Androgen Insensitivity

Abstract Androgen insensitivity is an X‐linked disorder of defective or absent virilisation in 46, XY individuals owing to complete or partial resistance to androgens in androgen‐dependent tissues and organs. The syndrome is part of a group of disorders of sex development (DSD). The molecular cause of the syndrome is mutations in the androgen receptor gene (locus: Xq11–12), resulting either in the absence of an androgen receptor protein or in the production of a mutant receptor with partial or complete loss of its activity. Androgen insensitivity displays a broad phenotypic and genotypic spectrum. The phenotype can vary from complete (CAIS, complete androgen insensitivity syndrome), partial (PAIS, partial androgen insensitivity syndrome) to mild (MAIS, mild androgen insensitivity syndrome). More than 450 different mutations in the androgen receptor gene have been reported. The majority of mutations are single‐base substitutions. However, deletions (1–6 bp), partial or complete gene deletions (>10 bp), insertions or duplications are also found. Key Concepts Androgens and the androgen receptor are indispensable for expression of the male phenotype. The androgen receptor is a ligand‐dependent transcription factor and belongs to the family of nuclear receptors. Despite two different ligands (testosterone and 5α‐dihydrotestosterone), only one androgen receptor cDNA has been identified and cloned. A highly polymorphic (CAG) n ‐CAA repeat, encoding a polyglutamine stretch, in exon 1 of the androgen receptor gene is used for identification of X‐chromosomes for carrier detection in pedigree analyses. Variations in the polyglutamine stretch modulate androgen receptor transcriptional activity. End‐organ resistance to androgens has been designated as androgen insensitivity syndrome (AIS) and is distinct from other XY disorders of sex development. Defects in the androgen receptor gene can prevent normal development of both the internal and external male structures in 46, XY individuals. End‐organ resistance to androgens is X‐linked, and only 46, XY individuals are affected. AR gene mutations are transmitted in an X‐linked manner, but in 30% of the cases, mutations arise de novo . A number of cases of AIS present with no identifiable mutation in the androgen receptor, which has been estimated at between 25% and 33% of individuals presenting with androgen resistance.