title: Heterozygous mutation of steroidogenic factor-1 in 46,XY subjects may mimic partial androgen insensitivity syndrome.
abstract: BACKGROUND
  The clinical and biological features of Sertoli cell and Leydig cell dysfunction are usually investigated when characterizing disorders of sex development in 46,XY individuals: This allows gonadal dysgenesis, a defective development of the gonad, to be distinguished from defects restricted to androgen synthesis or sensitivity. In humans, mutations in steroidogenic factor-1 (SF-1), one of the critical factors involved in testis development, have been reported to cause gonadal dysgenesis with or without adrenal failure in 46,XY individuals.
  
  
  OBJECTIVE
  We report a SF-1 mutation that caused ambiguous genitalia associated with strikingly different hormonal phenotypes in two affected 46,XY children from the same family.
  
  
  METHODS
  Hormonal evaluation included testosterone (T), anti-Mullerian hormone (AMH), inhibin B, FSH, and LH measurements during the first weeks of life, a period when physiological activation of the gonadotropin-gonadal system occurs. Direct DNA sequencing of the coding sequence of the SF-1 and the androgen receptor (AR) genes was performed.
  
  
  RESULTS
  Both 46,XY children had ambiguous genitalia with no Mullerian structures and no adrenal insufficiency. The older child showed normal elevation of T (up to 7.6 nmol/liter, 2.2 ng/ml), AMH (504 pmol/liter, 70.6 ng/ml), inhibin B (245 pg/ml), FSH, and LH during the first weeks, which led to a presumptive diagnosis of partial androgen insensitivity syndrome. The AR sequence was, however, normal. In the second child, T, AMH, and inhibin B were low, suggesting gonadal dysgenesis. In both children and their mother, a c.536delC frameshift mutation in the SF-1 gene was found. This mutation terminates translation at position 295, removing the ligand-binding domain and the activation function 2 (AF-2) domain, a critical domain for SF-1 transactivating activity.
  
  
  CONCLUSIONS
  The usual markers of testis dysgenesis may be normal in 46,XY individuals with SF-1 mutation. Screening for SF-1 mutation should be performed in subjects with apparent partial androgen insensitivity syndrome and no mutation in the AR gene.
authors.affiliation: Department of Pediatric Endocrinology, University Hospital, 4 rue Larrey, 49033 Angers Cedex 01, France. recoutant@chu-angers.fr
authors.forename: Régis
authors.initials: R
authors.lastname: Coutant
authors.forename: Delphine
authors.initials: D
authors.lastname: Mallet
authors.forename: Najiba
authors.initials: N
authors.lastname: Lahlou
authors.forename: Natacha
authors.initials: N
authors.lastname: Bouhours-Nouet
authors.forename: Agnès
authors.initials: A
authors.lastname: Guichet
authors.forename: Lionel
authors.initials: L
authors.lastname: Coupris
authors.forename: Anne
authors.initials: A
authors.lastname: Croué
authors.forename: Yves
authors.initials: Y
authors.lastname: Morel
mesh_terms: D013734:Androgen-Insensitivity Syndrome / Q000235:genetics*; D054304:Anti-Mullerian Hormone; D004247:DNA / Q000235:genetics; D003937:Diagnosis, Differential; D005260:Female; D016368:Frameshift Mutation / Q000235:genetics; D006023:Glycoproteins / Q000097:blood; D006061:Gonadal Dysgenesis, 46,XY / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007223:Infant; D007265:Inhibins / Q000097:blood; D008297:Male; D011944:Receptors, Androgen / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D054339:Steroidogenic Factor 1; D013735:Testicular Hormones / Q000097:blood; D013739:Testosterone / Q000097:blood; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D006023:Glycoproteins; D018398:Homeodomain Proteins; C515057:NR5A1 protein, human; D011944:Receptors, Androgen; D018160:Receptors, Cytoplasmic and Nuclear; D054339:Steroidogenic Factor 1; D013735:Testicular Hormones; D014157:Transcription Factors; C422364:inhibin B; D013739:Testosterone; D007265:Inhibins; D054304:Anti-Mullerian Hormone; D004247:DNA