Steroidogenic factor-1 (SF-1) gene mutation as a frequent cause of primary amenorrhea in 46,XY female adolescents with l
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RESEARCH
Open Access
Steroidogenic factor-1 (SF-1) gene mutation as a frequent cause of primary amenorrhea in 46,XY female adolescents with low testosterone concentration Pascal Philibert1†, Elodie Leprieur1,2†, Delphine Zenaty3, Elisabeth Thibaud4, Michel Polak4, Anne-Marie Frances5, James Lespinasse6, Isabelle Raingeard7, Nadège Servant1, Françoise Audran1, Françoise Paris1,2, Charles Sultan1,2*
Abstract Background: Primary amenorrhea due to 46,XY disorders of sex differentiation (DSD) is a frequent reason for consultation in endocrine and gynecology clinics. Among the genetic causes of low-testosterone primary amenorrhea due to 46,XY DSD, SRY gene is reported to be frequently involved, but other genes, such as SF1 and WT1, have never been studied for their prevalence. Methods: We directly sequenced SRY, SF1 and WT1 genes in 15 adolescent girls with primary amenorrhea, low testosterone concentration, and XY karyotype, to determine the prevalence of mutations. We also analyzed the LH receptor gene in patients with high LH and normal FSH concentrations. Results: Among the 15 adolescents with primary amenorrhea and low testosterone concentration, we identified two new SRY mutations, five new SF1 mutations and one new LH receptor gene mutation. Our study confirms the 10-15% prevalence of SRY mutations and shows the high prevalence (33%) of SF1 abnormalities in primary amenorrhea due to 46,XY DSD with low plasma testosterone concentration. Conclusions: The genetic analysis of low-testosterone primary amenorrhea is complex as several factors may be involved. This work underlines the need to systematically analyze the SF1 sequence in girls with primary amenorrhea due to 46,XY DSD and low testosterone, as well as in newborns with 46,XY DSD.
Background Adolescent primary amenorrhea is a frequent reason for consultation in pediatric and gynecological endocrine clinics. Primary amenorrhea may result from congenital abnormalities in gonadal or genital tract development or from a defect in the hypothalamic-pituitary-ovarian axis. Failure to menstruate by the age of 15 years requires investigation to determine the cause and establish a treatment plan. The standard investigation includes detailed clinical evaluation [1], endocrine assessment (gonadotropins, testosterone, AMH and inhibin B assays) and pelvic imaging. In addition, genetic exploration is crucial to * Correspondence: [email protected] † Contributed equally 1 Service d’Hormonologie, Hôpital Lapeyronie, CHU Montpellier, and Université Montpellier 1, France
classify the primary amenorrhea. Karyotyping, which discriminates normal from abnormal chromosomes (i.e., 45, X0 or 46,XY), is the first step. In the 46,XY disorders of sex differentiation (DSD) [2], primary amenorrhea may be caused by a genetic defect in fetal testis determination, failure of the fetal testis to produce testosterone, or androgen resistance [3]. The assessment of endocrine parameters thus often orients the exploration toward the most probable genetic cause [4]. For example, when plas
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