Androgen insensitivity syndrome in its complete form is a disorder of hormone resistance characterised by a female phenotype in an individual with an XY karyotype and testes producing age-appropriate normal concentrations of androgens. Pathogenesis is the result of mutations in the X-linked androgen receptor gene, which encodes for the ligand-activated androgen receptor--a transcription factor and member of the nuclear receptor superfamily. This Seminar describes the clinical manifestations of androgen insensitivity syndrome from infancy to adulthood, reviews the mechanism of androgen action, and shows examples of how mutations of the androgen receptor gene cause the syndrome. Management of androgen insensitivity syndrome should be undertaken by a multidisciplinary team and include gonadectomy to avoid gonad tumours in later life, appropriate sex-hormone replacement at puberty and beyond, and an emphasis on openness in disclosure.

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The severity of genital anomalies in this large cohort of infants with a 'PAIS-like' phenotype did not differentiate their AR status. Almost all the infants born small-for-gestational-age do not have an AR mutation. A category of 'XY DSD and fetal growth restriction, as yet unexplained' should be recognised.

The androgen insensitivity syndromes (AIS) fall within the generic category of 46,XY DSD (disorder of sex development) and present as phenotypes associated with complete or partial resistance to the action of androgens. Three categories are recognized: complete androgen insensitivity syndrome (CAIS), partial androgen insensitivity syndrome (PAIS), mild androgen insensitivity syndrome (MAIS). The androgen receptor (AR) is encoded by an 8 exon gene on the X chromosome long arm. More than 800 mutations in the AR gene have been reported in AIS patients (www.androgendb.mcgill.ca/). They are distributed throughout the gene with a preponderance located in the ligand binding domain. The most severe mutations are generally associated with a CAIS phenotype, but the correlation is less defined in PAIS. CAIS presents typically as primary amenorrhoea in an adolescent female and less commonly in infancy with bilateral inguinal/labial swellings due to testes. The differential diagnosis in CAIS is limited, whereas in PAIS, numerous other causes of DSD can also produce the typical phenotype of micropenis, severe hypospadias and bifid scrotum. Management issues in CAIS involve timing of gonadectomy, appropriate hormone replacement therapy and assessment of the need for vaginal dilation or rarely, vaginal surgery. The risk of gonadal germ cell tumor is low during childhood and adolescence but increases in later adulthood. Expert psychological counseling is mandatory to manage the disconnect between chromosomal, gonadal and phenotypic sex and to choreograph the evolving process of disclosure from late childhood through to maturity. It is implicit that management in AIS requires a multidisciplinary team and engagement with patient advocacy groups.