title: NR5A1 gene mutations: clinical, endocrine and genetic features in two girls with 46,XY disorder of sex development.
abstract: BACKGROUND
  Steroidogenic factor 1, encoded by the NR5A1 gene, is a key regulator of endocrine function within the hypothalamic-pituitary-steroidogenic axis. Both homozygous, compound heterozygous and heterozygous mutations in the NR5A1 gene may determine 46,XY disorders of sex development (DSD).
  
  
  METHODS
  NR5A1 gene sequencing was performed in a cohort of 6 patients with 46,XY DSD without specific diagnosis.
  
  
  RESULTS
  Heterozygous NR5A1 gene mutations were found in 2 girls, aged 0.5 years and 14 years. The older girl harbored the c.250C>T transition in exon 4 (p.Arg84Cys), previously reported in a Japanese girl. The younger girl presented a de novo novel exon 6 heterozygous frameshift mutation (c.1074dupG) in codon 359 associated with the p.Gly146Ala polymorphism the latter inherited from her father. This baby showed severe impairment of androgen secretion from the first months of life. Overt adrenal insufficiency did not occur, but the older girl showed subnormal cortisol peak after ACTH stimulation.
  
  
  CONCLUSIONS
  NR5A1 gene mutations are a relatively frequent cause of 46,XY DSD in humans. Clear indications for management of these individuals remain elusive, mainly when diagnosis is made in infancy. Long-term monitoring of adrenal function should be recommended.
authors.affiliation: Adolescent Medicine, Division of Pediatrics, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy.
authors.forename: Silvano
authors.initials: S
authors.lastname: Bertelloni
authors.forename: Eleonora
authors.initials: E
authors.lastname: Dati
authors.forename: Fulvia
authors.initials: F
authors.lastname: Baldinotti
authors.forename: Benedetta
authors.initials: B
authors.lastname: Toschi
authors.forename: Giacinto
authors.initials: G
authors.lastname: Marrocco
authors.forename: Maria R
authors.initials: MR
authors.lastname: Sessa
authors.forename: Angela
authors.initials: A
authors.lastname: Michelucci
authors.forename: Paolo
authors.initials: P
authors.lastname: Simi
authors.forename: Giampiero I
authors.initials: GI
authors.lastname: Baroncelli
mesh_terms: D000293:Adolescent; D000728:Androgens / Q000378:metabolism; D003062:Codon / Q000235:genetics; D015331:Cohort Studies; D058490:Disorder of Sex Development, 46,XY / Q000235:genetics* / Q000503:physiopathology*; D004703:Endocrine System / Q000378:metabolism / Q000503:physiopathology*; D005091:Exons / Q000235:genetics; D005260:Female; D006579:Heterozygote; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism; D007223:Infant; D009154:Mutation / Q000235:genetics*; D017422:Sequence Analysis, DNA; D054339:Steroidogenic Factor 1 / Q000235:genetics*
chemical_list: D000728:Androgens; D003062:Codon; C515057:NR5A1 protein, human; D054339:Steroidogenic Factor 1; D006854:Hydrocortisone