DISORDER OF

DETERMINATION AND SEX

DIFFERENTIATION
 Sex differentiation

What makes us Male or Female?

 Chromosomic Sex

•
 Chromosomic Sex
• Y Chromossome – SRY Gene – codes
for the testis determining factor.
In the absence of SRY there are no
testes.
• X Chromossome – DSS – Double dose
gene. Two DSS genes are required for
the ovaries to be fully functional
 Chromosomic number
Full trisomy of an individual occurs when a chromosome fails to saparate
during gamete formation. This can result in an extra or missing
chromosome in a sperm or egg cell. After fertilization, the resulting
fetus has 47/45 chromosome instead of the typical 46.
Partial/mosaic
• A partial trisomy occurs when part of an extra chromosome is
attached to one of the other chromosomes, or if one of the
chromosomes has two copies of part of its chromosome.
• A mosaic trisomy is a condition where extra chromosomal material
exists in only some of the organism's cells.
 Bipotential Gonads

• In the presence of SRY – Testes

• In the absence of SRY – Ovary like

• Two doses of DSS needed to develop fully

functioning ovaries.
 Brain
• Presence of androgens – Brain – Male

• Absence of androgens - Brain – Female

Genital Sex
Genital Sex
 Brain Differentiation

• In the presence of SRY – Testes

• In the absence of SRY – Ovary like

• Two doses of DSS needed to develop fully

functioning ovaries.
Brain Differentiation Rats
What Makes Us Male or Female?

• Chromosomic Sex
• Gonadal Sex
• Genital Sex
• Brain Differentiation
Hand
Finger length correlates with the concentration of androgens in uthero
DETERMINATION OF SEX.

-Karyotypic ( genetic) sex:

presence of a Y chromosome results in testicular
development.

-Gonadal sex:
Presence of ovarian or testicular tissue

-Ductal Sex:
Presence of Mullerian (female) or Wolffian (male) ducts

-Phenotypic ( genital ) sex:

external appearance of the genitalia.
Until 7 week of gestation , gonads are bipotential

In male fetus the Y chromosome acts as a dominant male

determinant

this result of the action

of a single gene, SRY.

SRY initiate testis

rather than ovary development
C. Genes implicated

Active in Male and Female fetuses

- WT1 (11p13): formation of the primitive gonads

- SF1 (9q33): regulation of steroidogenesis

Active in Male fetuses

- SRY (Yp11.3):
Induce testis differentiation

- SOX9 (17q24):
Activate expression of AMH

- AMH (19p13.3):
Induce regression of Müllerian ducts
Active in Female fetuses

- DAX1 (X p21.3):
Inhibit SRY and SOX9

- WNT4 (1p35):
regulation of female development,
antagonism of testosterone

- RSPO1(1p34):
Inhibit SOX9
C. Genes implicated

SRY Yp11.3
SF1 9q33
WT1 11p13
DAX1 Xp21.3
SOX 9 17q24
RSPO1 1p34
WNT 4a 1p35
AMH 19p13.3
2.Abnormal Sexual differentiation

Between 0.1% and 0.2% of live births are ambiguous

enough to become the subject of specialist medical
attention.

But for a lot of the following syndromes, problems may

only appear at puberty or later (infertility).

The specialists use the term « DSD »:

Disorders of Sex Development.

A. Abnormal number of sex Chromosomes:

46 YY and 45 Y are fatal.

We need at least one X chromosome to survive

Trisomy X (47 XXX)

Female, generally asymptomatic
extra Xs are inactivated

mild mental retardation

(more severe in 48 XXXX and 49 XXXXX patients)

1/2000 birth
Turner Syndrome (45 X, monosomy X)
bisa juga 46XX dengan 1 X tidak aktif

•Cystic hygroma and Hydrops fetalis.

•Congenital Heart disease, including coarction of the
aorta
•Short stature

•Common cause of female hypogonadism

•Failure to develop secondary sex characteristics
•Atrophic streaked ovaries
•Primary amenorrhea
> Infertility

•No Barr body present

Turner Syndrome
1/5000 birth
Turner Syndrome

short stature;
short webbed neck;
cubitus valgus;
Lymphedema.
 Turner

Missing X Chromosome

Low hair line

- Klinefelter syndrome (47,XXY)

& Klinefelter variants

(48,XXXY 49,XXXXY,etc)

•Caused by meiotic nondisjunction

•Common cause of male hypogonadism
 
•Testicular atrophy  hipoandrogen
•Infertility due to azoospermia
•Female distribution of hair
•Long limbs, narrow shoulders
•Gynecomastia 

1/2000 birth
 Klinefelter syndrome

Extra X/Y Chromosome

-   47, XYY syndrome

not associated to a particular phenotype

normal intelligence, not dysmorphic
normally fertile

> hyperactivity and impulsivity is frequent,

True psychopathology (« crime

chromosome ») is not common.

1/2000 birth
B. Abnormal sex differentiation with normal
Karyotype

Alteration (duplication, deletion or mutation)

of any of the implicated genes could result
in sex reversal and/or gonadal dysgenesis
46XY female - SRY deletion / mutation (Swyer Syndrome)
- WNT4 duplication
- DAX1duplication
- SOX9 deletion (campomelic dysplasia)
- WT1 mutation (Frasier & Denys-Drash
Syndrome)

46 XX male - SRY translocation

- SOX9 duplication
- RSPO1 mutation
Campomelic dysplasia

mutation of SOX9

- Dysmorphic

- bowing of long bones

- abnormal extremities
- Sex Reversal
- Gonadal Dysgenesis
Congenital Adrenal Hyperplasia (CAH)
Deficiency of 21-Hydroxylase
(90 % of the cases)
mineralocorticoid deficiency
> Female pseudohermaphrodism
60 % of the intersex cases at birth

1/15000 live birth

 CAH
• Penyakit bawaan pada kelenjar adrenal
• resesif
• Hormon kortisol dan aldosteron sangat sedikit
atau tidak ada, produksi hormon tertosteron dan
androgen terlalu banyak
• Pada wanita klitoris cenderung besar, rambut
wajah cenderung banyak, tidak subur.
• Ada 2 tipe : klasik dan non klasik
Congenital Adrenal Hyperplasia (CAH)
Ambiguous genitalia in CAH
5 alpha-reductase deficiency

Testosterone is not converted in DHT

Male pseudohermaphrodism

Mostly female phenotype

or ambiguous genitalia
Virilisation at puberty

The gene is located in 2p23

Autosomal recessive
5 alpha-reductase deficiency
5 alpha-reductase deficiency

MICROPENIS

Androgen Insensitivity Syndrome (AIS)

mutations in AR,
gene for the human Androgen Receptor,
located at Xq11-12

three subtypes :
1. complete * (female phenotype)
2. partial (male, female or ambiguous)  big
clitoris, small penis, hipospadia, ginekomastia
3. mild (male genitalia)

* =(Testicular feminization Syndrome)

1/20.000 birth
Androgen Insensitivity Syndrome (AIS)

Mild form Complete

infertil fenotip wanita

fenotipe pria uterus (-)
menstruasi (-)

testis tdk turun

 DIAGNOSA
USG panggul
Tes LH, FSH, testosteron
Tes kromosom
 SWYER SYNDROME

• Complete gonadal disgenesis 46XY

• Produksi AMH yang tidak adekuat
• Terjadi gangguan penghambatan perkembangan
duktur Mulleri sehingga tumbuh uterus
• Genetalia eksterna wanita, terbentuk uterus dan tuba
falopi tapi gonad tidak fungsional hanya ada gonadal
streak  resiko kanker  sarankan diangkat
• Tidak bisa ovulasi tapi bisa hamil dengan donor sel
telur atau embrio
Sporadic and/or environmental syndromes (1)

* Mayer Rokitansky Kuster Hauser Syndrome (MRKH)

Vaginal agenesis or incomplete vagina

Bisa disertai kelainan ginjal

Between 1940 and 1980, cases were associated to maternal intake

of Diethylstilbestrol (DES)

* MURCS association
Mullerian ducts hypoplasia (aplasia)
Renal agenesis
Cervical Somite dysplasia
Sporadic and/or environmental syndromes (2)

* Caudal regression syndrome

Variable defects of lumbar spine and inferior limbs

Uro-genital anomaly

extreme form > Sirenomelia

Associated to gestational diabetes

Caudal regression

49
C. True Hermaphrodism

Presence of both ovarian and testicular tissue

Genetic Sex: 46XX/46XY, 45X/ 46XY mosaics

Gonadal Sex:
Ovotestes: A gonad with both testicular and ovarian
tissue.
or more rarely ovary on one side and testes on the
other.

Ductal Sex: Often mixed

Phenotypic sex : Ambigous genitalia

Exceptionally rare.
C. True Hermaphrodism
D. Induced pseudohermaphrodism

- iatrogenic: female pseudohermaphrodism due to an

intake of progestational agents or androgens during the first
trimester.

- maternal endocrine disorders:

most endocrine maternal abnormalities usually prevent
pregnancy if initially present.
Some ovarian tumours have been reported as a cause of
virilisation of female fetus.
 Androgenized Genetic
Female Child

Genetic Female:XX
External Genitalia exposed to Androgens during genital

differentiation
 Androgenized Genetic
Female Child
• Progestin Induced Virilization –
androgens given to mothers to prevent
miscarriages.
• Congenital Adrenal Hyperplasia – need
medical attention at birth.
• Some anticonvulsant drugs
• Pollutants?
 Gender role preference behaviors in
congenital adrenal hyperplasia patients
 Intersex
• True hermaphrodites: have both gonads
• Pseudo hermaphrodites: external genitalia
does not mach internal gonodal sex.
THANK YOU
 KASUS 1
• A 16-year-old female presents to your clinic with primary amenorrhea.
She is not sexually active and to confirm you check a pregnancy test
which is negative. She had normal breast development that began at
age 12 and is now at a Tanner stage V. Pelvic exam reveals a blind
pouch that represents a very shortened vagina. Abdominal ultrasound
reveals bilateral normal appearing ovaries and a pelvic mass consistent
with a uterus. Chromosome analysis reveals that she is 46, XX. Which
is the most likely diagnosis?
• a. Testicular feminization
• b. Gonadal agenesis
• c. Mayer-Rokitansky-Kuster-Hauser
• d. Turner's syndrome
 KASUS 2
• An 18-year-old G0 presents to your clinic with primary amenorrhea.
She has normal breast development, but has limited development of
pubic or axillary hair. On pelvic exam you note that she has a
foreshortened vagina. Transvaginal and transabdominal ultrasound is
unable to identify a uterus. Chromosomal analysis shows that the
patient is 46, XY. What is this patient's diagnosis?
• a. Testicular feminization
• b. Gonadal agenesis
• c. Mayer-Rokitansky-Kuster-Hauser syndrome
• d. Swyer syndrome
• e. Turner syndrome
 KASUS 3
• Wanita 20 tahun, amenorea primer, pernah
mencoba coitus tapi penis tidak bisa masuk,
payudara berkembang normal
• Apa kemungkinan diagnosa?
• Pemriksaan penunjang apa yang
diperlukan?
BRENNER PAUL F. ( 1999 )

GROUP BUAH DADA UTERUS KETERANGAN

 Sentral
I    Perifer : gagal gonad
 Bedakan dengan cek FSH
 RKH (Rokitansky Kuster
Hauser)
II    Testicular Feminisasi /
insensitivitas androgen

 Kel. Seks Kromosom

III    Agonadisma

Hiperprolaktinemia
IV  
04/22/23 Amenore Sekunder 61
 KASUS 4
• Wanita 16 tahun datang dengan keluhan
belum pernah haid. Dari pemeriksaan tidak
ada rambut pubis dan tidak ada payudara
• Dari USG tampak uterus
• Apa kemungkinan diagnosa??
• Pemeriksaan penunjang apa yang diperlukan?
• Apa bisa hamil?