title: Homozygous disruption of P450 side-chain cleavage (CYP11A1) is associated with prematurity, complete 46,XY sex reversal, and severe adrenal failure.
abstract: Disruption of the P450 side-chain cleavage cytochrome (P450scc) enzyme due to deleterious mutations of the CYP11A1 gene is thought to be incompatible with fetal survival because of impaired progesterone production by the fetoplacental unit. We present a 46,XY patient with a homozygous disruption of CYP11A1. The child was born prematurely with complete sex reversal and severe adrenal insufficiency. Laboratory data showed diminished or absent steroidogenesis in all pathways. Molecular genetic analysis of the CYP11A1 gene revealed a homozygous single nucleotide deletion leading to a premature termination at codon position 288. This mutation will delete highly conserved regions of the P450scc enzyme and thus is predicted to lead to a nonfunctional protein. Both healthy parents were heterozygous for this mutation. Our report demonstrates that severe disruption of P450scc can be compatible with survival in rare instances. Furthermore, defects in this enzyme are inherited in an autosomal-recessive fashion, and heterozygote carriers can be healthy and fertile. The possibility of P450scc-independent pathways of steroid synthesis in addition to the current concept of luteoplacental shift of progesterone synthesis in humans has to be questioned.
authors.affiliation: Department of Pediatrics, Division of Pediatric Endocrinology, University Hospital Schleswig-Holstein, Campus Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany. hiort@paedia.ukl.mu-luebeck.de
authors.forename: Olaf
authors.initials: O
authors.lastname: Hiort
authors.forename: Paul-Martin
authors.initials: PM
authors.lastname: Holterhus
authors.forename: Ralf
authors.initials: R
authors.lastname: Werner
authors.forename: Christine
authors.initials: C
authors.lastname: Marschke
authors.forename: Ute
authors.initials: U
authors.lastname: Hoppe
authors.forename: Carl-Joachim
authors.initials: CJ
authors.lastname: Partsch
authors.forename: Felix G
authors.initials: FG
authors.lastname: Riepe
authors.forename: John C
authors.initials: JC
authors.lastname: Achermann
authors.forename: Dagmar
authors.initials: D
authors.lastname: Struve
mesh_terms: D000309:Adrenal Insufficiency / Q000235:genetics*; D000328:Adult; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000235:genetics*; D012734:Disorders of Sex Development; D005260:Female; D017353:Gene Deletion; D006801:Humans; D007231:Infant, Newborn; D009154:Mutation; D007752:Obstetric Labor, Premature / Q000209:etiology*; D011247:Pregnancy; D011374:Progesterone / Q000096:biosynthesis
chemical_list: D011374:Progesterone; D002786:Cholesterol Side-Chain Cleavage Enzyme