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Partial androgen insensitivity (PAIS)
PAIS primarily affects individuals with XY chromosomes, leading to a spectrum of presentations in sexual development, ranging from predominantly female external genitalia with internal testes to male external genitalia with underdeveloped features and infertility. It is caused by changes in the AR gene.
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Overview
Partial androgen insensitivity (PAIS) is a condition where the body does not fully respond to androgens, which are male sex hormones like testosterone. This reduced response means that the development of male sexual characteristics, both before birth and during puberty, is incomplete [PMID:31826046]. PAIS is part of a spectrum of conditions called Androgen Insensitivity Syndromes (AIS), which range from complete androgen insensitivity (CAIS), where there is no response to androgens, to mild forms with more subtle effects.
Symptoms & clinical features
The symptoms of PAIS vary significantly among affected individuals, even within the same family. This variation is due to the different degrees of the body's insensitivity to androgens. At birth, individuals with PAIS may have external genitalia that appear predominantly female, ambiguous (not clearly male or female), or predominantly male but with features such as hypospadias (where the opening of the urethra is on the underside of the penis) or an undescended testis [PMID:31826046].
During puberty, individuals with PAIS may experience incomplete masculinisation. This can include sparse pubic and armpit hair, reduced facial hair growth, and a lack of deepening of the voice. Breast development (gynaecomastia) can also occur. Many individuals with PAIS are infertile due to issues with sperm production or development of the reproductive tract [PMID:20301700]. Internal reproductive organs typically include testes, but the Wolffian ducts, which usually develop into structures like the epididymis and vas deferens, may be underdeveloped.
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Affected organs
PAIS primarily affects the reproductive system and the development of secondary sexual characteristics. The testes are present internally, as their development is not dependent on androgen action, but their function may be impaired, leading to infertility. The external genitalia are particularly affected, with their appearance ranging from female-like to ambiguous, or male with some feminised features. Other organs involved in androgen response, such as those responsible for hair growth patterns and bone density, can also be affected, leading to reduced bone mineral density in some cases.
Risks & severity
The severity of PAIS varies widely, from individuals who are assigned female at birth and raised as girls, to those who are assigned male with more subtle symptoms that may only become apparent at puberty or when investigating infertility. The exact prevalence of PAIS is not well established, but it is considered a rare condition. Individuals with PAIS and XY chromosomes have an increased risk of gonadal tumours, specifically germ cell tumours, in undescended testes [PMID:31826046]. This risk usually increases with age, making surveillance and management of undescended testes important. The psychological and social impact of PAIS, particularly regarding gender identity and body image, can also be significant and requires careful consideration and support.
Genetic causes
Partial androgen insensitivity is caused by pathogenic variants in the AR gene. This gene provides instructions for making the androgen receptor protein. The androgen receptor is found inside cells and plays a crucial role in binding to androgens. Once an androgen, like testosterone, binds to the receptor, the receptor-hormone complex moves into the cell's nucleus and attaches to specific DNA regions, regulating the activity of genes involved in male sexual development.
Pathogenic variants in the AR gene lead to a faulty or absent androgen receptor, or a receptor that cannot bind to androgens effectively. This impairs the cell's ability to respond to these hormones, even when they are present in normal amounts. In PAIS, the receptor retains some residual function, meaning there is a partial response to androgens, which explains the variable clinical presentations compared to complete androgen insensitivity.
- AR androgen receptorThe AR gene provides instructions for the androgen receptor protein, which is vital for male sexual development and other functions in both sexes by responding to hormones like testosterone.
Inheritance pattern
PAIS has an X-linked recessive (XLR) inheritance pattern. The AR gene is located on the X chromosome. For individuals with XY chromosomes, a single pathogenic variant in the AR gene is usually sufficient to cause the condition because they only have one X chromosome. Individuals with XX chromosomes are typically carriers if they have one pathogenic AR variant, meaning they usually do not experience symptoms themselves but can pass the variant on to their children.
If a mother is a carrier of an AR gene variant, each of her sons (who inherit an X chromosome from her) has a 50% chance of inheriting the variant and developing PAIS. Each of her daughters (who inherit one X chromosome from her and one from their father) has a 50% chance of being a carrier. Affected individuals with XY chromosomes cannot pass the variant to their sons, but all their daughters will be carriers of the variant.
X-linked recessive: sons of a carrier mother have a 50% chance of being affected. Daughters have a 50% chance of being carriers.
Diagnosis & testing
Diagnosis of PAIS typically begins with clinical observations, such as ambiguous genitalia at birth, or delayed/incomplete masculinisation during puberty. Blood tests may show normal or elevated levels of testosterone and other androgens, combined with reduced or absent virilisation. Hormone levels help to differentiate PAIS from other conditions affecting sexual development.
Genetic testing is used to confirm a diagnosis of PAIS by identifying pathogenic variants in the AR gene. Such testing is available through the NHS Genomic Medicine Service (GMS) and is typically requested by a clinical geneticist, paediatrician, or endocrinologist. The relevant NHS Genomic Test Directory R-code for conditions like PAIS affecting sex development is R143 (Disorders of sex development). Referral to a clinical genetics service is usually made following initial clinical assessment and hormone investigations.
Management & lifestyle
Management of PAIS is complex and highly individualised, focusing on optimising health outcomes and quality of life. A multidisciplinary team, including endocrinologists, geneticists, surgeons, psychologists, and genetic counsellors, typically provides care. Decisions regarding gender assignment and surgical interventions, if any, are made in careful consultation with the individual and their family, considering psychological and social factors.
Long-term monitoring for individuals with undescended testes is crucial due to the increased risk of germ cell tumours; this may involve regular examinations or, in some cases, surgical removal of the testes (gonadectomy). Hormone replacement therapy, such as oestrogen therapy for those raised female or higher doses of androgens for those with a male gender identity, may be considered to promote secondary sexual characteristic development and bone health. Psychological support and genetic counselling are essential throughout the individual's life journey to address the complex medical, social, and emotional aspects of living with PAIS.
UK care pathway
In the UK, individuals suspected of having PAIS or other disorders of sex development are typically referred to specialist NHS centres. Clinical geneticists and endocrinologists are usually involved in the diagnostic pathway, including requesting genetic testing under the NHS Genomic Medicine Service. Access to genetic counselling services is a key part of the care pathway, providing information about the condition, inheritance patterns, and support for individuals and families. The NHS Genomic Test Directory outlines the available genetic tests, with conditions like PAIS often falling under R-codes such as R143 for Disorders of Sex Development.
Frequently asked questions
What does X-linked recessive inheritance mean for my family?
X-linked recessive inheritance means the condition is linked to the X chromosome. Typically, only individuals with XY chromosomes are affected. If a mother is a carrier, each of her sons has a 50% chance of being affected, and each of her daughters has a 50% chance of being a carrier. Affected individuals with XY chromosomes will pass the variant to all their daughters, who will become carriers, but none of their sons.
Will my child with PAIS need surgery?
Surgical decisions for individuals with PAIS are highly individualised. They depend on the specific presentation, assigned gender, and the family's and individual's preferences. Some surgeries may be considered for cosmetic reasons, to address specific functional issues, or to manage risks such as tumour development in undescended testes. These decisions are made in careful discussion with a specialist multidisciplinary team.
What is the long-term outlook for individuals with PAIS?
The long-term outlook for individuals with PAIS varies greatly depending on the severity of the condition and the management approach. With appropriate medical care, hormonal management, and psychological support, individuals can lead fulfilling lives. Regular medical follow-up, especially regarding potential tumour risk in undescended testes and bone health, is important.
How does PAIS affect fertility?
Most individuals with PAIS who have XY chromosomes are infertile. This is often due to issues with the development and function of the testes, affecting sperm production, or underdeveloped reproductive tracts. Fertility options for individuals with PAIS are limited, but discussions with fertility specialists may be part of their care.
Where can I find support for PAIS in the UK?
In the UK, support for individuals and families affected by PAIS can be found through specialist NHS services, such as clinical genetics departments and endocrinology clinics. Genetic counsellors can provide information and emotional support. There are also patient advocacy groups and charities dedicated to supporting individuals with differences in sex development, which can offer valuable resources and community connections.