Androgen insensitivity syndrome (AIS) is a condition involving the inability to respond to androgens, typically due to androgen receptor dysfunction.
It affects 1 in 20,000 to 64,000 XY (karyotypically male) births. The condition results in the partial or complete inability of cells to respond to androgens. This unresponsiveness can impair or prevent the development of male genitals, as well as impairing or preventing the development of male secondary sexual characteristics at puberty. It does not significantly impair female genital or sexual development. The insensitivity to androgens is therefore clinically significant only when it occurs in genetic males, (i.e. individuals with a Y-chromosome, or more specifically, an SRY gene). Clinical phenotypes in these individuals range from a typical male habitus with mild spermatogenic defect or reduced secondary terminal hair, to a full female habitus, despite the presence of a Y-chromosome.
AIS is divided into three categories that are differentiated by the degree of genital masculinization: Mild androgen insensitivity syndrome (MAIS) is indicated when the external genitalia are those of a typical male (a penis and a scrotum) Partial androgen insensitivity syndrome (PAIS) is indicated when the external genitalia are partially, but not fully, masculinized Complete androgen insensitivity syndrome (CAIS) is indicated when the external genitalia are those of a typical female (a vulva)
Androgen insensitivity syndrome is the largest single entity that leads to 46,XY undermasculinized genitalia.
Management of AIS is currently limited to symptomatic management; no method is currently available to correct the malfunctioning androgen receptor proteins produced by AR gene mutations. Areas of management include sex assignment, genitoplasty, gonadectomy to reduce tumor risk, hormone replacement therapy, genetic counseling, and psychological counseling.
Genetics
The human androgen receptor (AR) is a protein encoded by a gene located on the proximal long arm of the X chromosome (locus Xq11-Xq12). The protein coding region consists of approximately 2,757 nucleotides spanning eight exons. Like other nuclear receptors, the AR protein consists of several functional domains: the transactivation domain (also called the transcription-regulation domain or the NH2-terminal domain), the DNA-binding domain, the hinge region, and the steroid-binding domain (also called the carboxyl-terminal ligand-binding domain). The transactivation domain is encoded by exon 1, and makes up more than half of the AR protein. Exons 2 and 3 encode the DNA-binding domain, while the 5' portion of exon 4 encodes the hinge region. The remainder of exons 4 through 8 encodes the ligand binding domain.
Trinucleotide satellite lengths and AR transcriptional activity The AR gene contains two polymorphic trinucleotide microsatellites in exon 1. The first microsatellite (nearest the 5' end) contains 8 to 60 repetitions of the glutamine codon "CAG" and is thus known as the polyglutamine tract. The second microsatellite contains 4 to 31 repetitions of the glycine codon "GGC" and is known as the polyglycine tract. The average number of repetitions varies by ethnicity, with Caucasians exhibiting an average of 21 CAG repeats, and Blacks 18. In men, disease states are associated with extremes in polyglutamine tract length; prostate cancer, hepatocellular carcinoma, and intellectual disability are associated with too few repetitions, while spinal and bulbar muscular atrophy (SBMA) is associated with a CAG repetition length of 40 or more. Some studies indicate that the length of the polyglutamine tract is inversely correlated with transcriptional activity in the AR protein, and that longer polyglutamine tracts may be associated with male infertility and undermasculinized genitalia in men. However, other studies have indicated no such correlation exists. A comprehensive meta-analysis of the subject published in 2007 supports the existence of the correlation, and concluded these discrepancies could be resolved when sample size and study design are taken into account. Some studies suggest longer polyglycine tract lengths are also associated with genital masculinization defects in men. Other studies find no such association.
AR mutations As of 2010, over 400 AR mutations have been reported in the AR mutation database, and the number continues to grow. Inheritance is typically maternal and follows an X-linked recessive pattern; individuals with a 46,XY karyotype always express the mutant gene since they have only one X chromosome, whereas 46,XX carriers are minimally affected. About 30% of the time, the AR mutation is a spontaneous result, and is not inherited. Such de novo mutations are the result of a germ cell mutation or germ cell mosaicism in the gonads of one of the parents, or a mutation in the fertilized egg itself. In one study, three of eight de novo mutations occurred in the postzygotic stage, leading to the estimate that up to one-third of de novo mutations result in somatic mosaicism. Not every mutation of the AR gene results in androgen insensitivity; one particular mutation occurs in 8 to 14% of genetic males, and is thought to adversely affect only a small number of individuals when other genetic factors are present.
Other causes Some individuals with CAIS or PAIS do not have any AR mutations despite clinical, hormonal, and histological features sufficient to warrant an AIS diagnosis; up to 5% of women with CAIS do not have an AR mutation, as well as between 27 and 72% of individuals with PAIS.
In one patient, the underlying cause for presumptive PAIS was a mutant steroidogenic factor-1 (SF-1) protein. In another patient, CAIS was the result of a deficit in the transmission of a transactivating signal from the N-terminal region of the androgen receptor to the basal transcription machinery of the cell. A coactivator protein interacting with the activation function 1 (AF-1) transactivation domain of the androgen receptor may have been deficient in this patient. The signal disruption could not be corrected by supplementation with any coactivators known at the time, nor was the absent coactivator protein characterized, which left some in the field unconvinced that a mutant coactivator would explain the mechanism of androgen resistance in CAIS or PAIS patients with a typical AR gene.
XY karyotype Depending on the mutation, a person with a 46,XY karyotype and AIS can have either a male (MAIS) or female (CAIS) phenotype, or may have genitalia that are only partially masculinized (PAIS). The gonads are testes regardless of phenotype due to the influence of the Y chromosome. A 46,XY female, thus, does not have ovaries, and can not contribute an egg towards conception. In some cases, 46, XY females do form a vestigial uterus and have been able to gestate children. Such examples are rare and have required the use of an egg donor, hormone therapy, and IVF.
Several case studies of fertile 46,XY males with AIS have been published, although this group is thought to be a minority. In some cases, infertile males with MAIS have been able to conceive children after increasing their sperm count through the use of supplementary testosterone.
A genetic male conceived by a man with AIS would not receive his father's X chromosome, thus would neither inherit nor carry the gene for the syndrome. A genetic female conceived in such a way would receive her father's X chromosome, thus would become a carrier.
XX karyotype Genetic females (46,XX karyotype) have two X chromosomes, thus have two AR genes. A mutation in one (but not both) results in a minimally affected, fertile, female carrier. Some carriers have been noted to have slightly reduced body hair, delayed puberty, and/or tall stature, presumably due to skewed X-inactivation. A female carrier will pass the affected AR gene to her children 50% of the time. If the affected child is a genetic female, she, too, will be a carrier. An affected 46,XY child will have AIS.
A genetic female with mutations in both AR genes could theoretically result from the union of a fertile man with AIS and a female carrier of the gene, or from de novo mutation. However, given the scarcity of fertile AIS men and low incidence of AR mutation, the chances of this occurrence are small. The phenotype of such an individual is a matter of speculation; as of 2010, no such documented case has been published.
Correlation of genotype and phenotype Individuals with partial AIS, unlike those with the complete or mild forms, present at birth with ambiguous genitalia, and the decision to raise the child as male or female is often not obvious. Unfortunately, little information regarding phenotype can be gleaned from precise knowledge of the AR mutation itself; the same AR mutation may cause significant variation in the degree of masculinization in different individuals, even among members of the same family. Exactly what causes this variation is not entirely understood, although factors contributing to it could include the lengths of the polyglutamine and polyglycine tracts, sensitivity to and variations in the intrauterine endocrine milieu, the effect of coregulatory proteins active in Sertoli cells, somatic mosaicism, expression of the 5RD2 gene in genital skin fibroblasts, reduced AR transcription and translation from factors other than mutations in the AR coding region, an unidentified coactivator protein, enzyme deficiencies such as 21-hydroxylase deficiency, or other genetic variations such as a mutant steroidogenic factor-1 protein. The degree of variation, however, does not appear to be constant across all AR mutations, and is much more extreme in some. Missense mutations that result in a single amino acid substitution are known to produce the most phenotypic diversity.
Pathophysiology
Androgens and the androgen receptor
The effects that androgens have on the human body (virilization, masculinization, anabolism, etc.) are not brought about by androgens themselves, but rather are the result of androgens bound to androgen receptors; the androgen receptor mediates the effects of androgens in the human body. Likewise, the androgen receptor itself is generally inactive in the cell until androgen binding occurs.
The following series of steps illustrates how androgens and the androgen receptor work together to produce androgenic effects:
In this way, androgens bound to androgen receptors regulate the expression of target genes, thus produce androgenic effects.
Theoretically, certain mutant androgen receptors can function without androgens; in vitro studies have demonstrated that a mutant androgen receptor protein can induce transcription in the absence of androgen if its steroid binding domain is deleted. Conversely, the steroid-binding domain may act to repress the AR transactivation domain, perhaps due to the AR's unliganded conformation.
Androgens in fetal development Human embryos develop similarly for the first six weeks, regardless of genetic sex (46,XX or 46,XY karyotype); the only way to tell the difference between 46,XX or 46,XY embryos during this time period is to look for Barr bodies or a Y chromosome. The gonads begin as bulges of tissue called the genital ridges at the back of the abdominal cavity, near the midline. By the fifth week, the genital ridges differentiate into an outer cortex and an inner medulla, and are called indifferent gonads. By the sixth week, the indifferent gonads begin to differentiate according to genetic sex. If the karyotype is 46,XY, testes develop due to the influence of the Y chromosome's SRY gene. This process does not require the presence of androgen, nor a functional androgen receptor.