Androgen Insensitivity Syndrome (AIS)

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Androgen Insensitivity Syndrome (AIS)

• Alice Mann
• Maureen OBrien
• Elizabeth Rueckert

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What is AIS?

• A genetic condition where affected people have
  male chromosomes and male gonads with complete or
  partial feminization of the external genitals
• An inherited X-linked recessive disease with a
  mutation in the Androgen Receptor (AR) gene
  resulting in
• Functioning Y sex chromosome
• Abnormality on X sex chromosome
• Types
• CAIS (completely insensitive to AR gene)
• External female genitalia
• Lacking female internal organs
• PAIS (partially sensitive-varying degrees)
• External genitalia appearance on a spectrum (male
  to female)
• MAIS (mildly sensitive, rare)
• Impaired sperm development and/or impaired
  masculinization
• Also called Testicular Feminization

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Androgen Insensitivity Visuals
No. 2
Image 1 A woman with an XY chromosome pattern
but insensitivity to androgens Image 2A newborn
genetic male (46XY) with complete androgen
insensitivity syndrome and female external
genitalia
No. 1
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Classification of AIS Forms

• Exists along continuum depending on degree of
  mutation in AR gene (Quigley and French)
• Grade 1 PAIS
• Male genitals, infertile
• Grade 2 PAIS
• Male genitals but mildly under-masculinized
• Grade 3 PAIS
• Male genitals more severely under-masculinized
• Grade 4 PAIS
• Ambiguous genitals
• Grade 5 PAIS
• Essentially female genitalia, with enlarged
  clitoris
• Grade 6 PAIS
• Female genitalia with pubic/underarm hair
• Grade 7 CAIS
• Female genitalia with little to no pubic/underarm
  hair

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History

• Possibly first mentioned in the Talmud (400 BC)
• Speculation of whether Joan of Arc (1412) and
  Queen Elizabeth I (1533-1603) had AIS
• First reported 1817
• Steglehner described apparently normal woman with
  undescended testes
• Dieffeneach (American geneticist) 1906
• Hereditary Pattern
• Petterson and Bonnier 1937
• Concluded that affected persons are genetically
  male
• Wilkins, 1957
• Found tissue unresponsiveness to androgens
• Androgen receptor gene cloned and sequenced in
  1988

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Statistics

• Affects 1 in 20,400 people
• 2/3 of cases inherited from mother
• 1/3 of cases come from a spontaneous mutation in
  the egg
• No effect on life expectancy
• For a carrier woman, there is a 1 in 4 chance in
  each pregnancy that the child will have AIS and a
  1 in 2 chance if the fetus is male
• No racial differences

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Normal Sexual Development
MALE
FEMALE
Normally chromosome sex determines gonad sex
which determines phenotypic sex
WHAT HAPPENS IN AIS?
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Androgen Receptor Gene

• AIS results from mutations in the androgen
  receptor gene, located on the long arm of the X
  chromosome (Xq11-q12).
• The AR gene provides instructions to make the
  protein called androgen receptor, which allows
  cells to respond to androgens, such as
  testosterone, and directs male sexual
  development.
• Androgens also regulate hair growth and sex drive
• Mutations include complete or partial gene
  deletions, point mutations and small insertions
  or deletions.

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The Process of Sexual Development

• In AIS the chromosome sex and gonad sex do not
  agree with the phenotypic sex
• Phenotypic sex results from secretions of
  hormones from the testicles
• The two main hormones secreted from the testicles
  are testosterone and mullerian duct inhibitor
• Testosterone is converted into dyhydrotestosterone
  
• Mullerian duct inhibitor suppresses the mullerian
  ducts and prevents the development of internal
  female sex organs in males
• Wolffian ducts help develop the rest of the
  internal male reproductive system and suppress
  the Mullerian ducts
• Defective androgen receptors cause the wolffian
  ducts and genitals to be unable to respond to the
  androgens testosterone and dihydrotestosterone.

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AIS Fetus Development

• Each fetus has non-specific genitalia for the
  first 8 weeks after conception
• When a Y-bearing sperm fertilizes an egg an XY
  embryo is produced and the male reproductive
  system begins to develop
• Normally the testes will develop first and the
  Mullerian ducts will be suppressed and
  testosterone will be produced
• Due to the inefficient AR gene cells do not
  respond to testosterone and female genitalia
  begin to form
• The amount of external feminization depends on
  the severity of the androgen receptor defect
• CAIS complete female external genitalia
• PAIS partial female external genitalia
• MAIS Mild female external genitalia, essentially
  male

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Testing for AIS

• Tests
• During Pregnancy
• Chorionic Villus Sampling (9-12 weeks)
• Ultrasound and Amniocentesis (after 16 weeks)
• After Birth
• Presence of XY Chromosomes
• Buccal Mouth Smear
• Blood Test
• Pelvic Ultrasound
• Histological Examination of Testes

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Biochemical Testing for Carriers

• Tests
• 1960-70s Skin biopsies-evaluate androgen binding
  capacity
• Carries 50 androgen binding
• Problem some cases skipped because mutation did
  not always take place in the binding region of
  the gene
• 1990s DNA Testing
• blood or mouth cavity smears
• Now
• Measure length of base pair repeat region in
  first exon of gene and compare it to a female
  relatives repeat region to determine if they are
  a carrier

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Non-Biochemical Testing

• Maternal relatives affected by AIS
• In an XX female
• Delayed puberty
• Reduced pubic-auxiliary hair
• Asymmetric pubic-auxiliary hair
• Reduced bone density

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Treatments

• Surgery
• Orchidectomy or gonadectomy
• Removal of the testes
• Vaginal lengthening
• Genital plastic surgery
• Reconstructive surgery on the female genitalia if
  masculinization occurs
• Phalloplasty
• Vaginoplasty
• Pressure dilation
• Clitorectomy
• Debate
• What age?
• Who decides?

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Treatments

• Hormone Replacement Therapy (HRT)
• Types
• Female Estrogen
• Progesterone (sometimes take to reduce risk of
  breast or uterine cancer)
• postorchidectomy
• Male Testosterone and DHT
• Form
• Oral, transdermal, implant, injection, vaginally
• Prevents osteoporosis (age 10 or 11)
• Body responds as if it is post-menopausal, thus
  body density decreases and osteoporosis occurs

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Psychological Issues

• Medical Care Services (geneticist and a pediatric
  endocrinologist)
• Criticisms
• Lack of emotional and psychological support
• Family
• When to tell their children about their disorder
• Knowledge of if they are a carrier and if so
  guidance on whether they should have children or
  not
• Patients
• Therapy
• Isolation
• Registration desk of a doctors office
• Group examination
• Androgen Insensitivity Syndrome Support Group
  (AISSG)

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Case Study

• Discovery at age
• 12 years old
• 18 years old
• Fears
• Support

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Bibliography

• http//www.geneclinics.org
• http//www.medhelp.org
• http//web.nexis.com
• http//www.androgendb.mcgill.ca/intro.htm