Clinical characteristics: Androgen insensitivity syndrome (AIS) is typically characterized by evidence of feminization (i.e., undermasculinization) of the external genitalia at birth, abnormal secondary sexual development in puberty, and infertility in individuals with a 46,XY karyotype. AIS represents a spectrum of defects in androgen action and can be subdivided into three broad phenotypes:
Complete androgen insensitivity syndrome (CAIS), with typical female external genitalia
Partial androgen insensitivity syndrome (PAIS) with predominantly female, predominantly male, or ambiguous external genitalia
Mild androgen insensitivity syndrome (MAIS) with typical male external genitalia
Diagnosis/testing: The diagnosis of AIS is established in an individual with a 46,XY karyotype who has: undermasculinization of the external genitalia, impaired spermatogenesis with otherwise normal testes, absent or rudimentary müllerian structures, evidence of normal or increased synthesis of testosterone and its normal conversion to dihydrotestosterone, and normal or increased luteinizing hormone (LH) production by the pituitary gland; AND/OR a hemizygous pathogenic variant in AR identified by molecular genetic testing.
Management: Treatment of manifestations: To prevent testicular malignancy, treatment of CAIS may include either removal of the testes after puberty when feminization is complete or prepubertal gonadectomy accompanied by estrogen replacement therapy. Because the risk of malignancy is low, however, removal of gonads is increasingly controversial. Additional treatment for CAIS may include vaginal dilation to avoid dyspareunia. Treatment of PAIS in individuals with predominantly female genitalia is similar to treatment of CAIS, but is more likely to include prepubertal gonadectomy to help avoid increasing clitoromegaly at the time of puberty. In individuals with PAIS and ambiguous or predominantly male genitalia, the tendency has been for parents and health care professionals to assign sex of rearing after an expert evaluation has been completed. Those individuals with PAIS who are raised as males may undergo urologic surgery such as orchiopexy and hypospadias repair. Those individuals with PAIS who are raised as females and who undergo gonadectomy after puberty may need combined estrogen and androgen replacement therapy. Males with MAIS may require mammoplasty for gynecomastia. A trial of androgen pharmacotherapy may help improve virilization in infancy. It is best if the diagnosis of AIS is explained to the affected individual and family in an empathic environment, with both professional and family support.
Prevention of secondary manifestations: Regular weight-bearing exercises and supplemental calcium and vitamin D are recommended to optimize bone health; bisphosphonate therapy may be indicated for those with evidence of decreased bone mineral density and/or multiple fractures.
Surveillance: Periodic reevaluation for gynecomastia during puberty in individuals assigned a male sex; monitoring of bone mineral density through DXA scanning in adults.
Evaluation of relatives at risk: For an apparently asymptomatic older or younger sib who has normal external female genitalia and who has not yet undergone menarche, a karyotype can be done first. For those phenotypic females who have a 46,XY karyotype, molecular genetic testing for the known AR variant in the family can be pursued next. If the AR variant in the family is not known, androgen binding assays could be considered.
Genetic counseling: AIS is inherited in an X-linked manner. Affected 46,XY individuals are almost always infertile. Each offspring of a female known to carry an AR pathogenic variant (heterozygote) is at a 25% risk for each of the following:
Having a 46,XY karyotype and being affected
Having a 46,XY karyotype and being unaffected
Having a 46,XX karyotype and being a carrier
Having a 46,XX karyotype and not being a carrier
Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the pathogenic variant in the family is known.
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