Androgen insensitivity syndrome

Androgen insensitivity syndrome (AIS, or "Androgen resistance syndrome") is a set of disorders of sexual differentiation that results from mutations of the gene encoding the androgen receptor. It has also been called androgen resistance in the medical literature. The nature of the resulting problem varies according to the structure and sensitivity of the abnormal receptor. Most of the forms of AIS involve variable degrees of undervirilization and/or infertility in XY persons of either sex. more...

A woman with complete androgen insensitivity syndrome (CAIS) has a nearly normal female body despite a 46XY karyotype and testes, a condition termed testicular feminization in the past.

Major changes in the understanding and management of the various forms of AIS have occurred since 1990. Laboratory research has greatly expanded our understanding of the molecular mechanisms of the clinical features, including a rare neuromuscular disorder. More importantly, patient advocacy groups for AIS and other intersex conditions have increased public awareness of these disorders, helped revise our understanding of gender identity, emphasized the value of accurate and sophisticated information for patients, and induced physicians to re-evaluate the effectiveness of the surgical corrections attempted in past decades. Surgery is increasingly seen as a very elective option even for the more ambiguous conditions.

Genetics, inheritance, and incidence

The gene, AR, for the human androgen receptor is located within the Xq11-12 area of the X chromosome. Effects of the AIS mutations behave as sex-linked recessive traits, causing minimal or no effects in 46,XX women. In other words, since 46,XX women have two X chromosomes, and hence two copies of the gene for the androgen receptor, no problems occur if one of the genes is defective. Since a 46,XY person has only a single X chromosome, a deleterious mutation of the androgen receptor gene on the only X chromosome can cause any of several forms of androgen insensitivity syndrome.

A 46,XX woman who has one mutated AR gene is a "carrier" of AIS and may pass androgen insensitivity on to her children. As in some other X-linked recessive conditions, carrier mothers may display some minor traits of the condition. AIS carriers often have reduced axillary and pubic hair and a reduction in normal adolescent acne.

Except in the rare instance of a new mutation, a 46,XY person affected with AIS has inherited his/her single X chromosome with the defective gene from his/her mother, who may have an affected sibling. Generally the condition caused by a familial mutation will affect family members similarly, though differing degrees of severity occasionally occur in different relatives with apparently the same mutation. Carrier testing is now available for relatives at risk when a diagnosis of AIS is made in a family member.

Over 100 AR mutations causing various forms of AIS have been reported. In general, the milder types of AIS (4 and 5 in the list below) are caused by simple missense mutations with single codon/single amino acid difference, while CAIS and the nearly complete forms result from mutations that more severely affect the shape and structure of the protein. About one third of cases of AIS are new mutations rather than familial. A single case of CAIS attributed to an abnormality of the AF-1 coactivator (rather than AR itself) has been reported (OMIM 300274).

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