title: Delayed diagnosis of disorder of sex development (DSD) due to P450 oxidoreductase (POR) deficiency.
abstract: METHODS
  A 36-year old man, operated on for cryptorchidism at the age of 8 years, was referred to the Outpatient Clinic of Reproductive Endocrinology for investigation of infertility. Clinical examination revealed ambiguous genitalia: penis 4-5 cm, testicular volume 2-3 ml, hypospadias, hypertrophic foreskin and scrotum bifida. Mild hypertension was confirmed. No skeletal malformations were detected.
  
  
  METHODS
  Hormonal and electrolytic determinations as well as semen analysis were conducted. PCR of the coding regions of 17-hydroxylase/17,20 lyase (P450c17) and of P450 oxidoreductase (POR) genes was also performed.
  
  
  RESULTS
  Normal levels of electrolytes, low levels of androgens, high levels of gonadotropins and 17-hydroxyprogesterone as well as azoospermia were detected. Karyotype was shown to be 46,XY. Both hCG and ACTH stimulation significantly increased 17-hydroxyprogesterone with no increase in androgens. The diagnosis was congenital adrenal hyperplasia with apparent combined P450c17 and P450c21 deficiency due to mutations in the POR gene. Sequencing of the POR gene revealed: one deletion in exon 12 (Del 1696_1698delGTC >del531Valine) and one missense mutation in exon 7 (A259G) as well as two polymorphisms: rs1057868 (C/T A503V) and rs1057870 (G/A S572S) in exons 12 and 13, respectively. No nucleotide changes were detected in the 8 exons of P450c17.
  
  
  CONCLUSIONS
  Molecular findings were consistent with the diagnosis of P450 oxidoreductase deficiency. Despite this severe deficiency, skeletal malformations simulating Antley-Bixler syndrome, which usually characterize the most severe forms, were not confirmed. This discrepancy could be attributed to the differential impact of a POR variant on each one of the P450 enzymes.
authors.affiliation: Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology, University of Patras Medical School, University Hospital, 26500, Patras, Greece.
authors.forename: Vasiliki
authors.initials: V
authors.lastname: Koika
authors.affiliation: Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology, University of Patras Medical School, University Hospital, 26500, Patras, Greece.
authors.forename: Anastasia K
authors.initials: AK
authors.lastname: Armeni
authors.affiliation: Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology, University of Patras Medical School, University Hospital, 26500, Patras, Greece. neoklisg@hol.gr.
authors.forename: Neoklis A
authors.initials: NA
authors.lastname: Georgopoulos
mesh_terms: D000328:Adult; D054882:Antley-Bixler Syndrome Phenotype / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology; D053713:Azoospermia / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics; D003456:Cryptorchidism / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics; D003577:Cytochrome P-450 Enzyme System / Q000172:deficiency / Q000235:genetics*; D004252:DNA Mutational Analysis; D057210:Delayed Diagnosis; D058490:Disorder of Sex Development, 46,XY / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology; D005091:Exons; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000379:methods*; D006801:Humans; D007621:Karyotyping; D008297:Male; D009154:Mutation; D010641:Phenotype; D011110:Polymorphism, Genetic; D011237:Predictive Value of Tests; D013254:Steroid 17-alpha-Hydroxylase / Q000235:genetics; D013255:Steroid 21-Hydroxylase / Q000235:genetics; D013997:Time Factors
chemical_list: C000602470:POR protein, human; D003577:Cytochrome P-450 Enzyme System; D013255:Steroid 21-Hydroxylase; D013254:Steroid 17-alpha-Hydroxylase