Androgen insensitivity syndrome (complete)

Overview

Complete Androgen Insensitivity Syndrome (CAIS) is a genetic condition that affects sexual development before birth and during puberty. Individuals with CAIS have XY chromosomes, which are typically associated with male biological sex. However, their bodies cannot respond normally to androgens, which are male hormones like testosterone. This lack of response means that, despite the presence of male hormones, the body develops external characteristics that are typically female [PMID:33678083].

CAIS is one form of Androgen Insensitivity Syndrome (AIS), which exists on a spectrum. Complete AIS means there is little to no response to androgens. This condition is present from birth, though it may not be recognised until puberty when expected changes, such as menstruation, do not occur. It is generally identified during adolescence.

Symptoms & clinical features

Individuals with CAIS have external genitalia that appear typically female, including a clitoris, labia, and a short, blind-ended vagina. Internally, they do not have a uterus, ovaries, or fallopian tubes. Instead, they have testes, which produce hormones but are usually located in the abdomen or groin rather than a scrotum [PMID:24810850].

At puberty, the testes produce oestrogen, leading to the development of female secondary sexual characteristics such as breast development. However, because there is no uterus, menstruation does not occur. Body hair may be sparse, and pubic and underarm hair may be reduced. Bone density may also be affected.

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Affected organs

The primary organs affected in CAIS are those involved in sexual development. These include the gonads (testes), which are typically located in the abdomen or groin rather than descended into a scrotum. The external genitalia develop as female, but the internal reproductive structures characteristic of females (uterus, fallopian tubes, ovaries) are absent.

The hormone-responsive tissues throughout the body, such as those involved in hair growth and bone development, are also affected by the inability to respond to androgens.

Breast & reproductive tissue

System or tissue involvement

Cellular impact

Mechanism at cellular level

Risks & severity

CAIS is a lifelong condition, but its severity is generally consistent in terms of the body's complete unresponsiveness to androgens. The condition is stable and does not worsen over time. The main health considerations relate to the location of the testes.

Undescended testes (testes not in the scrotum) carry a slightly increased risk of developing certain types of tumours, such as gonadal tumours. This risk is typically lower than in other conditions involving undescended testes, but surveillance or surgical removal of the testes (gonadectomy) is often considered, usually after puberty [PMID:24810850]. The estimated prevalence of CAIS is approximately 1 in 20,000 to 64,000 individuals with XY chromosomes.

Genetic causes

CAIS is caused by pathogenic variants in the AR gene. The AR gene is located on the X chromosome and provides instructions for making the androgen receptor protein. This protein acts like a key, allowing cells to respond to androgens such as testosterone. When androgens bind to the receptor, it triggers a series of steps that regulate genes essential for male sexual development.

In individuals with CAIS, pathogenic variants in the AR gene lead to a non-functional or poorly functional androgen receptor. This means that even though androgens are present, the body's cells cannot 'read' or respond to their signals effectively [PMID:33678083]. Consequently, the typical male sexual development pathway is disrupted, leading to the physical characteristics seen in CAIS.

• AR
  androgen receptor
  The AR gene provides instructions for the androgen receptor protein, which plays a critical role in male sexual development and other bodily functions by responding to androgen hormones.

Inheritance pattern

CAIS has an X-linked recessive inheritance pattern. This means the gene responsible, AR, is located on the X chromosome. Individuals with XY chromosomes have one X chromosome and one Y chromosome. If their single X chromosome carries a pathogenic variant in AR, they will develop CAIS because there isn't a second, functional copy of the gene to compensate.

Females with XX chromosomes typically have two X chromosomes. If one of their X chromosomes carries a pathogenic AR variant, they are usually unaffected carriers as their other X chromosome provides a functional copy of the gene. However, they have a 50% chance of passing the pathogenic variant to each child. A son who inherits the X chromosome with the variant would be affected with CAIS, while a daughter who inherits it would be an unaffected carrier.

Diagnosis & testing

The diagnosis of CAIS is often suspected at puberty if a young person with female external characteristics does not begin to menstruate (primary amenorrhoea). A clinical evaluation would typically include a physical examination, hormone level testing (e.g., testosterone, oestrogen, luteinising hormone), and imaging studies (e.g., ultrasound or MRI) to check for internal reproductive organs.

Confirmation of CAIS often involves genetic testing to identify pathogenic variants in the AR gene. Chromosome analysis (karyotyping) to determine the chromosomal sex (XY) is also a key diagnostic step. In the UK, genetic testing for conditions like CAIS is generally performed through the NHS Genomic Medicine Service, often following referral from an endocrinologist or a clinical genetics specialist. The relevant R-code for testing for disorders of sex development is R109.

Management & lifestyle

Management of CAIS involves a multidisciplinary approach, typically including endocrinologists, gynaecologists, surgeons, and genetic counsellors, often in specialised centres. Treatment plans are tailored to individual needs and preferences.

Key aspects of management include counselling and psychological support for both the individual and their family, particularly regarding gender identity and sexual development. Medical management often addresses hormone replacement therapy, usually oestrogen, to support bone health and maintain female secondary sexual characteristics, especially if the testes are removed. Decisions regarding the timing and necessity of gonadectomy (removal of the testes) are made collaboratively, often to mitigate the long-term risk of gonadal tumours while allowing for natural puberty where desired.

UK care pathway

In the UK, individuals suspected of having conditions like CAIS are typically referred through their GP to specialist services. This pathway often leads to a clinical genetics team, an endocrinologist, or a gynaecologist, who can assess the condition and coordinate investigations. Genetic testing, when appropriate, is carried out by the NHS Genomic Medicine Service, with specific tests linked to R-codes such as R109 for disorders of sex development.

Genetic counsellors play a vital role, providing information about the condition, inheritance patterns, and supporting families through diagnosis and onward management planning. Access to these services ensures a coordinated approach to care within the NHS.

Related conditions

Other conditions affecting sexual development, sometimes referred to as disorders of sex development (DSD), may present with some overlapping features. These include other forms of Androgen Insensitivity Syndrome (partial AIS, or PAIS), which result in varying degrees of androgen response, leading to a broader range of external genitalia.

Additionally, conditions affecting androgen production, such as deficiencies in enzymes involved in testosterone synthesis, can also result in atypical sexual development, though the underlying genetic mechanisms and specific clinical findings differ from CAIS.

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Frequently asked questions

References

1. Bhaskararao G, Himabindu Y, Nayak SR. Laparoscopic gonedectomy in a case of complete androgen insensitivity syndrome. Journal of human reproductive sciences. 2014. PMID: 25395750
2. Kasumi H, Komori S, Yamasaki N. Single nucleotide substitution of the androgen receptor gene in a case with receptor-positive androgen insensitivity syndrome (complete form). Acta endocrinologica. 1993. PMID: 8498155