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  1. 1. Androgen Insensitivity Syndrome (AIS)
  2. 2. An outline <ul><li>What is AIS? </li></ul><ul><li>Classification </li></ul><ul><li>History of AIS </li></ul><ul><li>What happens in AIS? </li></ul><ul><li>Testing </li></ul><ul><li>Treatment </li></ul><ul><li>Psychological Issues </li></ul>
  3. 3. What is AIS? <ul><li>Genetic condition where affected people have male chromosomes and male gonads with complete or partial feminization of the external genitals </li></ul><ul><li>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 </li></ul><ul><li>Types </li></ul><ul><ul><li>CAIS (completely insensitive to AR gene) External female genitalia Lacking female internal organs </li></ul></ul><ul><ul><li>PAIS (partially sensitive-varying degrees) External genitalia appearance on a spectrum (male to female) </li></ul></ul><ul><ul><li>MAIS (mildly sensitive, rare) Impaired sperm development and/or impaired masculinization </li></ul></ul><ul><li>Also called Testicular Feminization </li></ul>
  4. 4. 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
  5. 5. Classification of AIS form <ul><li>Exists along continuum depending on degree of mutation in AR gene (Quigley and French) </li></ul><ul><li>Grade 1: PAIS Male genitals, infertile </li></ul><ul><li>Grade 2: PAIS Male genitals but mildly ‘under-masculinized’ </li></ul><ul><li>Grade 3: PAIS Male genitals more severely ‘under-masculinized’ </li></ul><ul><li>Grade 4: PAIS Ambiguous genitals </li></ul><ul><li>Grade 5: PAIS Essentially female genitalia, with enlarged clitoris </li></ul><ul><li>Grade 6: PAIS Female genitalia with pubic/underarm hair </li></ul><ul><li>Grade 7: CAIS Female genitalia with little to no pubic/underarm hair </li></ul>
  6. 6. History <ul><li>Possibly first mentioned in the Talmud (400 BC) </li></ul><ul><li>Speculation of whether Joan of Arc (1412) and Queen Elizabeth I (1533-1603) had AIS </li></ul><ul><li>First reported 1817 Steglehner described apparently normal woman with undescended testes </li></ul><ul><li>Dieffeneach (American geneticist) 1906 Hereditary Pattern </li></ul><ul><li>Petterson and Bonnier 1937 Concluded that affected persons are genetically male </li></ul><ul><li>Wilkins, 1957 Found tissue unresponsiveness to androgens </li></ul><ul><li>Androgen receptor gene cloned and sequenced in 1988 </li></ul>
  7. 7. Statistics <ul><li>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 </li></ul><ul><li>No effect on life expectancy </li></ul><ul><li>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 </li></ul><ul><li>No racial differences </li></ul>
  8. 8. Normal Sexual Development 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
  9. 9. Androgen Receptor Gene <ul><li>AIS results from mutations in the androgen receptor gene, located on the long arm of the X chromosome (Xq11-q12). </li></ul><ul><li>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. </li></ul><ul><li>Androgens also regulate hair growth and sex drive </li></ul><ul><li>Mutations include complete or partial gene deletions, point mutations and small insertions or deletions. </li></ul>
  10. 10. The Process of Sexual Development <ul><li>In AIS the chromosome sex and gonad sex do not agree with the phenotypic sex </li></ul><ul><li>Phenotypic sex results from secretions of hormones from the testicles </li></ul><ul><li>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 </li></ul><ul><li>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. </li></ul>
  11. 11. AIS Fetus Development <ul><li>Each fetus has non-specific genitalia for the first 8 weeks after conception </li></ul><ul><li>When a Y-bearing sperm fertilizes an egg an XY embryo is produced and the male reproductive system begins to develop </li></ul><ul><ul><li>Normally the testes will develop first and the Mullerian ducts will be suppressed and testosterone will be produced </li></ul></ul><ul><li>Due to the inefficient AR gene cells do not respond to testosterone and female genitalia begin to form </li></ul><ul><li>The amount of external feminization depends on the severity of the androgen receptor defect </li></ul><ul><ul><li>CAIS: complete female external genitalia </li></ul></ul><ul><ul><li>PAIS: partial female external genitalia </li></ul></ul><ul><ul><li>MAIS: Mild female external genitalia, essentially male </li></ul></ul>
  12. 12. Testing for AIS <ul><li>Tests </li></ul><ul><li>During Pregnancy Chorionic Villus Sampling (9-12 weeks) Ultrasound and Amniocentesis (after 16 weeks) </li></ul><ul><li>After Birth Presence of XY Chromosomes Buccal Mouth Smear Blood Test </li></ul><ul><li>Pelvic Ultrasound </li></ul><ul><li>Histological Examination of Testes </li></ul>
  13. 13. Biochemical Testing for Carriers <ul><li>Tests </li></ul><ul><li>1960-70s: Skin biopsies-evaluate androgen binding capacity </li></ul><ul><ul><li>Carries: 50% androgen binding </li></ul></ul><ul><ul><li>Problem: some cases skipped because mutation did not always take place in the binding region of the gene </li></ul></ul><ul><li>1990s: DNA Testing </li></ul><ul><ul><li>blood or mouth cavity smears </li></ul></ul><ul><li>Now: </li></ul><ul><ul><li>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 </li></ul></ul>
  14. 14. Non-Biochemical Testing <ul><li>Maternal relatives affected by AIS </li></ul><ul><li>In an XX female Delayed puberty Reduced pubic-auxiliary hair Asymmetric pubic-auxiliary hair Reduced bone density </li></ul>
  15. 15. Treatments <ul><li>Surgery </li></ul><ul><li>Orchidectomy or gonadectomy </li></ul><ul><li>Removal of the testes </li></ul><ul><li>Vaginal lengthening </li></ul><ul><li>Genital plastic surgery Reconstructive surgery on the female genitalia if masculinization occurs Phalloplasty </li></ul><ul><li>Vaginoplasty </li></ul><ul><ul><ul><li>Pressure dilation </li></ul></ul></ul><ul><ul><ul><li>Clitorectomy </li></ul></ul></ul><ul><li>Debate What age? Who decides? </li></ul>
  16. 16. Treatments <ul><li>Hormone Replacement Therapy (HRT) </li></ul><ul><li>Types Female: Estrogen Progesterone (sometimes take to reduce risk of breast or uterine cancer) postorchidectomy Male: Testosterone and DHT </li></ul><ul><li>Form Oral, transdermal, implant, injection, vaginally </li></ul><ul><li>Prevents osteoporosis (age 10 or 11) Body responds as if it is post-menopausal, thus body density decreases and osteoporosis occurs </li></ul>
  17. 17. Psychological Issues <ul><li>Medical Care Services (geneticist and a pediatric endocrinologist) </li></ul><ul><ul><li>Criticisms </li></ul></ul><ul><ul><ul><li>Lack of emotional and psychological support </li></ul></ul></ul><ul><li>Family </li></ul><ul><ul><li>When to tell their children about their disorder </li></ul></ul><ul><ul><li>Knowledge of if they are a carrier and if so guidance on whether they should have children or not </li></ul></ul><ul><li>Patients </li></ul><ul><ul><li>Therapy </li></ul></ul><ul><ul><ul><li>Isolation </li></ul></ul></ul><ul><ul><ul><li>Registration desk of a doctor’s office </li></ul></ul></ul><ul><ul><ul><li>Group examination </li></ul></ul></ul><ul><ul><li>Androgen Insensitivity Syndrome Support Group (AISSG) </li></ul></ul>
  18. 18. <ul><li>Thank You </li></ul>