title: Testosterone production during puberty in two 46,XY patients with disorders of sex development and novel NR5A1 (SF-1) mutations.
abstract: BACKGROUND
  Steroidogenic factor 1 (SF-1, NR5A1) is a key transcriptional regulator of many genes involved in the hypothalamic-pituitary-gonadal axis and mutations in NR5A1 can result in 46,XY disorders of sex development (DSD). Patients with this condition typically present with ambiguous genitalia, partial gonadal dysgenesis, and absent/rudimentary Müllerian structures. In these cases, testosterone is usually low in early infancy, indicating significantly impaired androgen synthesis. Further, Sertoli cell dysfunction is seen (low inhibin B, anti-Müllerian hormone). However, gonadal function at puberty in patients with NR5A1 mutations is unknown.
  
  
  METHODS
  Clinical assessment, endocrine evaluation, and genetic analysis were performed in one female and one male with 46,XY DSD who showed spontaneous virilization during puberty. The female patient presented at adolescence with clitoral hypertrophy, whereas the male patient presented at birth with severe hypospadias and entered puberty spontaneously. Molecular analysis of NR5A1 was performed followed by in vitro functional analysis of the two novel mutations detected.
  
  
  RESULTS
  Testosterone levels were normal during puberty in both patients. Analysis of NR5A1 revealed two novel heterozygous missense mutations in the ligand-binding domain of SF-1 (patient 1: p.L376F; patient 2: p.G328V). The mutant proteins showed reduced transactivation of the CYP11A promoter in vitro.
  
  
  CONCLUSIONS
  Patients with 46,XY DSD and NR5A1 mutations can produce sufficient testosterone for spontaneous virilization during puberty. Phenotypic females (46,XY) with NR5A1 mutations can present with clitoromegaly at puberty, a phenotype similar to other partial defects of androgen synthesis or action. Testosterone production in 46,XY males with NR5A1 mutations can be sufficient for virilization at puberty. As progressive gonadal dysgenesis is likely, gonadal function should be monitored in adolescence and adulthood, and early sperm cryopreservation considered in male patients if possible.
authors.affiliation: Department of Pediatric Endocrinology, University Children's Hospital, Charité, Humboldt University, Augustenburger Platz 1, 13353 Berlin, Germany.
authors.forename: Sally
authors.initials: S
authors.lastname: Tantawy
authors.forename: Lin
authors.initials: L
authors.lastname: Lin
authors.forename: Ilker
authors.initials: I
authors.lastname: Akkurt
authors.forename: Guntram
authors.initials: G
authors.lastname: Borck
authors.forename: Dietrich
authors.initials: D
authors.lastname: Klingmüller
authors.forename: Berthold P
authors.initials: BP
authors.lastname: Hauffa
authors.forename: Heiko
authors.initials: H
authors.lastname: Krude
authors.forename: Heike
authors.initials: H
authors.lastname: Biebermann
authors.forename: John C
authors.initials: JC
authors.lastname: Achermann
authors.forename: Birgit
authors.initials: B
authors.lastname: Köhler
mesh_terms: D000293:Adolescent; D000328:Adult; D058490:Disorder of Sex Development, 46,XY / Q000097:blood / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D009154:Mutation; D011627:Puberty / Q000235:genetics*; D054339:Steroidogenic Factor 1 / Q000235:genetics*; D013739:Testosterone / Q000097:blood* / Q000235:genetics; D014770:Virilism / Q000097:blood / Q000235:genetics*
chemical_list: C515057:NR5A1 protein, human; D054339:Steroidogenic Factor 1; D013739:Testosterone