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Androgen+Insensitivity
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Transcript of Androgen+Insensitivity
Androgen Insensitivity Syndrome
(AIS)
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An outline What is AIS? Classification History of AIS What happens in AIS? Testing Treatment Psychological Issues
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What is AIS? 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 chromosomeAbnormality 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
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
Image 1
Image 2
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Classification of AIS form Exists along continuum depending on degree of mutation in AR gene (Quigley
and French)
Grade 1: PAISMale genitals, infertile
Grade 2: PAISMale genitals but mildly ‘under-masculinized’
Grade 3: PAISMale genitals more severely ‘under-masculinized’
Grade 4: PAISAmbiguous genitals
Grade 5: PAISEssentially female genitalia, with enlarged clitoris
Grade 6: PAISFemale genitalia with pubic/underarm hair
Grade 7: CAISFemale 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) 1906Hereditary Pattern
Petterson and Bonnier 1937Concluded that affected persons are genetically male
Wilkins, 1957Found 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 mother1/3 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
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MALE Sex Chromosome = XY
Gonads = Testes
External Genitalia = Male
FEMALE Sex Chromosome = XX
Gonads = Ovaries
Normally chromosome sex determines gonad sex which determines phenotypic sex
WHAT HAPPENS IN AIS?
External Genitalia = Female
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 dyhydrotestosteroneMullerian 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 PregnancyChorionic Villus Sampling (9-12 weeks)Ultrasound and Amniocentesis (after 16 weeks)
After BirthPresence of XY Chromosomes
Buccal Mouth SmearBlood 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 relative’s repeat region to determine if they are a carrier
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Non-Biochemical Testing Maternal relatives affected by AIS
In an XX femaleDelayed puberty Reduced pubic-auxiliary hairAsymmetric pubic-auxiliary hairReduced 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
DebateWhat age? Who decides?
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Treatments Hormone Replacement Therapy (HRT) Types
Female: EstrogenProgesterone (sometimes take to reduce risk of breast
or uterine cancer)postorchidectomy
Male: Testosterone and DHT
FormOral, 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 doctor’s office Group examination
Androgen Insensitivity Syndrome Support Group (AISSG)
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Thank You
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