Complete androgen insensitivity syndrome (CAIS) is a rare X-linked disorder caused by androgen receptor gene (AR) mutations that result in complete impairment of genital virilisation. Usually CAIS patients, who have normal production of AMH by Sertoli Cells, do not show Mullerian derivatives, although the persistence of Mullerian duct derivatives up to now have been described in nine cases.
Here, we report the case of a fetus aborted at 20 weeks for genital ambiguity. In particular, during autopsy, external and internal (upper third of vagina, uterus and fallopian tubes) properly developed female genitals were found. Moreover, undescended testes characterized by a large hyperplasia of Leydig cells were also identified. Interestingly, a cousin and two aunt showed a similar phenotype. The subsequent genetic analysis demonstrated a novel mutations affecting the ligand binding domain of AR (D768V). The immunoistochemistry of the testes for AMH was positive. In previous cases described in the literature no mutations of AMH and AMHR have been described and all the hypothesis that have been suggested to explain this phenotype such as inappropriate synthesis or action of AMH, in utero exposure to diethylstilboestrol, impaired uptake of AR complex at nuclear level and early testicular descent so that Mullerian structures are beyond the reach of AMH action, have been eventually ruled out. So, considering that AR mutation justify only half phenotype, that Sertoli cells during fetal life dont express AR and that AMH act within the first 8 weeks of gestation, before Leydig cells start to synthesize testosterone, we ruled out a possible connection between androgen resistance and the lack of Mullerian derivatives regression. We hypothesized the presence of an unknown gene involved in AMH processing or in downstream AMH transduction, suggesting the necessity of performing linkage analysis.
03 - 07 May 2008
European Society of Endocrinology