• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

Androgen Insensitivity Syndrome

Synonym: Testicular Feminization

, PhD, , PhD, and , MD.

Author Information
, PhD
Lady Davis Institute for Medical Research
Jewish General Hospital
Department of Human Genetics
McGill University
Montreal, Quebec
, PhD
Lady Davis Institute for Medical Research
Jewish General Hospital
Department of Medicine
McGill University
Montreal, Quebec
, MD
Lady Davis Institute for Medical Research
Department of Endocrinology
Jewish General Hospital
Department of Medicine
McGill University
Montreal, Quebec

Initial Posting: ; Last Update: July 10, 2014.

Summary

Disease 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 in individuals with a 46,XY karyotype is based on the following clinical findings: 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. AR is the only gene in which pathogenic variants are known to cause androgen insensitivity syndrome.

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 dilatation 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 healthcare 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.

Surveillance: Periodic reevaluation for gynecomastia during puberty in individuals assigned a male sex; monitoring of bone mineral density through DEXA scanning in adults.

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:

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.

GeneReview Scope

Androgen Insensitivity Syndrome: Included Disorders
  • Complete androgen insensitivity syndrome (CAIS)
  • Mild androgen insensitivity syndrome (MAIS)
  • Partial androgen insensitivity syndrome (PAIS)

For synonyms and outdated names see Nomenclature.

Diagnosis

Suggestive Findings

Androgen insensitivity syndrome (AIS) can be subdivided into three phenotypes: complete androgen insensitivity syndrome (CAIS), partial androgen insensitivity syndrome (PAIS), and mild androgen insensitivity syndrome (MAIS) (Table 1).

The clinical findings that permit a presumptive diagnosis of AIS include the following:

  • Absence of extragenital abnormalities
  • Two nondysplastic testes
  • Absent or rudimentary müllerian structures (i.e., fallopian tubes, uterus, and cervix) and the presence of a short vagina
  • Undermasculinization of the external genitalia at birth
  • Impaired spermatogenesis and/or somatic virilization (some degree of impaired virilization at puberty resulting from somatic mosaicism for a pathogenic variant in AR)

Table 1. Classification of AIS Phenotypes

Type External Genitalia (Synonyms)Findings
CAIS Female (“testicular feminization”)
  • Absent or rudimentary wolffian duct derivatives
  • Absence or presence of epididymides and/or vas deferens
  • Inguinal, labial, or abdominal testes
  • Short blind-ending vagina
  • Scant or absent pubic and/or axillary hair
PAIS Predominantly female (“incomplete AIS”)
  • Inguinal or labial testes
  • Clitoromegaly and labial fusion
  • Distinct urethral and vaginal openings or a urogenital sinus
Ambiguous
  • Microphallus (<1 cm) with clitoris-like underdeveloped glans; labia majora-like bifid scrotum
  • Descended or undescended testes
  • Perineoscrotal hypospadias or urogenital sinus
  • Gynecomastia (development of breasts) in puberty
Predominantly male
  • Simple (glandular or penile) or severe (perineal) “isolated” hypospadias with a normal-sized penis and descended testes or severe hypospadias with micropenis, bifid scrotum, and either descended or undescended testes
  • Gynecomastia in puberty
MAIS Male (“undervirilized male syndrome”)
  • Impaired spermatogenesis and/or impaired pubertal virilization
  • Gynecomastia in puberty

Family history may reveal other affected individuals related to each other in a pattern consistent with X-linked recessive inheritance. “Other affected family members” refers to:

  • Affected 46,XY individuals
  • Manifesting female (46,XX) carriers. About 10% of carrier females are manifesting carriers with asymmetric distribution and sparse or delayed growth of pubic and/or axillary hair.

Preliminary Tests

The following laboratory findings are consistent with the diagnosis of AIS:

  • Normal 46,XY karyotype
  • Evidence of normal or increased synthesis of testosterone (T) by the testes
  • Evidence of normal conversion of testosterone to dihydrotestosterone (DHT)
  • Evidence of normal or increased luteinizing hormone (LH) production by the pituitary gland
  • In CAIS, but not in PAIS: possible reduction in postnatal (0-3 months) surge in serum LH and serum T concentrations [Bouvattier et al 2002]

The following additional findings are consistent with the diagnosis of PAIS in an individual with the “predominantly male” phenotype (Table 1):

  • Impaired development of the prostate and of the wolffian duct derivatives demonstrated by ultrasonography or genitourography
  • Less-than-normal decline of sex hormone-binding globulin (SHBG) in response to a standard dose of the anabolic androgen, stanozolol [Sinnecker et al 1997]
  • Higher-than-normal levels of anti-müllerian hormone (AMH) during the first year of life or after puberty has begun

Establishing the Diagnosis

The diagnosis of CAIS is usually made on clinical findings and laboratory evaluations alone.

The diagnosis of PAIS and MAIS may also require a family history consistent with X-linked inheritance, as laboratory findings useful in establishing the diagnosis may not be present in all affected individuals [Gottlieb et al 1999a].

Molecular Genetic Testing

Gene. AR is the only gene in which pathogenic variants are known to cause androgen insensitivity syndrome.

Clinical testing

Table 2. Summary of Molecular Genetic Testing Used in Androgen Insensitivity Syndrome

Gene 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by This Method
Affected MalesCarrier Females
ARSequence analysis 2CAIS: 65%-95% 3, 4, 5Unknown 6
PAIS: <50% 3, 4, 5
MAIS: Unknown 7
(Multi)exonic or whole-gene deletion/duplication 8Unknown, but rareUnknown 6, 9

CAIS = complete androgen insensitivity syndrome

PAIS = partial androgen insensitivity syndrome

MAIS = mild androgen insensitivity syndrome

1. See Table A. Genes and Databases for chromosome locus and protein name. See Molecular Genetics for information on allelic variants detected in this gene.

2. Sequence analysis detects variants that are benign, likely benign, of unknown significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

3. Lack of amplification by PCR prior to sequence analysis can suggest a putative exon(s) or whole-gene deletion on the X chromosome in affected males; confirmation may require additional testing by deletion/duplication analysis.

4. Includes the mutation detection frequency using both sequence analysis and deletion/duplication analysis methods. However, deletions/duplications in AR that result in AIS are rare [Gottlieb et al 2004b].

5. A recent informal survey of AIS databases in Canada, United States, and Great Britain showed that AR pathogenic variant detection frequency ranged from 65% to 95% in individuals with CAIS and from 40% to 45% in those with PAIS. The AIS database at the Lady Davis Institute for Medical Research (Montreal, Canada) which includes 138 individuals with CAIS or PAIS, reflects this variable detection rate [Gottlieb et al 2012]. Indeed two additional reports have revealed substantial percentage of putative PAIS cases in which no AR variant has been found [Veiga-Junior et al 2012, Lek et al 2014].

6. Sequence analysis of genomic DNA cannot detect deletion of one or more exons or the entire X-linked gene in a heterozygous female.

7. AR pathogenic variant detection frequency in individuals with MAIS is more difficult to assess because of the assumption that MAIS diagnoses are often missed: (1) In the presence of deficient or defective androgen binding activity in genital skin fibroblasts in an XY individual with clinical findings of CAIS and PAIS, the likelihood of finding a pathogenic variant in the androgen binding domain of AR approached 40% [Weidemann et al 1996]. (2) In the presence of normal androgen binding in genital skin fibroblasts in an XY individual with clinical findings of PAIS, the likelihood of finding an AIS-causing AR variant is 10% or less, even when exon 1 is screened and/or sequenced in its entirety. [Author, personal observation]. (3) Because the presence of an AR pathogenic variant, not abnormal androgen binding, is now the primary diagnostic criterion for AIS, defective androgen binding activity in an XY individual with clinical findings of CAIS, PAIS, or MAIS who does not have an AR pathogenic variant may be inappropriately precluded from the above diagnostic categories [Gottlieb et al 2012, Lek et al 2014]. Indeed it has now been suggested that a new category of 46,XY disorder of sex development (DSD) be established in which no AR variant is found, although AR binding may be impaired [Lek et al 2014]. However, this would appear to be premature in light of the discovery of a number of cases of somatic mosaicism and intra-tissue genetic heterogeneity [Gottlieb et al 2012].

8. Testing that identifies exonic or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

9. Deletion/duplication analysis can detect the less common exonic, multiexonic, and gross deletions and rare duplications in AR in at-risk relatives who have a 46,XX karyotype.

Androgen Binding Assay

If PAIS is suspected and no pathogenic variant in AR is identified through molecular genetic testing, androgen binding activity of genital skin fibroblasts can be considered.

Testing Strategy

To confirm/establish the diagnosis in a proband

One genetic testing strategy is molecular genetic testing of the only gene in which pathogenic variants are known to cause androgen insensitivity syndrome (AIS).

1.

Perform sequence analysis of AR first.

2.

If no AR pathogenic variant is identified by sequence analysis, deletion/duplication analysis may be considered, particularly if other family members are known or thought to be affected.
Note: deletions/duplications in AR that result in AIS are rare.

An alternative genetic testing strategy is use of a multi-gene panel that includes AR and other genes of interest (see Differential Diagnosis).

Androgen binding assay. If molecular genetic testing fails to identify a pathogenic variant that can explain the affected individual’s phenotype, testing of a biopsy of genital skin for defective androgen binding may be considered.

Failure to detect an AR pathogenic variant in individuals with decreased or defective androgen binding activity may be explained as follows:

  • Variants in regulatory or deep intronic portions of AR are not identifiable with the clinically available tests [Gottlieb et al 1999b].
  • AR is normal; however, variants are present in genes whose products either collaborate with AR or are subject to androgenic control [Cheung-Flynn et al 2005].
  • Somatic mosaicism could result in a population of cells with an AR variant in genital skin (or a subpopulation of genital skin) but not in peripheral blood cells [Gottlieb et al 2001b, Gottlieb et al 2012].
  • AR is normal; however, there is a “timing problem” (acquisition of normal testosterone synthesis or normal androgen responsiveness is delayed beyond the critical periods for normal external and/or internal male genital differentiation).
  • AR is normal; however, post-genomic events (e.g., methylation, RNA editing, interacting microRNAs) could result in an AIS phenotype, although such tests are yet to be widely available [Gottlieb et al 2014].

Clinical Description

Natural History

Complete androgen insensitivity syndrome (CAIS, testicular feminization, Tfm). Individuals with CAIS have normal female external genitalia with absence of female internal genitalia. They typically present either before puberty with masses in the inguinal canal that are subsequently identified as testes or at puberty with primary amenorrhea and sparse to absent pubic or axillary hair. Breasts and female adiposity develop normally. Sexual identity and orientation are typically female and heterosexual.

CAIS almost always runs true in families; that is, affected XY relatives usually have normal female external genitalia and seldom have any sign of external genital masculinization, such as clitoromegaly or posterior labial fusion [Boehmer et al 2001]. On occasion, wolffian duct development is observed [Hannema et al 2004].

Partial AIS (PAIS) with predominantly female external genitalia (Table 1) presents in a manner similar to CAIS; however, affected individuals have signs of external genital masculinization including clitoromegaly or posterior labial fusion.

Partial AIS with ambiguous genitalia or predominantly male genitalia (PAIS, Reifenstein syndrome). Determining the sex of rearing may be an issue for children with frank genital ambiguity. In families with PAIS, phenotypic disparity may warrant male sex of rearing in one affected sib and female sex of rearing in another affected sib [Rodien et al 1996, Evans et al 1997, Boehmer et al 2001]. Individuals with PAIS and predominantly male genitalia are raised as males. Gynecomastia at puberty and impaired spermatogenesis occur in all individuals with PAIS. Pubic hair is usually moderate; facial, body, and axillary hair are often reduced.

Mild AIS (MAIS, undervirilized male syndrome). The external genitalia of affected individuals are unambiguously male. They usually present with gynecomastia at puberty. They may have undermasculinization that includes sparse facial and body hair and small penis. Impotence may be a complaint. Spermatogenesis may or may not be impaired. In some instances, the only observed abnormality appears to be male infertility [Gottlieb et al 2005]; therefore, MAIS could explain some cases of idiopathic male infertility [Goglia et al 2011].

MAIS almost always runs true in families.

Genotype-Phenotype Correlations

A correlation does exist among certain missense AR variants, their functional consequences, and external genital development, particularly in the case of CAIS (see the Androgen Receptor Gene Mutations Database).

The correlation is much less clear in PAIS, in which interfamilial phenotypic variation is observed [Brinkmann & Trapman 2000, Boehmer et al 2001, Deeb et al 2005, Gottlieb et al 2012, Lek et al 2014].

The Androgen Receptor Gene Mutations Database includes 45 instances in which identical AR variants produce different AIS phenotypes [Gottlieb et al 2001a, Gottlieb et al 2012].

In some instances, the variable expressivity associated with a number of single nucleotide variants may be attributed to somatic mosaicism rather than to the modifying influence of “background” genetic factors [Boehmer et al 1997, Holterhus et al 1997, Holterhus et al 2001, Kohler et al 2005]. See Gottlieb et al [2001b] for a detailed discussion of the possible role of somatic mosaicism as a cause of variable expressivity.

It remains to be determined whether specific missense variants can be correlated with normal or impaired spermatogenesis and with absence or presence of localized expressions of undervirilization (e.g., gynecomastia, high-pitched voice, impotence). Although specific variants associated with azoospermia have been reported [Zuccarello et al 2008, Mirfakhraie et al 2011], only a more extensive analysis of more cases of idiopathic male infertility is likely to identify definitive correlations. Melo et al [2010] noted that infertile males who do not produce sperm have a higher number of AR variants than do males with impaired sperm production. Recently, idiopathic infertility cases were found in both oligospermic and azoospermic men who had AR-CAG repeat lengths that were either significantly shorter (15-18 CAG repeat lengths) or significantly longer (22-28) than normal (19-21 CAG repeat lengths (see Gottlieb et al [2012], Giagulli et al [2014]).

Penetrance

No definitive data regarding penetrance exist, possibly because of under-ascertainment of affected individuals, particularly phenotypic but infertile males in whom AR molecular genetic testing may not be performed [Gottlieb et al 2005].

Nomenclature

The terms "testicular feminization" and androgen resistance syndrome are outdated and thus rarely used now.

Prevalence

Standard references quote a prevalence of 2:100,000 to 5:100,000 for complete AIS (CAIS) based on estimates derived from otherwise healthy phenotypic females found to have histologically normal inguinal or abdominal testes. A survey in the Netherlands over a ten-year period based on reported cases of AIS concluded that the minimal incidence was 1:99,000 [Boehmer et al 2001].

Partial AIS (PAIS) is at least as common as complete AIS.

The prevalence of mild AIS (MAIS) has not yet been determined. However, it is much less frequently reported than CAIS and PAIS [Hughes et al 2012].

Differential Diagnosis

Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome is diagnosed in phenotypic females who exhibit amenorrhea and have a partial or complete absence of the cervix, uterus, and vagina. Individuals with MRKH can be distinguished from those with CAIS by confirmation of a 46,XX karyotype [Sultan et al 2009].

Hypospadias resulting from AR mutation (and thus a part of the spectrum of PAIS) cannot be distinguished from hypospadias resulting from other (largely undefined) causes by the examination of the genitalia alone. AR variants associated with hypospadias are likely rare.

MAIS caused by single nucleotide variants of AR [Wang et al 1998] may be clinically indistinguishable from MAIS caused by expansion of the polymorphic CAG repeat in AR [Tut et al 1997]. Pathogenic expansion of this triplet repeat is the cause of spinal and bulbar muscular atrophy (SBMA), also known as Kennedy disease.

Undermasculinization of the external genitalia and pubertal undervirilization are components of many different syndromes that have no etiologic relation to AR. They may or may not have a pathogenic relation to the androgen receptor protein. The one exception is a contiguous gene deletion syndrome that includes the AR locus and results in intellectual disability and genital abnormalities [Davies et al 1997].

46,XY infants born small-for-gestational-age may have clinical features of PAIS with no identifiable AR pathogenic variant. It has been suggested that this association be termed ‘XY DSD with fetal growth restriction, as yet unexplained’ [Lek et al 2014].

A survey of the Androgen Receptor Gene Mutations Database suggests that AIS may be attributable to factors other than the presence of AR variants. Findings that suggest the presence of other identifiable diagnoses in 46,XY individuals with predominantly female, ambiguous, or predominantly male genitalia include the following:

  • Elevated levels of testosterone precursors caused by a partial testosterone biosynthetic defect in which compensatory serum LH concentrations stimulate a normal plasma testosterone concentration
  • The presence of müllerian duct derivatives as a result of a testicular organogenesis defect with impaired Sertoli cell production of anti-müllerian hormone
  • The presence of wolffian duct-derived internal male reproductive structures that differentiate in response to testosterone, suggesting 5-α-reductase deficiency, a partial testosterone biosynthetic defect, or PAIS. 5-α-reductase deficiency is the result of mutation in SRD5A2, which encodes the enzyme 5-α-reductase. The enzyme converts testosterone to dihydrotestosterone (DHT), which is primarily responsible for the development of the external genitalia before birth.

Issues to consider in individuals with some, but not all, of the clinical features of AIS:

  • Normal serum concentrations of T, DHT, and LH after birth do not prove that the concentration was normal during the critical period of fetal genital masculinization.
  • Normal responsiveness to androgen after birth does not prove that it was normal before birth. That is, in utero delay in the acquisition of normal androgen biosynthesis or normal androgen sensitivity may lead to features consistent with androgen insensitivity.
  • Subnormal sensitivity to androgen after birth may involve components of the overall androgen response system (AR-interacting proteins) beyond the androgen receptor itself.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and the needs of an individual diagnosed with androgen insensitivity syndrome, a complete evaluation by specialists in disorders of sex development (DSDs), which can include specialists in endocrinology, urology, medical genetics, psychology, and psychiatry [Hughes et al 2006, Parisi et al 2007, Douglas et al 2010], is ideal.

Evaluation of androgen receptor-binding properties (i.e., binding and dissociation of specific ligands) of genital skin can help predict the likely outcome of hormone treatments (see PAIS with Ambiguous Genitalia).

Treatment of Manifestations

A number of clinicians have sought to establish a consensus statement on management of DSD including AIS [Hughes & Deeb 2006]. A number of publications have subsequently discussed best management of these disorders [Diamond & Beh 2008 (full text), Douglas et al 2010 (full text), Pasterski et al 2010 (full text), Wiesemann et al 2010 (full text), Hughes et al 2012 (full text)].

Assignment of sex of rearing. The issue of sex assignment in infancy when the child is being evaluated for ambiguous genitalia is paramount. It requires informed decision making by parents and healthcare personnel and should be resolved as early as possible, after a multidisciplinary evaluation has been completed.

  • Even in CAIS this may not always be easy. Cheikhelard et al [2008] evaluated 29 individuals with CAIS; it was recommended that gonads be kept at least until the completion of spontaneous puberty and the possibility of virilization be evaluated before management decisions are made.
  • Psychological counseling and use of support groups can be of benefit [Cul & Simmonds 2010, Hughes et al 2012].

CAIS

A critical consideration of any surgical intervention is the nature and timing of such intervention; thus surgeons need to be involved with the affected individuals and pediatrician in any such decisions [Purves et al 2008, Munoz & Swan 2010]. Vidal et al [2010] reviewed the evolution of surgical techniques for ‘feminization’ and ‘masculinization’ and their possible outcomes.

A common practice is to remove the testes after puberty when feminization of the affected individual is complete, since feminization occurs partly by testicular estrogen and partly by peripheral conversion of androgen to estrogen.

The rationale for postpubertal gonadectomy is that testicular malignancy, which develops at the usual rate for cryptorchid testes, seldom occurs before puberty [Hannema et al 2006]. Prepubertal gonadectomy is now only considered if inguinal testes are physically or esthetically uncomfortable, and if inguinal herniorrhaphy is necessary. In this event, estrogen replacement therapy is necessary to initiate puberty, maintain feminization, and avoid osteoporosis.

However, the issue of gonadectomy is controversial. Some have argued that the true risk for malignant transformation of the gonads is small and have suggested postpubertal gonad biopsy as opposed to removal [Hughes et al 2006, Parisi et al 2007], which would allow affected individuals to retain a natural source of androgen production and avoid exogenous hormone replacement.

Vaginal dilatation to augment vaginal length and to avoid dyspareunia is typically the treatment of choice for those with short vaginal length. If this method fails, new treatments of blind vagina have been proposed, including autologous buccal mucosal graft vaginoplasty and enhanced balloon vaginoplasty [Zhoa et al 2009, El Saman et al 2011]. Surgical reconstruction frequently requires maintenance vaginal dilatation to decrease the likelihood of future stricture.

The question of how much and when to disclose the diagnosis of CAIS to an affected individual has not been resolved uniformly; however, it has become obvious that explanation of the diagnosis in an empathic setting is much preferable to systematic concealment or self-discovery of the diagnosis in an environment devoid of support from family, professionals, and other affected individuals [Conn et al 2005].

PAIS with Predominantly Female Genitalia (Incomplete AIS)

The issues are similar to those discussed under CAIS, except prepubertal gonadectomy helps avoid the emotional discomfort of increasing clitoromegaly at the time of puberty.

In instances in which the diagnosis of PAIS is difficult to establish because of the presence of somatic mosaicism, a change of sex assignment can result in concomitant problems [Kohler et al 2005].

PAIS with Ambiguous Genitalia or Predominantly Male Genitalia

The assignment of sex in an infant with ambiguous genitalia is a complex process that requires timely assessment by a multidisciplinary team in consultation with the family and should be resolved as early as possible. Aside from purely anatomic and surgical considerations, the choice of a male sex-of-rearing demands a therapeutic trial with pharmacologic doses of androgen to try to predict potential androgen responsiveness at puberty. Furthermore, appreciable phallic growth in response to administered androgen facilitates reconstructive surgery.

In instances in which maximum information is being gathered on an infant with no family history of AIS before sex is assigned, sequence analysis of AR may be considered; however, the lower probability of detecting an AR variant in individuals with the PAIS phenotype and the poor positive predictive value of any given variant regarding AIS phenotype need to be considered when making decisions about sex assignment.

It has also been reported that the length of the AR exon 1 CAG repeat can influence the efficacy of testosterone treatments: individuals with shorter repeat lengths are more likely to respond to hormonal treatments [Zitzmann 2009]. However, the efficacy of CAG repeat length as a possible marker to assess hormonal treatment must await further studies.

Based on experience with a small number of individuals, the role of long-term androgen pharmacotherapy in individuals with PAIS who are raised as males remains unclear. Response to androgen treatment may be substantial in individuals with certain missense variants in the DNA-binding domain of the androgen receptor [Weidemann et al 1998]; however, it is still difficult to accurately predict the efficacy of androgen treatment. Thus, considerable caution should be exercised with regard to androgen treatment [Werner et al 2010], in particular because special hormonal profiles to androgen insensitivity have often not been acknowledged in replacement strategies. It has been proposed that an external masculinization score in neonates could be a reasonable predictor of virilization at puberty in individuals with PAIS who have been assigned a male sex of rearing [Hughes et al 2012].

Gynecomastia that develops in puberty eventually requires reduction mammoplasty. It has been reported that tamoxifen has been used for treating pubertal gynecomastia in two siblings with PAIS [Saito et al 2014].

Those individuals with PAIS who are raised as females and who have gonadectomy after puberty may need combined estrogen and androgen replacement therapy, the latter to maintain libido.

MAIS

Men with MAIS often require reduction mammoplasty for treatment of gynecomastia.

A trial of androgen pharmacotherapy is recommended to attempt to improve virilization [Loy & Yong 2001].

Prevention of Primary Manifestations

The efficacy of androgen therapy in preventing manifestations such as gynecomastia is not clear.

Prevention of Secondary Manifestations

Women with CAIS have decreased bone mineral density, regardless of timing of gonadectomy [Oakes et al 2008].

  • In addition to estrogen replacement therapy, supplemental calcium and vitamin D are recommended.
  • Regular weight-bearing exercises are encouraged to maintain bone health.
  • Bisphosphonate therapy may be indicated for those individuals with evidence of decreased bone mineral density and/or multiple fractures.

Surveillance

Appropriate measures include the following:

  • Monitoring of postnatal development of genitalia that were ambiguous at birth for changes that could lead to reconsideration of the assigned sex
  • For individuals assigned a male sex, evaluation during puberty for signs of gynecomastia
  • In adults, monitoring of bone mineral density through DEXA (dual-emission x-ray absorptiometry) scanning [Oakes et al 2008]

Evaluation of Relatives at Risk

It is appropriate to evaluate the older and younger sibs of a proband in order to identify as early as possible those who would benefit from institution of treatment and preventive measures. If the pathogenic variant in the family is known, molecular genetic testing can be used to clarify the genetic status of at-risk sibs.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Other

Chen et al [2010] noted that Fkbp52 regulates AR transactivation activity and male urethra morphogenesis, suggesting that AR variants may require other genetic factors to produce hypospadias.

Apolipoprotein D (APOD) is a possible biomarker of AR function in AIS [Appari et al 2009].

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Androgen insensitivity syndrome (AIS) is inherited in an X-linked recessive manner.

Risk to Family Members

Parents of a 46,XY proband

  • The father of a proband is neither affected nor a carrier.
  • Women who have an affected child and one other affected relative are obligate heterozygotes.
  • If a woman has more than one affected child and the pathogenic variant cannot be detected in DNA extracted from her leukocytes, she has germline mosaicism.
  • If pedigree analysis reveals that the proband is the only affected family member, several possibilities exist regarding the carrier status of the proband's mother and other 46,XX females in her family:
  • The affected individual has a de novo AR mutation. Note: De novo mutations can be expected to occur approximately 30% of the time [Hughes & Deeb 2006]. The two mechanisms by which de novo AR mutation can occur are:
    • Germline mutation. A de novo mutation was present in the egg at the time of that person's conception and is therefore present in every cell of the affected individual's body. In this instance, the individual's mother does not have an AR pathogenic variant and no other family member is at risk.
    • Somatic mosaicism. Mutation occurred after conception and therefore the pathogenic variant is present in some, but not all, cells of the affected individual's body [Holterhus et al 1997, Kohler et al 2005]. In this instance the likelihood that the mother is a heterozygote is low but greater than that in the general population.
  • The affected individual's mother has a de novo AR mutation. The mechanisms by which de novo AR mutation could have occurred in the mother are:
    • Germline mutation. The pathogenic variant was present in the egg or sperm at the time of her conception, is present in every cell of her body, and is detectable in DNA extracted from leukocytes.
    • Germline mosaicism. The pathogenic variant is present only in her ovaries [Boehmer et al 1997] and is not detectable in DNA extracted from leukocytes.
    • Somatic mosaicism. The pathogenic variant is present in her ovaries and in some of her somatic cells and may or may not be detectable in DNA extracted from leukocytes [Kohler et al 2005]. In 22 of 30 simplex families with CAIS or PAIS, the mother was proven to be heterozygous for an AR the pathogenic variant. Of the eight individuals with a de novo mutation, three appeared to have somatic mosaicism [Hiort et al 1998].

      In these three instances, each of her offspring is at risk of inheriting the AR pathogenic variant; none of her sisters, however, is at risk of carrying the AR pathogenic variant.
  • The affected individual's maternal grandmother has a de novo mutation. In this instance, all of the maternal grandmother's daughters are at risk of being carriers of the AR pathogenic variant.
  • The risk to the sibs depends on the carrier status of the mother.
  • If the mother is a carrier, there is a 50% chance of transmitting the pathogenic variant to each sib.
  • Sibs with a 46,XY karyotype who inherit the AR pathogenic variant will be affected.
  • Sibs with a 46,XX karyotype who inherit the AR pathogenic variant will be carriers.
  • If the pathogenic variant in the proband cannot be detected in the leukocyte DNA of the mother of the only affected individual in the family, the risk to sibs is low, but greater than that of the general population because of the possibility of germline mosaicism.

Offspring of a proband. Individuals with a 46,XY karyotype who have any of the subtypes of AIS (i.e., CAIS, PAIS, MAIS) are almost always infertile.

Offspring of a carrier female

  • Each offspring of a female known to be a carrier of an AR pathogenic variant carrier (heterozygote) is at a 25% risk of 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
  • The phenotype of offspring with a 46,XY karyotype and CAIS or MAIS tends to be fairly predictable. The genital phenotype of individuals with PAIS within a family is generally consistent; however, a wide range of phenotypic variability is seen among families who share the same PAIS pathogenic variant, making it difficult to predict the phenotype in a simplex case.

Carrier Detection

Female carriers may be identified through a combination of the following:

  • Family history
  • Clinical findings. Ten percent of carriers are manifesting carriers with asymmetric distribution and sparse or delayed growth of pubic or axillary hair, a finding that results from random X-chromosome inactivation. The presence of normal pubic and axillary hair does not rule out the possibility that an individual with a 46,XX karyotype is a carrier.
  • Molecular genetic testing. Identification of female carriers requires either (a) prior identification of the disease-causing mutation in the family or, (b) if an affected male is not available for testing, molecular genetic testing first by sequence analysis, and then, if no mutation is identified, by methods to detect gross structural abnormalities.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Cohen-Kettenis [2010] reviews some similarities in relevant psychosocial and psychosexual issues associated with gender dysphoria in people with disorders of sex development (DSDs) and those with who do not have a DSD. Because few studies focusing on the psychosocial and psychosexual issues in individuals with DSDs have been completed, Cohen-Kettenis [2010] suggests that clinicians working with individuals and families with DSDs consider relying on the literature related to individuals with gender dysphoria who do not have a DSD.

Gender identity. In a long-term outcome study of DSDs that included CAIS, it was noted that while many patients fare well, dissatisfaction with original gender assignment has been underestimated and gender and sexual counseling should be part of the multidisciplinary service available to individuals with DSDs [Warne 2008].

Of particular interest is a case report of an individual with CAIS with male gender identity [Tsjoen et al 2011]. Further insight into issues of gender identity in persons with CAIS is available from analysis of accounts presented by an XY female on the UK AIS Support Group Web site [Garrett & Kirkman 2009].

An additional ethical and possibly legal issue is the genetic testing of other family members for AIS. In a 1999 court decision (unrelated to AIS) chromosome findings alone were used to determine an individual’s sex. Clinicians should be aware that information provided to individuals with AIS and their families (in the interest of facilitating appropriate medical care) could potentially have legal implications for such individuals/families [Berg et al 2007].

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

High-risk pregnancy. If the pathogenic variant has been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing for this disease/gene or custom prenatal testing.

Pregnancies not known to be at increased risk for AIS. Two papers report the prenatal diagnosis of AIS in two pregnancies not known to have been at risk. The diagnosis of AIS was suspected after discordance in sex identified by ultrasonography (female) and karyotype (46,XY) was found [Yalinkaya et al 2007, Bianca et al 2009].

Requests for prenatal testing for conditions which (like androgen insensitivity syndrome) do not affect intellect and have some treatment available are not common. Differences in perspective may exist among medical professionals and in families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the pathogenic variants have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Androgen Insensitivity Syndrome Support Group (AISSG)
    AISSG is a consortium of worldwide support groups.
    United Kingdom
    Email: uk@aissg.org; aissgusa@hotmail.com
  • Androgen Insensitivity Syndrome Support Group Australia (AISSG)
    PO Box 3239
    South Brisbane Queensland 4101
    Australia
    Email: aissgaustralia@gmail.com
  • Androgen Receptor Gene Mutations Database
    The Lady Davis Institute for Medical Research
    Montreal Quebec
    Canada
    Email: bruce.gottlieb@mcgill.ca
  • Intersex Society of North America (ISNA)
    Rohnert Park CA 94928
  • National Library of Medicine Genetics Home Reference
  • AIS-DSD Support Group for Women and Families

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Androgen Insensitivity Syndrome: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Androgen Insensitivity Syndrome (View All in OMIM)

300068ANDROGEN INSENSITIVITY SYNDROME; AIS
313700ANDROGEN RECEPTOR; AR

Gene structure. AR comprises nine exons. Nucleotide numbering varies depending on three principal factors:

  • Variable length of the polyglutamine and polyglycine repeats
  • Nucleotide at which the opening reading frame starts
  • Complementary DNA sequence used as the reference sequence

For a detailed summary of gene and protein information, see Table A, Gene Symbol. See also Normal protein product.

Coincidentally, two major species of AR mRNA (10-11 kb; ~7 kb) result from alternative splicing of a very long 3'-UTR. Two forms of the androgen receptor protein (A and B) exist. Their size difference suggests that the short form (B) represents translation initiation at the internal Met190 residue.

The issue of different forms of androgen receptor is somewhat confusing as a number of pathogenic variants that delete either whole exons or a substantial part of an exon, or affect splice sites, have been identified. In almost all cases when an attempt has been made to test these variant forms of androgen receptor protein, they have been found to be nonfunctional.

Note: The Androgen Receptor Gene Mutations Database has recently changed its nucleotide and amino acid numbering scheme to conform to the HGVS standards, which are based on NCBI cDNA reference sequence NM_000044.2.

Benign allelic variants. See Table 3.

Pathogenic allelic variants. More than 500 single nucleotide variants in AR have been found to cause AIS (see Androgen Receptor Gene Mutations Database). The great majority are missense variants that impair DNA or androgen binding and cause CAIS or PAIS; a small number have been proven to cause MAIS.

Single nucleotide variants in exon 1 are relatively uncommon; the majority of variants are either nonsense or small deletions or insertions that result in a frameshift; thus, they almost always cause CAIS; PAIS is seldom the result of exon 1 variants [Choong et al 1996]. That said, the number of single nucleotide variants identified in exon 1 has increased over the past few years; a considerable number are associated with the MAIS phenotype (see Androgen Receptor Gene Mutations Database).

A relatively small number of AR deletions/duplications of one or more exons or of the whole gene have been described (see Databases in Table A).

Expansion of the trinucleotide repeat tract (CAG)nCAA that encodes a polyglutamine tract to more than 38 repeats results in Kennedy disease (spinal and bulbar muscular atrophy) with some findings of MAIS, which are likely the result of the reduced transactivation of AR with long CAG repeat tracts of androgen receptor proteins that contain expanded polyglutamine tracts.

Table 3. AR Allelic Variants

Class of Variant AlleleDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
Benignc.172_174(7_37) 1p.Gln58(7_37) 2NM_000044​.3
NP_000035​.2
(GGT)3GGG(GGT)2-4GGC(n), where n=12-29 3, 4, 5(polyglycine tract) 3
1754G>A 4, 6p.= 7
Pathogenic172_174[>37] 4, 8, 9, 10Gln58(>37) 4, 11

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Trinucleotide repeat tract (CAG)n with a variable stretch of n=7-37 in the population starting at position 172 from the initiation AUG or 1287 from the beginning of the NM_000044​.3 transcript

2. A stretch of glutamines (Gln) starting at amino acid residue 58 which is found with a variable length from 7-17 in the population

3. Complex trinucleotide repeat beginning at position 2466 from the beginning of the NM_000044​.3 transcript that encodes a variable polyglycine tract [Lumbroso et al 1997]

4. Nomenclature given is an alias (i.e., a variant designation that does not conform to current naming conventions) in common use.

5. Standard nomenclature per ClinVar: c.1363GGT(2_4)GGC(12_29)

6. A silent 1754G>A variant in the coding region (at the third position of codon 213 in exon 1) is referred to as 709G>A in Hiort et al [1994], 995G>A in Batch et al [1992], and 1152G>A in Chang et al [1988].

7. p.= designates that protein has not been analyzed, but no change is expected.

8. Trinucleotide repeat tract (CAG)n with a variable stretch of n>-37 in the population starting at position 172 from the initiation AUG or 1287 from the beginning of the NM_000044​.3 transcript

9. Pathogenic allelic variant associated with SBMA

10. Standard nomenclature per ClinVar: c.172_174(38_?)

11. Standard nomenclature per ClinVar: p.Gln58(38_?)

Normal gene product. Androgen receptor. The entire N-terminal portion of the androgen receptor (~538 amino acids) is encoded by exon 1, the DNA-binding domain (amino acid residues 558-617) by exons 2 and 3, the bipartite nuclear localization signal (amino acid residues 618-637) by exons 3 and 4, and the androgen-binding domain (residues 646-920) by exons 4-8.

Two polyA-addition signals occur about 220 nucleotides apart. Coincidentally, two major species of AR mRNA (10-11 kb; ~7 kb) result from alternative splicing of a very long 3'-UTR. Two forms of the androgen receptor protein (A and B) exist. Their size difference suggests that the short form (B) represents translation initiation at the internal Met190 residue.

The different isoforms of the androgen receptor are somewhat confusing: a number of pathogenic variants that either delete whole exons or a substantial part of an exon, or affect splice sites, have been identified. When the functionality of these variant forms of androgen receptor protein is tested, almost all have been found to be nonfunctional.

The androgen receptor is a well-defined transcriptional regulatory factor. Once activated by binding to androgen, it collaborates with other co-regulatory proteins (some involve DNA binding, others do not) to achieve control over the rate of transcription of an androgen target gene that is under the influence of a nearby promoter. A large number of AR-associated proteins have now been identified [Heinlein & Chang 2002, Gottlieb et al 2004b, Gottlieb et al 2012]; for latest listing see the Androgen Receptor Gene Mutations Database.

Abnormal gene product. Nearly all single nucleotide variants in the androgen-binding domain impair androgen binding and, therefore, affect transactivation by the AR. Some decrease only the apparent equilibrium affinity constant; some increase only the non-equilibrium dissociation rate; others do both, either with all androgens or selectively with certain androgens. Still others are thermolabile or degrade excessively in the presence of androgen. Single nucleotide variants in the zinc fingers or α-helical portions of the DNA-binding domain impair binding to a sequence of regulatory nucleotides known as an androgen response element. Such binding is essential for the androgen receptor to exert transcriptional regulatory control over most of its target genes.

The polyglutamine-expanded androgen receptor causes spinal and bulbar muscular atrophy by a gain of function that is selectively motor neuronotoxic.

Insight into the relationship between variants and their possible effects on the functionality of the actual androgen receptor protein has been obtained by creating molecular models of the receptor using molecular dynamic modeling based on the x-ray crystal structure [Matias et al 2000]. This technique has produced dynamic models that have successfully simulated the effects of particular variants on the ligand-binding properties of mutant androgen receptors [Elhaji et al 2004, Wu et al 2004, Elhaji et al 2006]. It is hoped that this technique may eventually lead to treatments that return to normal the ligand-binding capacity of mutant androgen receptors.

Somatic AR alterations and cancer. Some cancers show somatic alterations in AR. These, however, appear to result in a gain of function rather than the loss of function seen in AIS. Cancers include [Gottlieb et al 2004a, Gottlieb et al 2012]:

  • Prostate cancer
  • Male breast cancer
  • Laryngeal cancer
  • Liver cancer
  • Testicular cancer
  • Bladder cancer [Rahmani et al 2013]

References

Published Guidelines/Consensus Statements

  1. Diamond M, Beh HG. Changes in the management of children with intersex conditions. Available online. 2008. Accessed 7-2-14.
  2. Douglas G, Axelrad ME, Brandt ML, Crabtree E, Dietrich JE, French S, Gunn S, Karaviti L, Lopez ME, Macias CG, McCullough LB, Suresh D, Sutton VR (2010) Consensus in guidelines for evaluation of DSD by the Texas Children’s Hospital multidisciplinary gender medicine team. Available online. 2010. Accessed 7-2-14. [PMC free article: PMC2963131] [PubMed: 20981291]
  3. Hughes IA, Davies JD, Bunch TI, Pasterski V, Mastroyannapoulou K, MacDougall J. Androgen Insensitivity Syndrome. Available online. 2012. Accessed 7-2-14.
  4. Pasterski V, Prentice P, Hughes IA (2010) Impact of the consensus statement and the new DSD classification system. Available online. 2010. Accessed 7-2-14. [PubMed: 20541147]
  5. Wiesemann C, Ude-Koeller S, Sinnecker GH, Thyen U (2010) Ethical principles and recommendations for the medical management of differences of sex development (DSD)/intersex in children and adolescents. Available online. 2010. Accessed 7-2-14. [PMC free article: PMC2859219] [PubMed: 19841941]

Literature Cited

  1. Appari M, Werner R, Wunsch L, Cario G, Demeter J, Hiort O, Rieppe F, Brooks JD, Holterhus PM. Apolipoprotein D (APOD) is a putative biomarker of androgen receptor function in androgen insensitivity syndrome. J Mol Med. 2009;87:623–32. [PubMed: 19330472]
  2. Batch JA, Williams DM, Davies HR, Brown BD, Evans BA, Hughes IA, Patterson MN. Androgen receptor gene mutations identified by SSCP in fourteen subjects with androgen insensitivity syndrome. Hum Mol Genet. 1992;1:497–503. [PubMed: 1307250]
  3. Berg JS, French SL, McCullogh LB, Kleppe S, Sutton VR, Gunn SK, Karaviti LP. Ethical and legal implications of genetic testing in androgen insensitivity syndrome. J Pediatr. 2007;150:434–8. [PubMed: 17382127]
  4. Bianca S, Cataliotti A, Bartoloni G, Torrente I, Barrano B, Boemi G, Lo Presti M, Indaco L, Barone C, Ettore G. Prenatal diagnosis of androgen insensitivity syndrome. Fetal Diagn Ther. 2009;26:167–9. [PubMed: 19844078]
  5. Boehmer AL, Brinkmann O, Bruggenwirth H, van Assendelft C, Otten BJ, Verleun-Mooijman MC, Niermeijer MF, Brunner HG, Rouwe CW, Waelkens JJ, Oostdijk W, Kleijer WJ, van der Kwast TH, de Vroede MA, Drop SL. Genotype versus phenotype in families with androgen insensitivity syndrome. J Clin Endocrinol Metab. 2001;86:4151–60. [PubMed: 11549642]
  6. Boehmer AL, Brinkmann AO, Niermeijer MF, Bakker L, Halley DJ, Drop SL. Germ-line and somatic mosaicism in the androgen insensitivity syndrome: implications for genetic counseling. Am J Hum Genet. 1997;60:1003–6. [PMC free article: PMC1712473] [PubMed: 9106550]
  7. Bouvattier C, Carel JC, Lecointre C, David A, Sultan C, Bertrand AM, Morel Y, Chaussain JL. Postnatal changes of T, LH, and FSH in 46,XY infants with mutations in the AR gene. J Clin Endocrinol Metab. 2002;87:29–32. [PubMed: 11788616]
  8. Brinkmann AO, Trapman J. Genetic analysis of androgen receptors in development and disease. Adv Pharmacol. 2000;47:317–41. [PubMed: 10582090]
  9. Chang CS, Kokontis J, Liao ST. Structural analysis of complementary DNA and amino acid sequences of human and rat androgen receptors. Proc Natl Acad Sci U S A. 1988;85:7211–5. [PMC free article: PMC282154] [PubMed: 3174628]
  10. Cheikhelard A, Morel Y, Thibaud E, Lotat-Jacob S, Jaubert F, Ploak M, Nihoul-Fekete C. Long-term follow up and comparison between genotype and phenotype in 29 cases of complete androgen insensitivity. J Urol. 2008;180:1496–501. [PubMed: 18710728]
  11. Chen H, Yong W, Hinds TD Jr, Yang Z, Zhou Y, Sanchez ER, Shou W. Fkbp52 regulates androgen receptor transactivation activity and male urethra morphogenesis. J Biol Chem. 2010;285:27776–84. [PMC free article: PMC2934645] [PubMed: 20605780]
  12. Cheung-Flynn J, Prapapanich V, Cox MB, Riggs DL, Suarez-Quian C, Smith DF. Physiological role for the cochaperone FKBP52 in androgen receptor signaling. Mol Endocrinol. 2005;19:1654–66. [PubMed: 15831525]
  13. Choong CS, Quigley CA, French FS, Wilson EM. A novel missense mutation in the amino-terminal domain of the human androgen receptor gene in a family with partial androgen insensitivity syndrome causes reduced efficiency of protein translation. J Clin Invest. 1996;98:1423–31. [PMC free article: PMC507569] [PubMed: 8823308]
  14. Cohen-Kettenis PT. Psychosocial and pycholsexual aspects of disorders of sex development. Best Pract Res Clin Endocrinol Metab. 2010;24:325–34. [PubMed: 20541155]
  15. Conn J, Gillam L, Conway GS. Revealing the diagnosis of androgen insensitivity syndrome in adulthood. BMJ. 2005;331:628–30. [PMC free article: PMC1215563] [PubMed: 16166136]
  16. Cul ML, Simmonds M. Importance of support groups for intersex (disorders of sexual development) patients, families and the medical profession. Sex Dev. 2010;4:310–2. [PubMed: 20606384]
  17. Davies HR, Hughes IA, Savage MO, Quigley CA, Trifiro M, Pinsky L, Brown TR, Patterson MN. Androgen insensitivity with mental retardation: a contiguous gene syndrome? J Med Genet. 1997;34:158–60. [PMC free article: PMC1050872] [PubMed: 9039995]
  18. Deeb A, Mason C, Lee YS, Hughes IA. Correlation between genotype, phenotype and sex of rearing in 111 patients with partial androgen insensitivity syndrome. Clin Endocrinol (Oxf). 2005;63:56–62. [PubMed: 15963062]
  19. Diamond M, Beh HG. Changes in the management of children with intersex conditions. Nat Clin Pract Endocrinol Metab. 2008;4:4–5. [PubMed: 17984980]
  20. Douglas G, Axelrad ME, Brandt ML, Crabtree E, Dietrich JE, French S, Gunn S, Karaviti L, Lopez ME, Macias CG, McCullough LB, Suresh D, Sutton VR. Consensus in guidelines for evaluation of DSD by the Texas Children’s Hospital multidisciplinary gender medicine team. Int J Pediatr Endocrinol. 2010;2010:919707. [PMC free article: PMC2963131] [PubMed: 20981291]
  21. Elhaji YA, Stoica I, Dennis S, Purisima EO, Trifiro MA. Impaired helix 12 dynamics due to proline 892 substitutions in the androgen receptor are associated with complete androgen insensitivity. Hum Mol Genet. 2006;15:921–31. [PubMed: 16449235]
  22. Elhaji YA, Wu JH, Gottlieb B, Beitel LK, Alvarado C, Batist G, Trifiro MA. An examination of how different mutations at arginine 855 of the androgen receptor result in different androgen insensitivity phenotypes. Mol Endocrinol. 2004;18:1876–86. [PubMed: 15118070]
  23. El Saman AM, Ismael AM, Zakherah MS, Nasr A, Tawfik RM, Bedaiwy MA. Enhancement balloon vaginoplasty for treatment of blind vagina due to androgen insensitivity. Fertil Steril. 2011;95:779–82. [PubMed: 21055746]
  24. Evans BA, Hughes IA, Bevan CL, Patterson MN, Gregory JW. Phenotypic diversity in siblings with partial androgen insensitivity syndrome. Arch Dis Child. 1997;76:529–31. [PMC free article: PMC1717223] [PubMed: 9245853]
  25. Garrett CC, Kirkman M. Being an XY female: an analysis of accounts from the website of the androgen insensitivity syndrome support group. Health Care Women Int. 2009;30:428–46. [PubMed: 19350438]
  26. Giagulli VA, Carbone MD, De Pergola G, Guastamacchia E, Resta F, Licchelli B, Sabbà C, Triggiani V. Could androgen receptor gene CAG tract polymorphism affect spermatogenesis in men with idiopathic infertility? J Assist Reprod Genet. 2014;31(6):689–97. [PMC free article: PMC4048386] [PubMed: 24691874]
  27. Goglia U, Vinanzi C, Zuccarello D, Malpassi D, Ameri P, Casu M, Minuto F, Fioresta C, Ferone D. Identification of a novel mutation in exon 1 of the androgen receptor gene in an azoospermic patient with mild androgen insensitivity syndrome: case report and literature review. Fert Steril. 2011;96:1165–9. [PubMed: 21962961]
  28. Gottlieb B, Beitel LK, Trifiro MA. Variable expressivity and mutation databases: the androgen receptor gene mutations database. Hum Mutat. 2001a;17:382–8. [PubMed: 11317353]
  29. Gottlieb B, Beitel LK, Trifiro MA. Somatic mosaicism and variable expressivity. Trends Genet. 2001b;17:79–82. [PubMed: 11173116]
  30. Gottlieb B, Beitel LK, Wu J, Elhaji YA, Trifiro M. Nuclear receptors and disease: androgen receptor. Essays Biochem. 2004a;40:121–36. [PubMed: 15242343]
  31. Gottlieb B, Beitel LK, Wu JH, Trifiro M. The androgen receptor gene mutations database (ARDB): 2004 update. Hum Mutat. 2004b;23:527–33. [PubMed: 15146455]
  32. Gottlieb B, Beitel LK, Nadarajah A, Paliouras M, Trifiro M. The androgen receptor gene mutations database (ARDB): 2012 update. Hum Mutat. 2012;33:887–94. [PubMed: 22334387]
  33. Gottlieb B, Beitel LK, Trifiro MA. Changing genetic paradigms: creating next generation genetic databases as tools to understand the emerging complexities of genotype to phenotype relationships. Hum Genomics. 2014;8:9. [PMC free article: PMC4040485] [PubMed: 24885908]
  34. Gottlieb B, Lumbroso R, Beitel LK, Trifiro MA. Molecular pathology of the androgen receptor in male (in)fertility. Reprod Biomed Online. 2005;10:42–8. [PubMed: 15705293]
  35. Gottlieb B, Pinsky L, Beitel LK, Trifiro M. Androgen insensitivity. Am J Med Genet. 1999a;89:210–7. [PubMed: 10727996]
  36. Gottlieb B, Vasiliou DM, Lumbroso R, Beitel LK, Pinsky L, Trifiro MA. Analysis of exon 1 mutations in the androgen receptor gene. Hum Mutat. 1999b;14:527–39. [PubMed: 10571951]
  37. Hannema SE, Scott IS, Hodapp J, Martin H, Coleman N, Schwabe JW, Hughes IA. Residual activity of mutant androgen receptors explains wolffian duct development in the complete androgen insensitivity syndrome. J Clin Endocrinol Metab. 2004;89:5815–22. [PubMed: 15531547]
  38. Hannema SE, Scott IS, Rajpert-De Meyts E, Skakkebaek NE, Coleman N, Hughes IA. Testicular development in the complete androgen insensitivity syndrome. J Pathol. 2006;208:518–27. [PubMed: 16400621]
  39. Heinlein CA, Chang C. Androgen receptor (AR) coregulators: an overview. Endocr Rev. 2002;23:175–200. [PubMed: 11943742]
  40. Hiort O, Klauber G, Cendron M, Sinnecker GH, Keim L, Schwinger E, Wolfe HJ, Yandell DW. Molecular characterization of the androgen receptor gene in boys with hypospadias. Eur J Pediatr. 1994;153:317–21. [PubMed: 8033918]
  41. Hiort O, Sinnecker GH, Holterhus PM, Nitsche EM, Kruse K. Inherited and de novo androgen receptor gene mutations: investigation of single-case families. J Pediatr. 1998;132:939–43. [PubMed: 9627582]
  42. Holterhus PM, Bruggenwirth HT, Brinkmann AO, Hiort O. Post-zygotic mutations and somatic mosaicism in androgen insensitivity syndrome. Trends Genet. 2001;17:627–8. [PubMed: 11672858]
  43. Holterhus PM, Bruggenwirth HT, Hiort O, Kleinkauf-Houcken A, Kruse K, Sinnecker GH, Brinkmann AO. Mosaicism due to a somatic mutation of the androgen receptor gene determines phenotype in androgen insensitivity syndrome. J Clin Endocrinol Metab. 1997;82:3584–9. [PubMed: 9360511]
  44. Hughes IA, Davies JD, Bunch TI, Pasterski V, Mastroyannapoulou K, MacDougall J. Androgen insensitivity syndrome. Lancet. 2012;380:1419–28. [PubMed: 22698698]
  45. Hughes IA, Deeb A. Androgen resistance. Best Pract Res Clin Endocrinol Metab. 2006;20:577–98. [PubMed: 17161333]
  46. Hughes IA, Houk C, Ahmed SF, Lee PA. Consensus statement on management of intersex disorders. Arch Dis Child. 2006;91:554–63. [PMC free article: PMC2082839] [PubMed: 16624884]
  47. Kohler B, Lumbroso S, Leger J, Audran F, Grau ES, Kurtz F, Pinto G, Salerno M, Semitcheva T, Czernichow P, Sultan C. Androgen insensitivity syndrome: somatic mosaicism of the androgen receptor in seven families and consequences for sex assignment and genetic counseling. J Clin Endocrinol Metab. 2005;90:106–11. [PubMed: 15522944]
  48. Lek NB, Miles H, Bunch T, Pilfold-Wilkie V, Tadoroko-Cuccaro R, Davis J, Ong KK, Hughes IA. Low frequency of androgen receptor gene mutations in 46XY DSD, and fetal growth restriction. Arch Dis Child. 2014;99:358–61. [PubMed: 24366239]
  49. Loy CJ, Yong EL. Sex, infertility and the molecular biology of the androgen receptor. Curr Opin Obstet Gynecol. 2001;13:315–21. [PubMed: 11396657]
  50. Lumbroso R, Beitel LK, Vasiliou DM, Trifiro MA, Pinsky L. Codon-usage variants in the polymorphic (GGN)n trinucleotide repeat of the human androgen receptor gene. Hum Genet. 1997;101:43–6. [PubMed: 9385367]
  51. Matias PM, Donner P, Coelho R, Thomaz M, Peixoto C, Macedo S, Otto N, Joschko S, Scholz P, Wegg A, Basler S, Schafer M, Egner U, Carrondo MA. Structural evidence for ligand specificity in the binding domain of the human androgen receptor. Implications for pathogenic gene mutations. J Biol Chem. 2000;275:26164–71. [PubMed: 10840043]
  52. Melo CC, Daninb AR, Silva DM, Tacon JA, Moura KK, Costa EO, da Cruz AD. Association between malre infertility and androgen receptor mutations in Brazilian patients. Genet Mol Res. 2010;9:128–33. [PubMed: 20198568]
  53. Mirfakhraie R, Kalantar SM, Mirzajani F, Montazeri M, Salsabili N, Houshmand M, Hashemi-Gorji F, Pourmand G. A novel mutation in the transactivation-regulating domain of the androgen receptor in a patient with azoospermia. J Androl. 2011;32:367–70. [PubMed: 21127309]
  54. Munoz JA, Swan KG. Disorders of sexual differentiation: surgical challenges of vaginal reconstruction in complete androgen insensitivity syndrome. Am Surg. 2010;76:188–92. [PubMed: 20336898]
  55. Oakes MB, Eyvazzadeh AD, Quint E, Smith YR. Complete androgen insensitivity syndrome – a review. J Pediatr Adolesc Gynecol. 2008;21:305–10. [PubMed: 19064222]
  56. Parisi MA, Ramsdell LA, Burns MW, Carr MC, Grady RE, Gunther DF, Kletter GB, McCauley E, Mitchell ME, Opheim KE, Pihoker C, Richards GE, Soules MR, Pagon RA. A gender assessment team: experience with 250 patients over a period of 25 years. Genet Med. 2007;9:348–57. [PubMed: 17575501]
  57. Pasterski V, Prentice P, Hughes IA. Impact of the consensus statement and the new DSD classification system. Best Pract Res Clin Endocrinol Metab. 2010;24:187–95. [PubMed: 20541147]
  58. Purves JY, Miles-Thomas J, Migeon C, Gearhart JP. Complete androgen insensitivity:the role of the surgeon. J Urol. 2008;180:1716–9. [PubMed: 18715581]
  59. Rahmani AH, Alzohairy M, Babiker AYY, Khan AA, Aly SM, Rizvi MA. Implication of androgen receptor in urinary bladder cancer:a critical mini review. Int J Mol Epidemiol Genet. 2013;4:150–5. [PMC free article: PMC3773566] [PubMed: 24046807]
  60. Rodien P, Mebarki F, Mowszowicz I, Chaussain JL, Young J, Morel Y, Schaison G. Different phenotypes in a family with androgen insensitivity caused by the same M780I point mutation in the androgen receptor gene. J Clin Endocrinol Metab. 1996;81:2994–8. [PubMed: 8768864]
  61. Saito R, Yamamoto Y, Goto M, Araki S, Kubo K, Kawagoe R, Kawada Y, Kusuhara K, Igarashi M, Fukami M. Tamoxifen treatment for pubertal gynecomastia in two siblings with partial androgen insensitivity syndrome. Horm Res Paediatr. 2014;81(3):211–6. [PubMed: 24577144]
  62. Sinnecker GH, Hiort O, Nitsche EM, Holterhus PM, Kruse K. Functional assessment and clinical classification of androgen sensitivity in patients with mutations of the androgen receptor gene. German Collaborative Intersex Study Group. Eur J Pediatr. 1997;156:7–14. [PubMed: 9007482]
  63. Sultan C, Biason-Lauber A, Philibert P. Mayer-Rokitansky-Kuster-Hauser syndrome: Recent clinical and genetic findings. Gynecol Endocrinol. 2009;25:8–11. [PubMed: 19165657]
  64. Tsjoen G, De Cuypere G, Monstrey S, Hoebeke P, Freedman FK, Appari M, Holterhus PM, Van Borsel J, Cools M. Male gender identity in complete androgen insensitivity syndrome. Arch Sex Behav. 2011;40(3):635–8. [PubMed: 20358272]
  65. Tut TG, Ghadessy FJ, Trifiro MA, Pinsky L, Yong EL. Long polyglutamine tracts in the androgen receptor are associated with reduced trans-activation, impaired sperm production, and male infertility. J Clin Endocrinol Metab. 1997;82:3777–82. [PubMed: 9360540]
  66. Veiga-Junior NN, Medaets PA, Petroli RJ, Calais FL, de Mello MP, Castro CC, Guaragna-Filho G, Sewaybricker LE, Marques-de-Faria AP, Maciel-Guerra AT, Guerra-Junior G. Clinical and Laboratorial Features That May Differentiate 46,XY DSD due to Partial Androgen Insensitivity and 5α-Reductase Type 2 Deficiency. Int J Endocrinol. 2012;2012:964876. [PMC free article: PMC3238364] [PubMed: 22194745]
  67. Vidal I, Gorduza DB, Haraux E, Gay CL, Chatelain P, Nicolino M, Mure PY, Mouriquand P. Surgical optons in disorders of sex development (dsd) with ambiguous genitalia. Best Pract Res Clin Endocrinol Metab. 2010;24:311–24. [PubMed: 20541154]
  68. Wang Q, Ghadessy FJ, Trounson A, de Kretser D, McLachlan R, Ng SC, Yong EL. Azoospermia associated with a mutation in the ligand-binding domain of an androgen receptor displaying normal ligand binding, but defective trans-activation. J Clin Endocrinol Metab. 1998;83:4303–9. [PubMed: 9851768]
  69. Warne GL. Long-term outcome of disorders of sex development. Sex Dev. 2008;2:268–77. [PubMed: 18987501]
  70. Weidemann W, Linck B, Haupt H, Mentrup B, Romalo G, Stockklauser K, Brinkmann AO, Schweikert HU, Spindler KD. Clinical and biochemical investigations and molecular analysis of subjects with mutations in the androgen receptor gene. Clin Endocrinol (Oxf). 1996;45:733–9. [PubMed: 9039340]
  71. Weidemann W, Peters B, Romalo G, Spindler KD, Schweikert HU. Response to androgen treatment in a patient with partial androgen insensitivity and a mutation in the deoxyribonucleic acid-binding domain of the androgen receptor. J Clin Endocrinol Metab. 1998;83:1173–6. [PubMed: 9543136]
  72. Werner R, Grotsch H, Hiort O. 46-XY disorders of sex development- the undermasculinised male with disorders of androgen action. Best Pract Res Clin Endocrinol Metab. 2010;24:263–77. [PubMed: 20541151]
  73. Wiesemann C, Ude-Koeller S, Sinnecker GH, Thyen U. Ethical principles and recommendations for the medical management of differences of sex development (DSD)/intersex in children and adolescents. Eur J Pediatr. 2010;169:671–9. [PMC free article: PMC2859219] [PubMed: 19841941]
  74. Wu JH, Gottlieb B, Batist G, Sulea T, Purisima EO, Beitel LK, Trifiro M. Bridging structural biology and genetics by computational methods: an investigation into how the R774C mutation in the AR gene can result in complete androgen insensitivity syndrome. Hum Mutat. 2003;22(6):465–75. [PubMed: 14635106]
  75. Yalinkaya A, Yayala M, Erdermoglu M. Prenatal diagnosis of fetus with androgen insensitivity syndrome. Prenat Diagn. 2007;27:856–57. [PubMed: 17605153]
  76. Zhoa M, Pengcheng L, Senkai L, Qiang L. Use of Autologous micromucosa graft for vaginoplasty in vaginal agenesis. Ann Plast Surg. 2009;63:645–9. [PubMed: 19816155]
  77. Zitzmann M. Pharmacogenetics of testosterone replacement therapy. Pharmacogenomics. 2009;10:1341–9. [PubMed: 19663677]
  78. Zuccarello D, Ferlin A, Vinanzi C, Prana E, Garolla A, Callewaert L, Claessens F, Brinkmann AO, Foresta C. Detailed functional studies on androgen receptor mild mutations demonstrate their association with male infertility. Clin Endocrinol (Oxf). 2008;68:580–8. [PubMed: 17970778]

Suggested Reading

  1. Bennett NC, Gardiner RA, Hooper JD, Johnson DW, Gobe GC. Molecular cell biology of androgen receptor signaling. Int J Biochem Cell Biol. 2010;42:813–27. [PubMed: 19931639]
  2. Galani A, Kitsiou-Tzeli S, Sofokelous C, Kanavakis E, Kalpini-Mavrou A. Androgen insensitivity syndrome: clinical features and molecular defects. Hormones (Athens). 2008;7:217–29. [PubMed: 18694860]

Chapter Notes

Author History

Lenore K Beitel, PhD (2004-present)
Bruce Gottlieb, PhD (2004-present)
Leonard Pinsky, MD, FACMG; McGill University (1999-2004)
Mark A Trifiro, MD (1999-present)

Revision History

  • 10 July 2014 (me) Comprehensive update posted live
  • 6 October 2011 (me) Comprehensive update posted live
  • 24 May 2007 (cd) Revision: deletion/duplication analysis available on a clinical basis
  • 19 September 2006 (me) Comprehensive update posted to live Web site
  • 8 April 2004 (me) Comprehensive update posted to live Web site
  • 12 December 2002 (lp) Revision: Testing
  • 19 November 2001 (me) Comprehensive update posted to live Web site
  • 24 March 1999 (pb) Review posted to live Web site
  • 1998 (lp/mt) Original submission
Copyright © 1993-2014, University of Washington, Seattle. All rights reserved.

For more information, see the GeneReviews Copyright Notice and Usage Disclaimer.

For questions regarding permissions: ude.wu@tssamda.

Bookshelf ID: NBK1429PMID: 20301602
PubReader format: click here to try

Views

  • PubReader
  • Print View
  • Cite this Page
  • Disable Glossary Links

Tests in GTR by Gene

Tests in GTR by Condition

Related information

  • MedGen
    Related information in MedGen
  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to pubmed
  • Gene
    Gene records cited in chapters on the NCBI bookshelf. Links are provided by the authors or the NCBI Bookshelf staff.

Related citations in PubMed

See reviews...See all...