ESPE Abstracts

Background: Androgen receptor (AR) gene mutations are the most frequent cause of 46,XY disorders of sex development and are associated with a variety of phenotypes, ranging from phenotypic women (complete androgen insensitivity syndrome) to milder degrees of undervirilization (partial and mild forms).

Aims and objectives: To specify how a phenotype-genotype correlation can be refined by in vitro study based on the nature of amino acid substitution.

Patients and methods: We report a 2-month-old girl who was admitted to the Pediatric Surgery Unit of the University Hospital of Montpellier for inguinal hernia. Inguinal gonads were present, whereas no uterus was identified at ultrasonography. Karyotype was 46,XY. Inguinal surgery was performed and the gonads were reintegrated in the abdominal position. Family questioning revealed that one of the mother’s sisters was infertile. AR gene analysis found a new W752G AR mutation. We performed in vitro study of this new mutation and the only other reported W752R mutation.

Results: Transfection studies confirmed the decrease in AR transactivation despite increased androgen concentration, whereas for the other p.W752R AR mutation previously reported in two sisters with ICA, transactivation increased only at androgen concentrations above 10–8 M.

Discussion and conclusions: Although newborns diagnosed as CAIS carriers are always raised as females, the time of gonadectomy tends to be later today than it was some years ago. This later gonadectomy timing allows spontaneous puberty, but it raises questions about potential pubertal virilization and male identity in cases of the persistence of residual AR activity. Through this report of a new W752G mutation of the AR gene in a CAIS patient, we underline the usefulness of in vitro study to better understand the virilization defect and thus better organize the follow-up of these patients based on the nature of the amino acid substitution.