title: Pubertal presentation in seven patients with congenital adrenal hyperplasia due to P450 oxidoreductase deficiency.
abstract: BACKGROUND
  P450 oxidoreductase (POR) is a crucial electron donor to all microsomal P450 cytochrome (CYP) enzymes including 17α-hydroxylase (CYP17A1), 21-hydroxylase (CYP21A2) and P450 aromatase. Mutant POR causes congenital adrenal hyperplasia with combined glucocorticoid and sex steroid deficiency. P450 oxidoreductase deficiency (ORD) commonly presents neonatally, with disordered sex development in both sexes, skeletal malformations, and glucocorticoid deficiency.
  
  
  OBJECTIVE
  The aim of the study was to describe the clinical and biochemical characteristics of ORD during puberty.
  
  
  METHODS
  Clinical, biochemical, and genetic assessment of seven ORD patients (five females, two males) presenting during puberty was conducted.
  
  
  RESULTS
  Predominant findings in females were incomplete pubertal development (four of five) and large ovarian cysts (five of five) prone to spontaneous rupture, in some only resolving after combined treatment with estrogen/progestin, GnRH superagonists, and glucocorticoids. Pubertal development in the two boys was more mildly affected, with some spontaneous progression. Urinary steroid profiling revealed combined CYP17A1 and CYP21A2 deficiencies indicative of ORD in all patients; all but one failed to mount an appropriate cortisol response to ACTH stimulation indicative of adrenal insufficiency. Diagnosis of ORD was confirmed by direct sequencing, demonstrating disease-causing POR mutations.
  
  
  CONCLUSIONS
  Delayed and disordered puberty can be the first sign leading to a diagnosis of ORD. Appropriate testosterone production during puberty in affected boys but manifest primary hypogonadism in girls with ORD may indicate that testicular steroidogenesis is less dependent on POR than adrenal and ovarian steroidogenesis. Ovarian cysts in pubertal girls may be driven not only by high gonadotropins but possibly also by impaired CYP51A1-mediated production of meiosis-activating sterols due to mutant POR.
authors.affiliation: Centre for Endocrinology, Diabetes and Metabolism, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham B15 2TT, United Kingdom.
authors.forename: Jan
authors.initials: J
authors.lastname: Idkowiak
authors.forename: Stephen
authors.initials: S
authors.lastname: O'Riordan
authors.forename: Nicole
authors.initials: N
authors.lastname: Reisch
authors.forename: Ewa M
authors.initials: EM
authors.lastname: Malunowicz
authors.forename: Felicity
authors.initials: F
authors.lastname: Collins
authors.forename: Michiel N
authors.initials: MN
authors.lastname: Kerstens
authors.forename: Birgit
authors.initials: B
authors.lastname: Köhler
authors.forename: Luitgard Margarete
authors.initials: LM
authors.lastname: Graul-Neumann
authors.forename: Maria
authors.initials: M
authors.lastname: Szarras-Czapnik
authors.forename: Mehul
authors.initials: M
authors.lastname: Dattani
authors.forename: Martin
authors.initials: M
authors.lastname: Silink
authors.forename: Cedric H L
authors.initials: CH
authors.lastname: Shackleton
authors.forename: Dominique
authors.initials: D
authors.lastname: Maiter
authors.forename: Nils
authors.initials: N
authors.lastname: Krone
authors.forename: Wiebke
authors.initials: W
authors.lastname: Arlt
mesh_terms: D000293:Adolescent; D000312:Adrenal Hyperplasia, Congenital / Q000503:physiopathology*; D000568:Amenorrhea / Q000209:etiology; D000728:Androgens / Q000097:blood / Q000627:therapeutic use; D015331:Cohort Studies; D005260:Female; D005835:Genitalia / Q000002:abnormalities; D006061:Gonadal Dysgenesis, 46,XY / Q000201:enzymology / Q000503:physiopathology; D012739:Gonadal Steroid Hormones / Q000097:blood; D020249:Hormone Replacement Therapy; D006801:Humans; D007231:Infant, Newborn; D007621:Karyotyping; D008297:Male; D008598:Menstruation; D009251:NADPH-Ferrihemoprotein Reductase / Q000172:deficiency*; D010048:Ovarian Cysts / Q000188:drug therapy / Q000235:genetics; D010053:Ovary / Q000473:pathology; D010641:Phenotype; D011627:Puberty / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013256:Steroids / Q000652:urine; D055815:Young Adult
chemical_list: D000728:Androgens; D012739:Gonadal Steroid Hormones; D013256:Steroids; D009251:NADPH-Ferrihemoprotein Reductase