title: Anorectal and urinary anomalies and aberrant retinoic acid metabolism in cytochrome P450 oxidoreductase deficiency.
abstract: BACKGROUND
  Cytochrome P450 oxidoreductase (POR) is an electron donor for all microsomal P450 enzymes including CYP26 involved in inactivation of all-trans retinoic acid (atRA). Although previous studies in Por knockout mice suggest that atRA accumulation is relevant to various posterior organ abnormalities, a systematic analysis has not been performed for anorectal and urinary anomalies in patients with POR deficiency (PORD).
  
  
  OBJECTIVE
  To report the frequencies of anorectal and urinary anomalies and plasma atRA values in PORD patients.
  
  
  METHODS
  We studied 37 Japanese patients with PORD, consisting of 15 homozygotes for R457H (group A), 15 compound heterozygotes for R457H and one apparently null mutation (group B), and seven patients with other combinations of mutations (group C). Since R457H is a severe hypomorphic mutation, the residual POR function is predicted to be higher in group A than in group B.
  
  
  RESULTS
  Imperforate anus was observed in four patients (10.8%) and vesicoureteral reflux was found in three patients (8.1%), with no significant difference in the frequencies of such anomalies between groups A and B. In addition, a complex urogenital malformation including penile agenesis was identified in one patient. Plasma atRA values were above the reference range in nine of 12 patients examined, and were similar between groups A and B and between patients with and without anomalies.
  
  
  CONCLUSIONS
  The results imply that aberrant atRA metabolism due to CYP26 deficiency underlies various anorectal and urinary anomalies in patients with PORD. Clinical phenotypes may be primarily determined by maternal oral retinol intake during pregnancy, and plasma atRA values may be largely influenced by the amount of postnatal oral retinol intake in such patients.
authors.affiliation: Department of Endocrinology and Metabolism, National Research Institute for Child Health and Development, Tokyo, Japan. mfukami@nch.go.jp
authors.forename: Maki
authors.initials: M
authors.lastname: Fukami
authors.forename: Toshiro
authors.initials: T
authors.lastname: Nagai
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mochizuki
authors.forename: Koji
authors.initials: K
authors.lastname: Muroya
authors.forename: Gen
authors.initials: G
authors.lastname: Yamada
authors.forename: Kimitaka
authors.initials: K
authors.lastname: Takitani
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Ogata
mesh_terms: D000293:Adolescent; D000818:Animals; D001006:Anus, Imperforate / Q000201:enzymology / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D003577:Cytochrome P-450 Enzyme System / Q000172:deficiency / Q000235:genetics; D005260:Female; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007420:Intestine, Large / Q000002:abnormalities*; D008297:Male; D051379:Mice; D009154:Mutation; D009251:NADPH-Ferrihemoprotein Reductase / Q000172:deficiency* / Q000235:genetics*; D011247:Pregnancy; D000072516:Retinoic Acid 4-Hydroxylase; D014212:Tretinoin / Q000378:metabolism*; D014551:Urinary Tract / Q000002:abnormalities*; D014564:Urogenital Abnormalities / Q000201:enzymology / Q000235:genetics; D014718:Vesico-Ureteral Reflux / Q000151:congenital / Q000201:enzymology / Q000235:genetics
chemical_list: D014212:Tretinoin; D003577:Cytochrome P-450 Enzyme System; D000072516:Retinoic Acid 4-Hydroxylase; D009251:NADPH-Ferrihemoprotein Reductase