title: Functional glucocorticoid receptor gene variants do not underlie the high variability of 17-hydroxyprogesterone screening values in healthy newborns.
abstract: OBJECTIVE
  17-Hydroxyprogesterone (17-OHP) screening for classical congenital adrenal hyperplasia (CAH) is part of many newborn screening programs worldwide. Cut-off values are relatively high, and screening sensitivity does not reach 100%. Recently, the glucocorticoid receptor (GR) N363S-variant has been linked to relatively low degree of virilization and comparatively lower 17-OHP serum concentrations in clinically diagnosed female CAH patients. We sought to determine whether functional GR gene variants, either increasing (N363S, BclI) or decreasing GR sensitivity (R23K), underlie the variable 17-OHP screening levels in healthy newborns.
  
  
  METHODS
  GR genotypes were compared with 17-OHP screening values in 1000 random samples from routine screening. 17-OHP was measured by conventional immunoassay (TRFIA) and a liquid chromatography-tandem mass spectrometry method (LC-MS/MS), which has been shown to increase screening specificity by steroid profiling and avoiding cross-reactions of the 17-OHP-antibody.
  
  
  RESULTS
  There was no significant association of 17-OHP with GR genotypes, even after inclusion of gestational and postnatal age as covariates. However, among LC-MS/MS steroid measurements, we observed some unexpected trends, including lower 11-deoxycortisol concentrations in both 363S- and 23K-carriers. For carriers of the frequent BclI variant, linear regression analysis revealed a significant increase of 4-androstenedione levels with every mutant allele inherited.
  
  
  CONCLUSIONS
  Functional GR variants do not underlie the variation of 17-OHP values observed in healthy individuals. However, whether and to which extent genetically determined differences in individual GR sensitivity influence 17-OHP screening levels in conditions of a pathological hypothalamus-pituitary-adrenal gland-axis stimulation and thus may explain false-negative screening results in those affected by CAH remains to be investigated.
authors.affiliation: Pediatric Endocrinology Division, Children's Hospital, University of Bonn, Bonn, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Schreiner
authors.forename: Magdalini
authors.initials: M
authors.lastname: Tozakidou
authors.forename: Rita
authors.initials: R
authors.lastname: Maslak
authors.forename: Ute
authors.initials: U
authors.lastname: Holtkamp
authors.forename: Michael
authors.initials: M
authors.lastname: Peter
authors.forename: Bettina
authors.initials: B
authors.lastname: Gohlke
authors.forename: Joachim
authors.initials: J
authors.lastname: Woelfle
mesh_terms: D019326:17-alpha-Hydroxyprogesterone / Q000097:blood*; D000312:Adrenal Hyperplasia, Congenital / Q000097:blood / Q000175:diagnosis; D000483:Alleles; D002851:Chromatography, High Pressure Liquid; D003350:Cortodoxone / Q000097:blood; D004247:DNA / Q000235:genetics; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007231:Infant, Newborn; D012150:Polymorphism, Restriction Fragment Length; D011965:Receptors, Glucocorticoid / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053719:Tandem Mass Spectrometry
chemical_list: D011965:Receptors, Glucocorticoid; D019326:17-alpha-Hydroxyprogesterone; D004247:DNA; D003350:Cortodoxone