Androgen Insensitivity Syndrome
(AIS)
Alice Mann
Maureen O’Brien
Elizabeth Rueckert
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
Androgen Insensitivity Visuals
QuickTime™ and a
TIFF (LZW) decompressor
are needed to see this picture.
No. 2
No. 1
Image 1: A woman with an XY
chromosome pattern but insensitivity
to androgens
Image 2:A newborn genetic male
(46XY) with complete androgen
insensitivity syndrome and female
external genitalia
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
History




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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
Statistics



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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
Normal Sexual Development
Sex Chromosome = XY
MALE
Gonads = Testes
External Genitalia = Male
FEMALE
Sex Chromosome = XX
Gonads = Ovaries
External Genitalia = Female
Normally chromosome sex determines gonad sex which determines
phenotypic sex
WHAT HAPPENS IN AIS?
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.
QuickTime™ and a
TIFF (LZW) decompressor
are needed to see this picture.
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.
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
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
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 relative’s
repeat region to determine if they are a carrier
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
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?
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
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 doctor’s office
• Group examination
– Androgen Insensitivity Syndrome Support Group (AISSG)
Case Study

Discovery at age
– 12 years old
– 18 years old
 Fears
 Support
Bibliography

http://www.geneclinics.org
 http://www.medhelp.org
 http://web.nexis.com
 http://www.androgendb.mcgill.ca/intro.htm