1. Androgen Insensitivity Syndrome (AIS)
Alice Mann
Maureen O’Brien
Elizabeth Rueckert

2. 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

3. Androgen Insensitivity Visuals
No. 2
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
No. 1

4. 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

5. History Possibly first mentioned in the Talmud (400 BC)
Speculation of whether Joan of Arc (1412) and Queen Elizabeth I ( ) 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

6. 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

7. Normal Sexual Development
MALE
Sex Chromosome = XY
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?

8. 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.
Mutations can cause cells to be less responsive to androgens or prevent cells from being responsive at all
In approximately 10% of women who are carries for the altered androgen receptor gene, clinical signs such as sparse pubic hair, armpit hair and delay in the onset of menstruation are commonly observed.

9. 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.

10. 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

11. 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

12. Biochemical Testing for Carriers
Tests
s: 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

13. 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

14. Treatments Surgery Debate 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?

15. Treatments Hormone Replacement Therapy (HRT) Types Form
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

16. 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)

17. Case Study
Discovery at age
12 years old
18 years old
Fears
Support

18. Bibliography http://www.geneclinics.org http://www.medhelp.org