ESPE Abstracts

Background: Androgen insensitivity syndrome in its complete form (CAIS) is a disorder of hormone resistance characterised by a female phenotype in an individual with an XY karyotype and testes producing age-appropriated normal concentrations of androgens. Pathogenesis is the result of mutations in the x-linked androgen receptor (AR) gene, which encodes for the ligand-activated AR. We report the clinical, biochemical and molecular features of two affected sisters in whom a novel mutation has been detected.

Cases: Two sisters were referred presenting primary amenorrhea. A 17-year-old woman (patient 1) and her 15-year-old sister (patient 2) presented with normal breast development (Tanner V) and absent axillary and pubic hair. The phenotype and external genitalia were female. The endocrine profile revealed elevated testosterone and abnormally high LH. Patient 1: Testosterone:5.1 μg/l (2.7–8.3), LH:30 UI/l (2–9), FSH:8 UI/l (2–10), Oestradiol:14 ng/l (20–45); Patient 2: Testosterone:2.7 μg/l (2.7–8.3), LH:36 UI/l (2–9), FSH:7 UI/l (2–10), Oestradiol:12 ng/l (20–45). Transabdominal pelvic ultrasonography showed internal gonads and absence of uterus. Karyotype was 46, XY. Analysis of AR showed a point mutation in intron 5, two nucleotides preceding exon 6: c.2319-2A>G in both. This nucleotide is located in the splice site regulatory transcription region (AG/GT). It can, therefore, be predicted that this mutation gives rise to an anomalous and inactive protein. At present, gonadectomy has been deferred to complete puberal development and optimize bone density, although it will be recommended from the second decade of age to prevent the risk of gonadal tumours.

Conclusions: This mutation had not been previously reported. AR gene mutation is the most frequent cause of 46, XY disorder of sex development, with a clearly higher frequency in the complete phenotype. Loss of function mutations can be found in most women with suspected CAIS, but only in about 15-20% of subjects with suspected partial androgen insensitivity syndrome (PAIS).