. Cortisol response to ACTH stimulation was <18.2 μg/dl (500 nmol/l) in 14 NCCAH patients (28%) and none of the heterozygotes or IPP children. Among the 55 NCCAH patients, 54.5% were homozygous for mild CYP21A2 mutations, 41.8% were compound heterozygotes for one mild and one severe CYP21A2 gene mutations, and 3.6% had two severe CYP21A2 gene mutations.
  
  
  CONCLUSIONS
  In children with PP, baseline 17-OHP levels are not useful to rule out the diagnosis of NCCAH, which is accomplished by means of ACTH testing only. The different percentages of severe and mild CYP21A2 gene mutations found in PP children compared with adult NCCAH patients is an indirect evidence that the enzyme defect is under-diagnosed in childhood, and it might not lead to the development of hyperandrogenic symptoms in adulthood. Stress-dose glucocorticoids should be considered in patients with suboptimal cortisol response to ACTH stimulation.
authors.affiliation: Division of Endocrinology, Diabetology, and Metabolism, Department of Internal Medicine, University of Turin, Corso Dogliotti 14, 10126 Turin, Italy. lucia.ghizzoni@unito.it
authors.forename: Lucia
authors.initials: L
authors.lastname: Ghizzoni
authors.forename: Marco
authors.initials: M
authors.lastname: Cappa
authors.forename: Alessandra
authors.initials: A
authors.lastname: Vottero
authors.forename: Graziamaria
authors.initials: G
authors.lastname: Ubertini
authors.forename: Daniela
authors.initials: D
authors.lastname: Carta
authors.forename: Natascia
authors.initials: N
authors.lastname: Di Iorgi
authors.forename: Valentina
authors.initials: V
authors.lastname: Gasco
authors.forename: Maddalena
authors.initials: M
authors.lastname: Marchesi
authors.forename: Vera
authors.initials: V
authors.lastname: Raggi
authors.forename: Anastasia
authors.initials: A
authors.lastname: Ibba
authors.forename: Flavia
authors.initials: F
authors.lastname: Napoli
authors.forename: Arianna
authors.initials: A
authors.lastname: Massimi
authors.forename: Mohamad
authors.initials: M
authors.lastname: Maghnie
authors.forename: Sandro
authors.initials: S
authors.lastname: Loche
authors.forename: Ottavia
authors.initials: O
authors.lastname: Porzio
mesh_terms: D019326:17-alpha-Hydroxyprogesterone / Q000097:blood*; D000312:Adrenal Hyperplasia, Congenital / Q000097:blood / Q000235:genetics; D000328:Adult; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005260:Female; D005838:Genotype; D006801:Humans; D006854:Hydrocortisone / Q000097:blood*; D007223:Infant; D007558:Italy; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000502:physiology; D011629:Puberty, Precocious / Q000097:blood* / Q000235:genetics*; D012189:Retrospective Studies; D013255:Steroid 21-Hydroxylase / Q000235:genetics*
chemical_list: D019326:17-alpha-Hydroxyprogesterone; C531510:CYP21A2 protein, human; D013255:Steroid 21-Hydroxylase; D006854:Hydrocortisone