REVIEW ARTICLE

ENDOCRINOLOGY SUBDIVISION
SADIYAH MANDA TIKUPADANG

ANDROGEN INSENSITIVITY
SYNDROME (AIS) IN CHILDREN

1
INTRODUCTION
Virilizatio
n failure PAIS
CAIS
AR
mutation

AIS
X-linked
recessive
(Xq11-12)

DSD
1 : 20.400

2
 PATOPHYS
IOLOGY

TREATME SYMPTOM
NT S $ SIGNS

AIM
AIM

COMPLICA LABORAT
TION ORY

3
4
NORMAL SEX
DEVELOPMENT
•46, XY; 46, XX Sex Determination
6 CHROMOSOME •SRY
m
g GONAD Testes; Ovarium
g

•Testosterone, AMH, DHT Sex Differentiation

HORMONE •Receptor

INTERNAL
GENITALIA

EXTERNALGENITALI
EXTERNALGENITALI
A
5
FETAL NORMAL SEX
DEVELOPMENT
YOLK
GENITAL RIDGE SAC

WOLFFIAN BIPOTENSIAL GONAD MULLERIAN

DUCT (FGF9, WNT4) DUCT
(+) SO
X9
RY
-S -S
X9 RY
S O (-)

↑ FGF9/WNT4 ↓ FGF9/WNT4

TESTES
OVARIAN
6
 OVARIUM
TESTES
.....fetal
LEYDIG SERTOLI
9W

MIF
INSL3 TESTOSTERON

TESTES WOLFFIAN
DHT
DHT(-) MULLERIAN
DESCENT DUCT
DUCT
APOPTOSIS
DEVELOP

VAGINA 2/3 DIST

PENIS EPIDIDIMIS
UTERUS
CLITORIS
SKROTUM FALLOPPIAN
VAS DEFERENS
TUBE
MINOR LABIAL
PROSTAT VESICA
VAGINASEMINALIS
1/3 PROX
MAJOR LABIAL
7
 OVARIUM

MIF (-)

DHT (-) MULLERIAN

DUCT
DEVELOP

VAGINA 2/3 DIST

UTERUS
CLITORIS
FALLOPPIAN TUBE
MINOR LABIAL
VAGINA 1/3 PROX
MAJOR LABIAL
8
PUBERTY

ANDROGEN

GENITAL PUBIC, AXILLA,

VOICE
MATURATI & EXTREMITY
ON HAIR GROWTH CHANGES

9
INTERNAL GENITALIA
DIFFERENTIATION Gonad
Müllerian Duct
Wolffian Duct

Sinus Urogenitalis
AMH (-) &
Testosterone (-) AMH (+) & Testosterone (+)

Ovarium
Ves Urin
Ves urin
Tuba Testes
Deferens
Uterus Seminal Vesicle
Prostate
Vagina
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EKSTERNAL GENITALIA
DIFFERENTIATION

11
12
EMBRIONAL STRUCTURAL DEVELOPMENT
OF EXTERNAL GENITALIA

Embrional Male Female

structure
Urogenital sinus Prostat 2/3 lower vagina
Genital tubercle Penis Clitoris
Genital fold Uretra & Phallus Minor labia
Genital swelling Scrotum Major labia

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14
ANDROGEN RECEPTOR

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ANDROGEN RECEPTOR

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SEX DIFFERENTIATION TIME
TABLE

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PATOPHYSIOLOGY
 AR MUTATION/ RESISTANCE 
loss of AR function  androgen-
target cell binding fail  loss of
androgen effect on target cell.

18
 TESTES
...pathophysiology
LEYDIG SERTOLI

ma tized
Aro
MIF
TESTOSTERON
ESTROGEN
T-AR complex (-)
DHT
MULLERIAN
* MAMMAE WOLFFIAN DUCT
ENLARGEMENT DHT-AR DUCT APOPTOSIS
* PRIMARY complex (-)
AMENORRHEA

VAGINA 2/3 DIST NONE : NONE:

PENIS EPIDIDIMIS
CLITORIS EPIDIDIMIS UTERUS
SKROTUM VAS DEFERENS
MINOR LABIAL VAS DEFERENS FALLOPPIAN TUBE
PROSTAT VESICA SEMINALIS
MAJOR LABIAL VESICA SEMINALIS VAGINA 1/3 PROX
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CLASSIFICATION
●
Varies widely
●
Bangsboll et al (a large Danish study): 1 per 20,400 male births
●
Grumbach and Conte: 1-2% female infants presenting with
Complete AIS ●
inguinal hernia
Prevalence worldwide 2:100,000 to 5:100,000
●
Incidence in Netherlands over a ten year period: minimal
1:99,000

●
Not as common as complete AIS (1/10 of
Partial AIS CAIS)

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GRADING
 1 PAIS Normal masculinization in utero
2 PAIS Male genitals but mildly 'under-masculinized', isolated hypospadias
Male phenotype with severe defect in masculinization  perineal
3 PAIS hypospadias, small penis, cryptorchidism i.e. undescended testes,
and / or bifid scrotum)
Severe genital ambiguity  clitoral-like phallus, labioscrotal folds, single
4 PAIS
perineal orifice
5 PAIS Female phenotype with posterior labial fusion and clitoromegaly
6 PAIS Female phenotype with pubic hair present in adulthood
7 CAIS Female phenotype with no pubic hair

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 SIGNS & SYMPTOMS
FEMALE INTERNAL GENITAL (-)
BREAST ENLARGEMENT
INFERTILLITY
NO MENSTRUATION

PAIS
CAIS
AMBIGOUS GENITALIA / UNDER-
FEMALE EXTERNAL
VIRILIZE
GENITALIA
PARTIALLY DESCENDED TESTES
UNDESCENDED TESTES
INTROITUS VAGINA : SHORT/ABSENT
SHORT INTROITUS VAGINA
HIPOSPADIA
NO PUBIC/AXILLA HAIR
SPARSE PUBIC/AXILLA HAIR

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LABORATORIES & OTHER
SUPPORTING EXAMINATION

CHROMOSOME LABORATORI
ANALYSIS ES
46,XY
T & DHT
AR MUTATION
PRENATAL DX N/increased
CARIER ↑ LH & FSH
DETECTION ↑ T/DHT

USG
MOLECULAR TO DETECT
INTERNAL
GENETIC
GENITALIA
TESTING : (mullerian
AR MUTATION absent/rudimenta
ry, testes)

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DIAGNOSIS
●
ANAMNESIS ●
PHISICAL EXAM

Female/genitali
Female with
a ambigous,
amenorrhea or
undescended
inguinal hernia,
testes, sparse
family history
pubic, axilla, &
extremity hair,

T & DHT
N/increased
USG
↑ LH & FSH
(INTERNAL
↑ T/DHT
GENITALIA)
46 XY
AR MUTATION
●
OTHER
SUPPORTING ●
LABORATORY
EXAM

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Clinical findings
presumptive
diagnosis of
AIS

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CAIS
 WINEWSKY et al.:
1. Testes + N female external genitalia
on 46 XY
2. AR gene mutation
3. Spontaneous feminization on
puberty without menstruation, high
testosteron + absent of virilization
4. Sparse pubic & axilla hair.

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 MANAGEMENT

 GOALS :
1. Maximum preservation of
fertility/reproduction
2. Ensure maximum sexual function
3. Ensure the concordance of fenotyp &
psycosocial toward the chosen
gender

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 EXTREMELY SMALL PHALLUS 
PAIS  MALE/FEMALE (CHILD’S
GENDER ESTABLISHMENT

FEMALE RECOMENDED
CAIS  FEMALE

SURGERY
DET ERMI NE AS FEMALE (CAIS/SEVERE
DECISION)

PAIS)  Orchidectomy (hernia correction, 19

YO, Dx bef ore 6MO)
DET ERMINE AS MALE  Orchidopexi
(ASAP), chordae& uretroplasty (6-18 MO)
PAI S  O rchidectomy 19YO
Vaginoplasty  19 YO

MANAGEMENT

MULTIDICIPLNE & PSYCHOLOGY

psychology/psychi atry, genetic,
(endocrinology, surgery/urology,
neonatol ogy, etics commitee,
T OR DHT  PAIS & MALE

COUNSELLING
FEMALE

nursing)
PREVENT OSTEOPOROSIS) 
SEXUAL CHARACTERISTIC &
ESTROGEN (SECONDARY
HRT

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TODD PURVES (AAP 2007)
DELAYED GONADECTOMY
Low risk of malignancy before
puberty (three cases in the literature)
Delays HRT until late adolescence
May enhance breast development
and bone mineralization better than
does exogenous
hormones
DELAYED VAGINOPLASTY
Most affected patients elect not to
have surgery
Sexual function does not always
require surgery
Sexually functional genitalia are not
required in childhood
Older, more mature patients are
better prepared to face complications
& psychological issues associated
with surgery
80% of patients in the earlier Hopkins
study cited late adolescence or early
adulthood as the optimal time for
surgery
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COMPLICATION
 Gonad tumor
 Infertility
 Osteoporosis
 Psychologic sequele

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PROGNOSIS
 Qua ad vitam : bonam
 Qua ad sanationem : dubia

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PREVENTION
 CARRIER IDENTIFICATION
 PRENATAL IDENTIFICATION

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DIFFERENT DIAGNOSIS
 5-alfa reductase deficiency
 17-beta hydroxisteroid dehydrogenase
deficiency
 XY gonadal dysgenesis (Swyer Syndrome)
 Testicular dysgenesis
 Sindrom Mayer Rokitansky Kuster Hauser
 Persistant Mullerian dysgenesis syndrome

35
SUMMARY
 Androgen insensitivity syndrome (AIS) is a
resessive x-linked disorder. This disorder result in
a failure in the process of normal masculinization
of external genital on genotypically male
individual, presented as complete androgen
insensitivity syndrome (CAIS) or partial androgen
insensitivity syndrome (PAIS), depending on the
remaining receptor function. AIS can be
diagnozed since the gestational age of 9-12
weeks by obtaining villi chorealis sample and on
16 weeks of gestational age through USG and
amniocentesis.
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 In adolescence, CAIS & PAIS commonly suspected
in one of the following two conditions, a female
presented with inguinal hernia while testes were
found on surgery or primary amenorrhea at
adolescent. To diagnosed, the laboratories should
be performed (testosteron, DHT, LH, FSH),
genitogram, and chromosome analysis (genotype
dan gene mutation analysis). The complications
are infertility, seminoma, Sertoli cell tumor, Leydig
cell tumor, osteoporosis, and psychology sequele.
Multidicipline treatment are needed, including
psychology counselling, surgery, dan hormon
replacement therapy. The Prognosis of qua ad
vitam is good and of qua ad sanationem is dubia.
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Pathways of Steroid Biosynthesis in the Adrenal Cortex

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21-hydroxilase deficiency

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Androgen methabolism & defect

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ANDROGEN RECEPTOR

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