androgen insensitivity syndrome (ais)

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Androgen Insensitivity Syndrome

(AIS) 

1. dr. Singgih Annas F 5. dr. Arif N.

2. dr. Indra Sapta D. 6.dr. Benny G.3. dr. Mujiran 7. dr. Sinung B.

4. dr. Saiful Islam

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What is AIS?

A genetic condition where affected people have male chromosomesand male gonads with complete or partial feminization of the externalgenitals

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

QuickTime™ an d a

TIFF (LZW) decompressor are needed to s ee this picture.

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 femaleexternal genitalia

No. 1 

No. 2

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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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Normal Sexual Development

WHAT HAPPENS IN AIS? 

Sex Chromosome = XX 

Gonads = Ovaries 

External Genitalia = Female

Sex Chromosome = XY 

Gonads = Testes 

External Genitalia = Male

MALE 

Normally chromosome sex determines gonad sex which determinesphenotypic sex 

FEMALE 

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Androgen Receptor Gene

AIS results from mutations in the androgen receptor gene, locatedon the long arm of the X chromosome (Xq11-q12).

The AR gene provides instructions to make the protein calledandrogen 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, pointmutations and small insertions or deletions.

QuickTime™ an d aTIFF (LZW) decompressor 

are needed to see this p icture.

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AIS Fetus Development

• Each fetus has non-specific genitalia for the first 8 weeks afterconception

• When a Y-bearing sperm fertilizes an egg an XY embryo isproduced and the male reproductive system begins to develop

• Normally the testes will develop first and the Mullerian ductswill be suppressed and testosterone will be produced

• Due to the inefficient AR gene cells do not respond totestosterone and female genitalia begin to form

The amount of external feminization depends on the severity ofthe 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 bindingcapacity

•

Carries: 50% androgen binding• Problem: some cases skipped because mutation did

not always take place in the binding region of thegene

 – 1990s: DNA Testing

• blood or mouth cavity smears

 – Now:

• Measure length of base pair repeat region in firstexon of gene and compare it to a female relative’srepeat 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 ifmasculinization 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 breastor 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 pediatricendocrinologist) – 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 onwhether 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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