Androgen insensitivity syndrome

Androgen insensitivity syndrome (AIS) affects the development of the genitals and reproductive organs.

A child born with AIS is genetically male, but their genitals may appear female or somewhere between male and female.

At an early stage of development, all unborn babies, whether they are male or female, have identical genitals. The development of the genitals into either male or female is dictated by which pair of sex chromosomes the baby receives from its parents - XX or XY (see box).

What happens in AIS

A child with AIS is born with a set of genetically male sex chromosomes (XY). The presence of the Y chromosome stops the development of the ovaries and womb and causes the development of testes (two egg-shaped male reproductive organs), which also happens in normal male sexual development. The testes produce male hormones, called androgens, which normally cause male sex organs (such as the penis) to develop.

However, in AIS, the body ignores the androgen or is insensitive to it, so the genitals develop along female lines and the testes usually remain inside the body.

Types of AIS

There are two forms of AIS, which are determined by the level of insensitivity to androgen.

Complete androgen insensitivity syndrome

Complete androgen insensitivity syndrome (CAIS) is where the person is totally insensitive to androgen and develops external genitals that are entirely female. Most children born with CAIS are brought up as girls.

Partial androgen insensitivity syndrome 

Partial androgen insensitivity syndrome (PAIS) is where the person has some sensitivity to androgen. The level of sensitivity determines how the genitals develop.

The person can look almost entirely male, entirely female, or somewhere in between

Some babies are born with a slightly enlarged clitoris, while others may have an almost fully formed penis.

Children with PAIS can be brought up as girls or boys. The decision is often based on the type of genital development.

Disorder of Sex Development

AIS is a Disorder of Sex Development (DSD) which is also sometimes known as intersex. AIS should not be confused with gender dysphoria, which is also known as transsexuality or being transgender.

Gender dysphoria is where the reproductive organs and genitals have developed normally, but the person feels that their gender identity (their sense of what sex they are) does not match their biological sex.

Who is affected

AIS is thought to occur in one in every 20,400 births, although the exact figures are unknown. CAIS is believed to be more common than PAIS.

Outlook

People with AIS will need hormone therapy and psychological support (see Androgen Insensitivity Syndrome - Treatment for more information). Most people with AIS will be infertile. 

Most people with AIS who have received appropriate care and support come to terms with their condition and live normal lives. AIS does not reduce life expectancy.


Sex chromosomes

Sex chromosomes are a pair of DNA molecules (called either X or Y) that play a vital role in our sexual development. Females typically have two X chromosomes; males typically have one X and one Y chromosome.

It is the Y chromosome that stimulates the development of male testes and stops the development of female ovaries. When there is no Y chromosome, the female reproductive system and genitals develop.

Most people born with androgen insensitivity syndrome (AIS) will be infertile, as the development of the female internal organs is usually suppressed by male hormones from the testes in the body. These people will have no womb, ovaries or fallopian tubes.

Only people with very mild androgen insensitivity may be fertile. 

Complete androgen insensitivity syndrome (CAIS)

In approximately half of babies born with CAIS, their undescended (internal) testes result in a hernia, which brings the condition to light during infancy. Otherwise, there are no external physical signs of the condition in infants.

The first obvious symptoms usually do not appear until puberty, when the child will:

  • have no, or very little, pubic and underarm hair
  • not start their periods, due to an absence of ovaries
  • not experience the acne normally associated with puberty (acne is a reaction to androgen)

Also, the vagina of a woman with CAIS is usually about two-thirds the length of normal vagina (6cm/2.4 inches), and can be even shorter.

Partial androgen insensitivity syndrome (PAIS)

The development of children with PAIS will depend on their level of insensitivity to androgen. A child with a high level of insensitivity will develop as a girl during puberty, while those with a low level will develop as a boy, though there may be some breast development in the latter.

In some cases, babies with PAIS may be raised as boys but become more female as they develop during puberty. Hormone therapy can sometimes be used to "direct" puberty towards a certain gender. Or, treatment can be used to delay puberty until a child is old enough to make an informed decision about their preferred gender identity.

Grading system for AIS

The grading system used for AIS runs from grade 1 to grade 7. AIS grades 6/7 are at the CAIS end of the spectrum and children are usually brought up as girls. In those with PAIS, genital appearance can be anywhere from completely female (grade 5) to completely male (grade 1). Very slight androgen insensitivity may contribute to infertility in some men.

  • Grade 1 - PAIS - Male genitals, infertility
  • Grade 2 - PAIS - Male genitals, but they may be small. The opening of the urethra (urine tube) may also be on the underside of the penis (known as hypospadias).
  • Grade 3 - PAIS - Predominantly male genitals, but very small. May have hypospadias and undescended (internal) testes.
  • Grade 4 - PAIS - Ambiguous genitals. The structure of a penis may be there, but is so small it is not possible to determine whether it is a penis or a clitoris.
  • Grade 5 - PAIS - Essentially female genitals, including separate urethral and vaginal passages. Clitoris may appear enlarged.
  • Grade 6 - PAIS - Female genitals with pubic and underarm hair.
  • Grade 7 - CAIS - Female genitals with little or no pubic and underarm hair.

Androgen insensitivity syndrome (AIS) is caused by an alteration (mutation) in the gene that produces androgen receptors. The androgen hormone cannot work properly until it locks onto these receptor molecules. Without enough of these androgen receptors, cells cannot react to androgen, or the reaction is weaker than normal.

For example, a person with complete androgen insensitivity syndrome (CAIS) has no reaction to androgen and the male genitals and reproductive organs do not develop.

In around a third of AIS cases, the alteration to the androgen receptor gene occurs for the first time in the family either during the formation of the mother's eggs or in one of the embryo cells just after conception. The reasons for this are unclear.

In other cases, the altered gene is inherited as part of the X chromosome from the mother, who is a carrier.

A female child will receive two X chromosomes: one from her mother and one from her father. If one of these X chromosomes carries the altered gene, the other X chromosome will balance out its effects and she will develop normally but be a carrier. This means that if she has a baby, the baby has a chance of inheriting one altered X chromosome and one Y chromosome. The Y chromosome will not be able to balance out the effect of the alteration, and the baby will develop AIS.

If a woman carries one altered X chromosome, during every pregnancy she has a:

  • one-in-four chance of having a girl who is unaffected, but can pass on the altered gene to her children (altered X and normal X)
  • one-in-four chance of having a normal boy (normal X and normal Y)
  • one-in-four chance of having a girl who is unaffected and does not carry the altered gene (normal X and normal X)
  • one-in-four chance of having a child with AIS (altered X and normal Y)

Glossary

Chromosome
Chromosomes are the parts of a body cell that carry genes. A human cell usually has 23 pairs of chromosomes.
Gene
Genes contain information that you inherit from your parents, such as eye or hair colour. They are carried by chromosomes.

Physical diagnosis

Partial androgen insensitivity syndrome (PAIS) can usually be diagnosed at birth, as the genitals are visibly different.

A physical diagnosis of complete androgen insensitivity syndrome (CAIS) is more difficult. Many children are diagnosed early in life when their testes cause hernias (soft bulges or swellings under the skin). When the hernias are operated on, the testes are discovered and CAIS is diagnosed.

If a girl with CAIS does not develop a hernia, the condition may not be diagnosed until puberty, when her periods do not start and a lack of pubic and underarm hair becomes apparent.

Blood test

Androgen insensitivity syndrome (AIS) can be confirmed using blood tests, which measure the level of hormones in the blood and reveal the altered X chromosome.

Ultrasound scan

An ultrasound scan (a way of producing pictures of inside the body using sound waves) can be used to confirm the absence of female internal reproductive organs when AIS is suspected.

Before birth

If the alteration (mutation) in the gene that produces the androgen receptors has been identified, AIS can be diagnosed after the 11th week of pregnancy. This is done either by chorionic villus sampling (CVS), which involves taking cells from the placenta (or afterbirth), or from the 15th week of pregnancy by amniocentesis (taking fluid from around the baby).

The decision to have a test in a pregnancy may be complex and require careful genetic counselling. Because the condition is rare, unborn babies are not routinely tested for AIS unless there is a family history of the condition.

Parents who have a child born with androgen insensitivity syndrome (AIS) will have to decide whether to raise their child as a boy or a girl and assign their gender accordingly. As children with complete androgen insensitivity syndrome (CAIS) have female genitals, they are normally raised as girls.

For children with partial androgen insensitivity syndrome (PAIS) the decision can be more difficult, especially if the genitals have both significant male and female characteristics.

If your child has PAIS, you should receive advice from both medical specialists and psychologists about your child's future development and the gender they are most likely to identify with.

Most children with PAIS stay with the genders they were assigned as babies, but some will decide this does not represent who they are, and change their gender.

Genital reconstructive surgery

In the past, children with PAIS had reconstructive surgery on their genitals at a very young age, to establish the gender that had been decided for them. This is not usually recommended now. Many experts believe that any reconstructive surgery should be postponed until the child is old enough to make their own decision about their wishes for the future.

Removal of the testes

Women who have CAIS are recommended to have their internal testes removed, as they can become cancerous. Cancer develops in around 9% of women with CAIS, though hardly ever before puberty.

The operation to remove the testes (an orchidectomy) used to be carried out at an early age but many experts now recommend leaving the operation until the girl has finished puberty. This is because the testes can help convert androgen to oestrogen, so the girl can develop a normal female body without the need for hormone treatments.

Boys with PAIS can have operations to move their testes into their scrotum (orchiopexy) and to straighten their penis so they can urinate standing up (hypospadias repair).

Vaginal lengthening

Some women with AIS choose to have vaginal-lengthening procedures to make sexual intercourse easier. Historically this was done before puberty, but doctors now usually wait until after puberty, when the woman can decide whether she wants to have the procedure, and which one to have.

The vagina can be lengthened using a method called dilation, which involves gradually widening and deepening the vagina through the use of small plastic rods. A surgical procedure called a vaginoplasty is another option.

Women with PAIS can also have surgery to reduce their clitoris and enlarge their vaginal opening. The operation may make the clitoris less sensitive, but they should still be able to orgasm.

Hormone therapy

Women with CAIS who have gone through puberty and had their testes removed will need to take a supplement of the hormone oestrogen to prevent them getting menopausal symptoms and developing weak bones (osteoporosis).

Women with CAIS tend to be taller as their Y chromosome carries genes for extra height. Oestrogen can also regulate the growth of their bones during puberty and prevent them growing excessively tall. If the testes are removed in infancy or childhood, hormone treatment is usually started at the age of 10 or 11 to initiate puberty.

Children with PAIS may also need to take hormone supplements. Girls with PAIS who have had their testes removed may need to take a combination of oestrogen and androgen to encourage female development during puberty. Boys with PAIS may need to take androgens (male sex hormones) to encourage certain male characteristics, such as beard growth or the deepening of the voice.

Psychological support

Psychological support is probably the most important aspect of care, both for someone with AIS and for their parents.

If your child is diagnosed with AIS, you should be offered psychological counselling. A diagnosis of AIS can come as a terrible shock to parents and feelings of shame, guilt, anger and anxiety are common. Counselling can help parents to come to terms with their feelings. Talking to other parents who have a child with AIS can also be useful.

Often, young children with AIS do not need any psychological support because their condition is natural to them. Parents often wonder when and what they should say to their child about their condition. Many people feel it is best to explain the basic facts about the condition to the child as soon as possible. Then, as the child becomes older, they can be given more detailed information as their ability to understand increases.

It is recommended that a child fully understands their condition before they reach puberty. Puberty can be a stressful time and the pressure to conform can be huge. If your child begins puberty without knowing the possible changes they may experience, or the differences between them and their friends, they could find it traumatic.

As a child grows older, they may need psychological support from a therapist with experience in the condition. A long-term relationship between the child and therapist is recommended so that new issues can be discussed as the child matures.

A late diagnosis of CAIS, when it is not spotted until your daughter has begun puberty, can be very difficult, both for your daughter and yourself. You should both be offered psychological counselling, as well as appointments with a gynaecologist and endocrinologist (specialist in hormones).

Most people with AIS who have received appropriate care and support are able to come to terms with their condition and go on to live normal lives.

Genetic counselling

If you are found to be carrying the altered X chromosome that can cause AIS, you can also have genetic counselling. It aims to provide you with information about AIS, what effect it can have on your life and the options available to you in the future.

Content provided by NHS Choices www.nhs.uk and adapted for Ireland by the Health A-Z.

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