Funded by the NIH • Developed at the University of Washington, Seattle
Funded by the NIH • Developed at the University of Washington, Seattle
[Androgen Resistance Syndrome, Testicular Feminization. Includes: Complete Androgen Insensitivity Syndrome (CAIS), Partial Androgen Insensitivity Syndrome (PAIS), Mild Androgen Insensitivity Syndrome (MAIS)]
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Authors:
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Bruce Gottlieb, PhD
Lenore K Beitel, PhD Mark A Trifiro, MD |
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Initial Posting:
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Last Revision:
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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 genitalia; partial androgen insensitivity syndrome (PAIS) with predominantly female, predominantly male, or ambiguous genitalia; and mild androgen insensitivity syndrome (MAIS) with typical male 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, normal or increased luteinizing hormone (LH) production by the pituitary gland, and deficient or defective androgen-binding activity of genital skin fibroblasts. Molecular genetic testing of the AR gene, the only gene known to be associated with androgen insensitivity syndrome, detects mutations in more than 95% of probands with complete androgen insensitivity and is available clinically. Its yield in individuals with partial or mild forms of AIS is unknown.
Management. To prevent testicular malignancy, treatment of CAIS includes either removal of the testes after puberty when feminization is complete or prepubertal gonadectomy accompanied by estrogen replacement therapy. 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, parents and healthcare professionals should assign sex of rearing as early as possible in infancy. 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. Systematic disclosure of the diagnosis of AIS in an empathic environment, with both professional and family support, is encouraged. Surveillance includes periodic reevaluation for gynecomastia during puberty in individuals assigned a male sex.
Genetic counseling. AIS is inherited in an X-linked recessive manner. Affected 46,XY individuals are almost always infertile. Carrier females have a 50% chance of transmitting the AR gene mutation in each pregnancy. Carrier testing is available on a clinical basis once the AR mutation has been identified in an affected family member. Prenatal molecular genetic testing is possible for pregnancies of women who are known carriers of the AR mutation present in the family.
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:
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Adapted from Sinnecker et al 1997
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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, Pinsky et al 1999].
The laboratory findings required for the diagnosis of AIS include the following:
Family history. The diagnosis of CAIS can be established by clinical and laboratory findings alone; however, the diagnosis of PAIS and MAIS may require a family history of other affected individuals related to each other in a pattern consistent with X-linked recessive inheritance. "Other affected family members" refers to:
Additional findings in affected individuals with no family history of the syndrome that substantiate the apparent diagnosis of PAIS in an individual with the "predominantly male" phenotype (Table 1):
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information. —ED.
Gene. AR is the only gene known to be associated with androgen insensitivity syndrome.
Clinical uses
Clinical testing
Sequence analysis. Sequencing of all eight exons of the AR gene detects mutations in more than 95% of individuals with CAIS. The mutation detection rate for milder phenotypes is not known; however, it is less than 50% for PAIS and even less for MAIS.
In the presence of deficient or defective androgen-binding activity in genital skin fibroblasts, the likelihood of finding a mutation in the androgen-binding domain of the AR gene approaches 40% [Weidemann et al 1996]. In the presence of normal androgen binding in genital skin fibroblasts, the likelihood of finding an AIS-causing mutation in the AR gene is 10% or less, even when exon 1 is screened and/or sequenced in its entirety.
Affected individuals. Deletion/duplication analysis is available clinically to detect the less common exonic, multi-exonic, and gross deletions and rare duplications in the AR gene in affected individuals.
Carrier testing. Multiplex ligation-dependent probe amplification (MLPA) is available clinically to detect the less common exonic, multi-exonic, and gross deletions and rare duplications in the AR gene in at-risk XX relatives of affected individuals.
Table 2
summarizes molecular genetic testing for this syndrome.
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Test Method
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Mutations Detected
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Mutation Detection Rate
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Test Availability
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Clinical
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AR deletions/duplications
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Unknown
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Interpretation of test results
Expansion of the polymorphic CAG repeat within the AR gene causes spinobulbar muscular atrophy (SBMA; Kennedy disease).
Other disease conditions associated with alterations to the AR gene [Gottlieb, Beitel, Wu, Elhaji et al 2004] include the following:
In addition, variations in length of CAG repeat in the AR gene have been associated with the following conditions:
Complete androgen insensitivity syndrome (CAIS; testicular feminization; Tfm). Individuals with CAIS have normal female external 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 unaffected.
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 opposite sexes-of-rearing [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 idiopathic male infertility.
MAIS almost always runs true in families.
A correlation does exist among certain missense AR mutations, 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 et al 2000 , Boehmer et al 2001 , Deeb et al 2005].
In addition, over 25 instances in which identical AR mutations produce different AIS phenotypes are listed in the AR database [Gottlieb et al 2001a].
In some instances, the variable expressivity associated with a number of point mutations 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]. A detailed discussion of the possible role of somatic mosaicism as a cause of variable expressivity is presented by Gottlieb et al (2001b).
It remains to be determined whether specific missense mutations can be correlated with normal or impaired spermatogenesis and with absence or presence of localized expressions of undervirilization such as gynecomastia, high-pitched voice, and impotence.
In addition to causing different forms of AIS, AR gene mutations have also been associated with cancers and prostate cancer in particular [Gottlieb, Beitel, Wu, Elhaji et al 2004]. The allelic variants associated with cancer, however, appear to result in a gain of function rather than loss of function as seen in AIS.
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].
No definitive data exist for AIS.
The terms "testicular feminization" and androgen resistance syndrome are outdated and thus rarely used now.
Standard references quote 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 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 been determined.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
Hypospadias that results from an AR gene mutation (and thus is part of the spectrum of PAIS) cannot be distinguished from hypospadias resulting from other (largely undefined) causes by the examination of the genitalia alone.
Several investigators have determined how often hypospadias of varying severity can be attributed to AR gene mutations. In studies using mutation scanning, Sutherland et al (1996) found one AR gene mutation among 40 males with penile hypospadias, while Hiort et al (1994) found no AR mutations in 12 males with coronal (glandular) or penile hypospadias but did find one person with an AR mutation among nine males with severe (penoscrotal, perineal) hypospadias. Batch et al (1992 and Batch et al (1993) found an AR mutation in two brothers with isolated severe (perineal) hypospadias. Allera et al (1995) sequenced the AR gene in nine males with isolated severe hypospadias and found an AR mutation in one. McPhaul et al (1997) found that two of the remaining eight individuals originally studied by Allera et al (1995) had androgen receptors that were transactivation deficient when their genital skin fibroblasts were infected with a recombinant adenovirus carrying an androgen-responsive reporter gene.
MAIS caused by point mutations of the AR gene [Wang et al 1998] may be clinically indistinguishable from MAIS caused by expansion of the polymorphic CAG repeat in the AR gene [Tut et al 1997]. Pathological expansion of this triplet repeat is the cause of spinobulbar 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 the AR gene. 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 gene locus and results in mental retardation and genital abnormalities [Davies et al 1997].
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 supranormal LH levels 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, which suggests 5 
-reductase deficiency (However, such structures are also found in individuals with a partial testosterone biosynthetic defect or PAIS.)
Issues to consider in individuals with some, but not all, of the clinical features of AIS:
Normal plasma 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, early developmental delay in the acquisition of normal androgen biosynthesis or normal androgen sensitivity may simulate androgen insensitivity after birth.
Subnormal sensitivity to androgen after birth may involve components of the overall androgen response system (AR-interacting proteins) beyond the androgen receptor itself.
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 ambiguous genitalia below).
A recent review seeks to establish a consensus statement on management of intersex disorders including AIS [Hughes et al 2006].
CAIS. 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. Prepubertal gonadectomy is indicated 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.
Vaginal length may be sufficiently short to require dilatation in an effort to avoid dyspareunia.
The questions of how much to tell individuals with CAIS, and when to tell them, have not been resolved uniformly. It has become obvious, however, that systematic disclosure 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.
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 is feasible. Aside from purely anatomical and surgical considerations, the choice of a male sex-of-rearing demands a therapeutic trial with pharmacologic doses of androgen in an effort 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 the AR gene may be considered; however, the low probability of detecting an AR mutation in individuals with the PAIS phenotype and the poor positive predictive value of any given mutation regarding AIS phenotype need to be considered when making decisions about sex assignment. The status of the androgen receptor is useful in deciding if hormone treatment could be effective and has sometimes helped in decisions about sex assignment.
Based on a small number of individuals, the role of long-term androgen pharmacotherapy in individuals with PAIS who are raised as males remains unclear. There is reason to believe that response to androgen treatment may be substantial in individuals with certain missense mutations in the DNA-binding domain of the androgen receptor [Weidemann et al 1998].
Gynecomastia that develops in puberty eventually requires reduction mammoplasty.
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].
The efficacy of androgen therapy in preventing such primary manifestations such as gynecomastia is not clear.
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.
Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.
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. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory. —ED.
AIS is inherited in an X-linked recessive manner.
Parents of a 46,XY proband
The father of a proband is not affected and is not a carrier.
Women who have an affected child and one other affected relative are obligate heterozygotes.
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 gene mutation. There are two mechanisms by which a de novo AR gene mutation could occur:
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 mutation and no other family member is at risk.
Somatic mosaicism. The mutation occurred after conception and therefore 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 found in the general population.
Germline mutation. The mutation was present in the egg or sperm at the time of her conception, is present in every cell of her body, and is detectable DNA extracted from leukocytes.
Germline mosaicism. The mutation is present only in her ovaries [Boehmer et al 1997] and is not detectable in DNA extracted from leukocytes.
Somatic mosaicism. The mutation 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 these instances, each of her offspring is at risk of inheriting the AR mutation; none of her sisters, however, is at risk of inheriting the AR mutation.
In 22 of 30 simplex families with CAIS or PAIS, the mother was proven to be heterozygous for an AR mutation. Of the eight individuals with de novo mutations, three appeared to have somatic mosaicism [Hiort et al 1998].
Sibs of a proband
Offspring of a proband. Individuals who have a 46,XY karyotype and have any of the subtypes of AIS (i.e., CAIS, PAIS, MAIS) are almost always infertile.
Offspring of a carrier female
Female carriers may be identified through a combination of the following:
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. Carrier testing is available on a clinical basis once the AR mutation has been identified in the proband.
Androgen-binding studies on genital skin fibroblasts. In exceptional cases (i.e., no AR mutation can be identified), if an affected family member with a 46,XY karyotype is known to have deficient or defective androgen-binding activity in a genital skin fibroblast cell line, heterozygotes may be identified by the assay for deficient or defective androgen-building activity of single-cell clones from a genital skin fibroblast line.
Gender assignment. The issue of sex assignment in infancy when the child is being evaluated for ambiguous genitalia is paramount. It requires delicate decision making by parents and healthcare personnel and should be resolved as early as is feasible.
Disclosure of diagnosis. The questions of how much to tell individuals with AIS, and when to tell them, have not been resolved uniformly. It has become obvious, however, that systematic disclosure 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].
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.
DNA banking. 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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant in situations in which the sensitivity of currently available testing is less than 100%. See DNA Banking for a list of labora