Heterozygous mutation of steroidogenic factor-1 in 46,XY subjects may mimic partial androgen insensitivity syndrome.
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.
Coutant
Régis
R
Department of Pediatric Endocrinology, University Hospital, 4 rue Larrey, 49033 Angers Cedex 01, France. recoutant@chu-angers.fr
Mallet
Delphine
D
Lahlou
Najiba
N
Bouhours-Nouet
Natacha
N
Guichet
Agnès
A
Coupris
Lionel
L
Croué
Anne
A
Morel
Yves
Y
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*
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