Mutational Analysis of Androgen Receptor (AR) Gene in 46,XY Patients with Ambiguous Genitalia and Normal Testosterone Secretion: Endocrinological Characteristics of Three Patients with AR Gene Mutations

The prevalence of abnormalities in androgen receptor gene (AR) among patients withambiguous genitalia is unknown. Moreover, endocrinological data from prepubertal patientswith AR mutation are very limited. Thus, the aim of this study was to examine theprevalence of abnormalities in AR among patients with both ambiguous genitalia, which wasdefined as a combination of two or more genital abnormalities (i.e. hypospadias,microphallus (penile length < 25 mm), hypoplastic scrotum, bifid scrotum, undescendedtestis) in this study, and normal to elevated T levels. We also compared theendocrinological data of prepubertal patients with AR mutation and ambiguous genitaliawith that of those without the AR mutation. We screened 26 Japanese prepubertal 46,XYpatients (five from three families were included) with both ambiguous genitalia and normalto elevated T levels. Mutations in AR were found in three (two of the three were related).Among the 23 patients without mutation in AR, the steroid 5-alpha-reductase 2 gene(SRD5A2) was also examined in eight patients with elevated T/dehydrotestosterone ratioafter the hCG (>10) or with undervirilized family members. No mutation in SRD5A2 wasfound. Characteristics of the three patients with mutation in AR were compared with the 23patients without mutation. In two patients, basal T levels (0.3, 0.2 ng/ml) and peak Tlevels after the hCG tests (8.3, 8.5 ng/ml) tended to be higher, and the peak LH/ peak FSHratios after the GnRH tests (4.6, 4.0) were higher than in patients without mutation, atthe ages of 1 yr and 9 mo and 3 yr and 8 mo, respectively. In conclusion, an abnormalityin either AR or SRD5A2 was not common among patients with ambiguous genitalia and normaltestosterone secretion. Elevated peak LH/peak FSH ratio (≥4) after the GnRH test inaddition to detectable basal T levels and elevated peak T levels after the hCG test mayinfer AR abnormality in prepubertal patients with ambiguous genitalia at the age of oneand over, although further study is needed, because our data were limited.