Androgen insensitivity syndrome

Did You Know?

• Preimplantation genetic diagnosis for AIS is permitted in the UK as a serious genetic disease, though some ethicists and intersex advocates argue this screening is based on social norms rather than medical necessity.
• Recording artist Dalea, who has CAIS, founded the non-profit diversity awareness initiative Girl Comet.
• The film Orchids, My Intersex Adventure features Phoebe Hart and Bonnie Hart, both women with CAIS, documenting their exploration of AIS and intersex issues.

Genetics

The androgen receptor (AR) is encoded by a gene on the X chromosome at locus Xq11-Xq12. Its protein coding region spans about 2,757 nucleotides across eight exons. The AR protein contains a transactivation domain (encoded by exon 1), a DNA-binding domain (exons 2 and 3), a hinge region (5' portion of exon 4), and a steroid-binding domain (remainder of exons 4 through 8). Exon 1 includes two polymorphic trinucleotide microsatellites: a polyglutamine tract (CAG repeats, averaging 21 in Caucasians and 18 in Blacks) and a polyglycine tract (GGC repeats). Extremes in polyglutamine length are associated with disease states in men: too few repeats with prostate cancer, hepatocellular carcinoma, and intellectual disability; 40 or more repeats with spinal and bulbar muscular atrophy. Some studies link longer polyglutamine tracts to male infertility and undermasculinized genitalia, though other studies found no such correlation. A 2007 meta-analysis supported the correlation, attributing earlier discrepancies to sample size and study design. Longer polyglycine tracts have also been suggested to relate to genital masculinization defects, but this association is not consistently found.

Pathophysiology

Androgenic effects such as virilization and masculinization result from androgens binding to androgen receptors, which then regulate target gene expression. The androgen receptor is generally inactive until androgen binding occurs. In theory, mutant receptors lacking the steroid-binding domain can function without androgens, as in vitro studies show they can induce transcription in the absence of ligand; the unliganded steroid-binding domain may repress the transactivation domain. Human embryos develop similarly for the first six weeks regardless of genetic sex. By the fifth week, genital ridges form, and by the sixth week, indifferent gonads begin differentiating according to genetic sex. In 46,XY embryos, testes develop under the influence of the SRY gene on the Y chromosome, a process that does not require androgen or a functional androgen receptor.

Diagnosis

Diagnosing androgen insensitivity syndrome requires first ruling out other conditions, since its features are not exclusive to AIS. Common clinical signs include a short vagina or underdeveloped male genitalia, partial or full regression of Müllerian structures, testes that are present and not dysplastic, and problems with sperm production or male-typical development. Lab results typically show a 46,XY karyotype and normal or high levels of testosterone, luteinizing hormone, and estradiol after puberty. Androgen binding in genital skin cells is often reduced, though not always, and the conversion of testosterone to dihydrotestosterone can be impaired. A confirmed diagnosis comes from finding a mutation in the androgen receptor gene, but some people with AIS, especially the partial form, do not have such a mutation. Each of the three types—complete, partial, and mild—has its own list of possible alternative diagnoses, which can include Klinefelter syndrome or mosaic Turner syndrome. A seven-grade scale proposed in 1995 by Charmian A. Quigley and colleagues provides more detail on genital masculinization: grades 1 through 6 describe increasing feminization of the genitals, while grade 7 looks like grade 6 until puberty, when it is set apart by a lack of secondary terminal hair.

History

Descriptions of AIS effects date back centuries, but understanding of its histopathology emerged in the 1950s. In 1950, Lawson Wilkins administered daily methyltestosterone to a 46,XY female patient who showed no virilization, providing the first documented demonstration of AIS pathophysiology. In 1970, Mary F. Lyon and Susan Hawkes reported that an X-linked gene caused complete androgen insensitivity in mice. Barbara Migeon et al. narrowed the human AR gene locus to Xq11-Xq13 in 1981. The human AR gene was first cloned and partially analyzed in 1988, with Terry Brown et al. reporting the first mutations proven to cause AIS. In 1989, Brown et al. reported the exact locus (Xq11-Xq12), and Dennis Lubahn et al. published its intron-exon boundaries. The androgen receptor gene mutations database was created in 1994.