Clinical Guidance

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 [, , , , ]. The Androgen Receptor Gene Mutations Database includes 45 instances in which identical AR variants produce different AIS phenotypes . 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 [, , , ]. See for a detailed discussion of the possible role of somatic mosaicism as a cause of variable expressivity.

Source: GeneReviews — "Androgen Insensitivity Syndrome"

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 . The problem is compounded by situations where there is a genotype-phenotype disconnect and when individuals with features of AIS are not found to have an identifiable AR pathogenic variant.

Source: GeneReviews — "Androgen Insensitivity Syndrome"

Diagnostic Criteria

No formal diagnostic criteria for identifying AIS have as yet been published; large variance is seen at the molecular, biochemical, and morphologic levels due to the extreme variation in these characteristics with the various AIS phenotypes .

Suggestive Findings

Androgen insensitivity syndrome (AIS) should be suspected in an individual with the following clinical, family history, radiologic, and supportive laboratory findings.

Clinical features

• Absence of extragenital abnormalities

• Two nondysplastic testes

• Absent or rudimentary mllerian 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)

Source: GeneReviews — "Androgen Insensitivity Syndrome"

Differential Diagnosis

Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome (OMIM 277000) 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 . Hypospadias resulting from an AR pathogenic variant (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 may be clinically indistinguishable from MAIS caused by expansion of the polymorphic CAG repeat in AR .

Source: GeneReviews — "Androgen Insensitivity Syndrome"

Management Guidelines

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, gynecology, clinical genetics, psychology, and psychiatry , is ideal.

Treatment of Manifestations

A number of clinicians have sought to establish a consensus statement on management of DSD including AIS . A number of publications have subsequently discussed best management of these disorders. See (full text), (full text), (full text), (full text), and (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 health care personnel and should be resolved as early as possible, after a multidisciplinary evaluation has been completed.

Source: GeneReviews — "Androgen Insensitivity Syndrome"

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe 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.

Source: GeneReviews — "Androgen Insensitivity Syndrome"

Surveillance Guidelines

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 DXA (dual-energy x-ray absorptiometry) scanning

Source: GeneReviews — "Androgen Insensitivity Syndrome"