title: Novel H6PDH mutations in two girls with premature adrenarche: 'apparent' and 'true' CRD can be differentiated by urinary steroid profiling.
abstract: BACKGROUND
  Inactivating mutations in the enzyme hexose-6-phosphate dehydrogenase (H6PDH, encoded by H6PD) cause apparent cortisone reductase deficiency (ACRD). H6PDH generates cofactor NADPH for 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1, encoded by HSD11B1) oxo-reductase activity, converting cortisone to cortisol. Inactivating mutations in HSD11B1 cause true cortisone reductase deficiency (CRD). Both ACRD and CRD present with hypothalamic-pituitary-adrenal (HPA) axis activation and adrenal hyperandrogenism.
  
  
  OBJECTIVE
  To describe the clinical, biochemical and molecular characteristics of two additional female children with ACRD and to illustrate the diagnostic value of urinary steroid profiling in identifying and differentiating a total of six ACRD and four CRD cases.
  
  
  METHODS
  Clinical, biochemical and genetic assessment of two female patients presenting during childhood. In addition, results of urinary steroid profiling in a total of ten ACRD/CRD patients were compared to identify distinguishing characteristics.
  
  
  RESULTS
  Case 1 was compound heterozygous for R109AfsX3 and a novel P146L missense mutation in H6PD. Case 2 was compound heterozygous for novel nonsense mutations Q325X and Y446X in H6PD. Mutant expression studies confirmed loss of H6PDH activity in both cases. Urinary steroid metabolite profiling by gas chromatography/mass spectrometry suggested ACRD in both cases. In addition, we were able to establish a steroid metabolite signature differentiating ACRD and CRD, providing a basis for genetic diagnosis and future individualised management.
  
  
  CONCLUSIONS
  Steroid profile analysis of a 24-h urine collection provides a diagnostic method for discriminating between ACRD and CRD. This will provide a useful tool in stratifying unresolved adrenal hyperandrogenism in children with premature adrenarche and adult females with polycystic ovary syndrome (PCOS).
authors.affiliation: CEDAM Centre for Endocrinology, Diabetes and Metabolism, Institute of Biomedical Research, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: G G
authors.initials: GG
authors.lastname: Lavery
authors.forename: J
authors.initials: J
authors.lastname: Idkowiak
authors.forename: M
authors.initials: M
authors.lastname: Sherlock
authors.forename: I
authors.initials: I
authors.lastname: Bujalska
authors.forename: J P
authors.initials: JP
authors.lastname: Ride
authors.forename: K
authors.initials: K
authors.lastname: Saqib
authors.forename: M F
authors.initials: MF
authors.lastname: Hartmann
authors.forename: B
authors.initials: B
authors.lastname: Hughes
authors.forename: S A
authors.initials: SA
authors.lastname: Wudy
authors.forename: J
authors.initials: J
authors.lastname: De Schepper
authors.forename: W
authors.initials: W
authors.lastname: Arlt
authors.forename: N
authors.initials: N
authors.lastname: Krone
authors.forename: C H
authors.initials: CH
authors.lastname: Shackleton
authors.forename: E A
authors.initials: EA
authors.lastname: Walker
authors.forename: P M
authors.initials: PM
authors.lastname: Stewart
mesh_terms: D042842:11-beta-Hydroxysteroid Dehydrogenases / Q000172:deficiency / Q000235:genetics / Q000652:urine; D058489:46, XX Disorders of Sex Development / Q000175:diagnosis* / Q000235:genetics / Q000652:urine; D000293:Adolescent; D050499:Adrenarche / Q000235:genetics* / Q000652:urine; D000328:Adult; D002237:Carbohydrate Dehydrogenases / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D003937:Diagnosis, Differential; D005260:Female; D006628:Hirsutism / Q000151:congenital* / Q000175:diagnosis / Q000235:genetics / Q000652:urine; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010913:Pituitary-Adrenal System / Q000378:metabolism; D043202:Steroid Metabolism, Inborn Errors / Q000175:diagnosis* / Q000235:genetics / Q000652:urine; D013256:Steroids / Q000652:urine*
chemical_list: D013256:Steroids; D002237:Carbohydrate Dehydrogenases; C020552:galactose-6-phosphate dehydrogenase; D042842:11-beta-Hydroxysteroid Dehydrogenases