Drs. Soeharno, M.S.

Fakultas Kedokteran UHT

 Sexual reproduction which greatly enhances

genetic variation within species, requires
mechanism that result in sexual differentiation
A wide variety of genetic mechanisms have
evolved in organisms leading to sexual
dimorphism
Most often, specific genes, usually on a single
chromosome cause maleness or femaleness
during development

 In human the presence of extra X or Y

chromosomes beyond the diploid number may be
tolerated but often lead to syndromes
demonstrating distinctive phenotypes
While segregation of sex determing chromosome
should theoritically lead to one to one sex ratio of
males to females, in humans this ratio greatly
favors males at copception
In mammals females contain two X chromosomes
compared to one in males, but the extra genetic
information in female is compensated by random
in activation of one of the X chromosomes early in
development

 Genetalia & internal ducts male testis

rudmentairy and fail to produce sperm
They are tall, long arms & leg and large hands & feet
Gaemocomastia (enlargment of the breast and the
hips are often roinded)
IQ : below normal range
Abnormal social development
Ambigious sexual development
Occurs 2 of every 1000 male births
Karyotype

47 XXY
48 XXXY
49 XXXXY

49 XXXYY

Severe in individuals with agreater number of X

chromosomes

 Female ext genetalia & internal duets ovary are

rudimentery
Short stature (< 1.5 m)
Skin flaps on the back of the necle
Underdevelopt breast
IQ : Normal
Inordense : is observed in about 1 2000 female
births
Karyotype 45 XX including mosaic
somatic cells, displays two different
genetic cell lines
Common combination 45 X / 46 XY
45 X fetuses die in 45 X / 46 XX
Utero aborted spontaneously

1912 H. Von Wimiwater 47 chromosomes

(spermatogonial metafase)
1920 Theopillus Painte 45 48 chromosomes in
testicular tissne and Y chromosomes (small
1956 Joe Hin Tjio & Albert Levan discoverred
better way to prepare cromosomes
John L. Hamerton confirm this finding the familiar
karyotype of human based on Tjio Le Van
technique
The human female has 2 X chromosome
male has 1 X chromosome Y

Early development : every human embryo undergoes potentially

hermaphrodite
Fifth week of gestation:
GONADAL PRIMORDIAL
(tissue that will form gonade)
ARISE a pair of ridges, associated with embryo nic kidney

Primordial germs migrate to this ridges become :

OUTER CORTEX

Developing into ovary

INNER (medulla)

Developing into testis

Two sets of undifferentiated

MULLERIAN

Female ducts

WOLFIAN

Male ducts

The absence of the Y

chromosome, no male
development occurs
The cortex of genital ridge form
Ovarium tissue
12 weeks of fetal development
Oogonium within ovaries begin meiosis
Primary Oocyte
25 weeks of gestation all oocyte become
arrested in meiosis remain dormant until
puberty (10 15 years later)

It has been thought mostly black genetically Y

chromosomes contains fewer genes than the X
f.e. at both ends of the Y chromosome are the so called
pseudo autosomal regions (PARs)
SRY : encodes a gene that controls male
sexuals development
SEX determining region Y
Encodes a gene product of the
undifferentiated gonadal tissue of the
embryo testis
This product is called TDF (Testis Determining
Factor)
MSY : Male specific region of the Y

Primary sex ratio :

reflects the proportion of males

to females conceived in
population

Secondary sex ratio : the proportion of each sex

that is born
1969 Census data among
caucasian in USA
secondary sex ratio little leads than 1,06 (106
males were born for each 100 females)

It is believed that many more males than females are

concewed in the human population
Ratio : 1.20 1.60
Assumption upon which the theoretical ratio is based
1. Because of segregation males produce equal
numbers of X and Y bearing sperm
2. Each type of sperm has equivalent viability and
motility in the female reproductive organ
3. The egg surface is equally receptive to both X and
Y bearing sperm

Primary

Male
Ext genetalia:
Penis scrotum
Glans penis
Internal genetalia:
Testis
Ductus deferens
Prostate
Seminal vesicle

Secondary Sex Characteristic

Female
Ext genetalia:
Vagina
Lab Majora
Lab. Minora
Internal genetalia:
Ovary
Oviduct
Uterus

Discovery of : Sex chromatin / BARR bodies

Sex chromatin
(-)

sex chromatin
(+)

Sex chromatin X in activation

Lyon hyphothesis
(one X chromosom in female is in
activated)
Sexual phenotype
Karyotype
Barr bodies
Male
46 XY, 47 XYY
0
47 XXY, 48 XXYY
1
48 XXXY, 49 XXXYY
2
49 XXXXY
3
Female
45
46
47
48
49

X
XX
XXX
XXXX
XXXXX

0
1
2
3
4

Disorder

Karyotype

Phenotype

Sexual
developme
nt

Kleinefelter
syndrome

47 XXY

Tall male

Infertile
atrophi

Educ
problem 65%

XYY
syndrome

47 XYY

Tall male

Normal

Normal

Trisomi X

47 XXX

Female tall

Usually
normal

Educ
problem 70%

Turner
syndrome

45 X

Short female Infertile

streak
gonads

IQ

Normal

DATA Ratcliffe, Paul (1986)

Studies on children with sex chromosome aneuploidy

F. Body

(+)

(-)

Drumstick

(-)

(+)

The Lyon Hyphothesis (1966)

One of the two X chromosomes in the cell of
normal female is genetically inactivated
The inactivated X chromosomes can be either
the maternal or paternal one in a different cells
of the same individu
The inactivation occurs early in embryonic
development and once it had occurred, remain
fixed throughout the further development of
each cell line

The four well defined syndromes associated with

sex chromosome aneuploidy are as follows:
KLEINEFELTER SYNDROME (47 XXY)
The phenotype of KS :
The patients are tall and thin with relatively long
legs
The appear physically normal until puberty
Hypogonadism obvious testis remain small
The secondary sex characteristic remain under
developed
KS patients are almost always infertile

 Half of the cases result from errors in paternal

meiosis I
One third from errors in maternal meiosis I
The remainder from error in meiosis II or from post
zygotic mitotic error leading to mosaiscism
The most common mosaic karyotype LS 46 XY/47
XXY (consequence of loss of one X chromosome in
an XXY concept during post zygotic division
IQ reduced
have educational problem/dyslexia
Testicular size below average
Gaemocomastia

47 XYY SYNDROME
Higher in the population of maximum security
prison
3% of males prisoners and mental hospital
Origin of error that leads to the XYY karyotype due
because of paternal non disjunction at meiosis III
producing YY sperm
Less common XXYY and XXXYY varianths originate
from father, in sequence with non disjunctional
events at both meiosis I and meiosis II
Fertility is normal, this syndrome have
chromosomally abnormal child

TRISOMI X 47 XXX
Trisomi X and the rarer tetrasomy (48 XXXX) and
petasomy (49 XXXXX) syndromes are the
counterpart of the female KS in the male
The tetrasomy X syndrome is associated with more
serious retardation in both physical and mental
development and the pentasomy X syndrome
usually includes severe developmental retardation
with multiple physical defects of Downs syndrome
IQ test - 70% of the patient have serious
learning problems

TURNER SYNDROME (TS)

(45 XO and variants)
Can often be identified at birth or before puberty
by their distinctive phenotype features
Incidence : 1 5000 live births
Karyotype 45 X or 45 XO with no second
chromosome either X or Y
About one quarter of TS involve mosaic
Other Karyotype
45 X
53%
45 X/46XX mosaic
15%
46 Xi (Xq)
10%
46 X / 46 Xi (Xq) mosaic
8%
46 XXq- or 46 XX q- deletions 6%
other 45 X ? Mosaic
8%

Typical abnormalities in TS
Short stature
Gonadal dysgenesis
Facies (webbed-neck)
Low posterior hair line
Widely space nipples
Renal & cardiovascular anomalies
Majority females, rarely phenotypic male

TRUE HERMAPHRODITE
+ Testicular & ovarium tissue
- Ambigous genetalia
mostly 46 XX or 46 XY (10%)
Chimeras tissue composed of mixtive XX, XY cells
Composed of cells derwed from different zygote

PSEUDOHERMAPHRODITES
+ gonadal tissue of only one sex

MALE PSEUDOHERMAPHRODITE
Karyotype : 46 XY or mosaic with an XY cell line
In either case, the external genetalia ambigious or
characteristic of the opposite chromosomal sex
Caused by dysgenesis of the gonads
During embryonal development
Abnormal in gonadotropins
Inborn errors of testosteron
Abnormality of androgen targets

FEMALE PSEUDOHERMAPHRODITE
Congenital adrenal hyperplasia, autosomal
resecive of cortisol biosynthesis
External genetalia in female fetuses
Can be masculinized excessive male female sex
hormon
Ambigious genetalia or hypospadia are frequent or
occasional features
Mental retardation abnormal facies skletal
anomalies crytorchidism, hypospadia

 Incidence : 1 20.000 live birth

Male pseudohermaphroditism one of which is an X
linked defect
Receptor function known as the complete
androgen in sensitivity syndrome (formerly known
as testicular feminization)
Appearance:
- Chromosomals males (46 XY) with apparently
normal female ext. genetalia who have a blind
vagina and no oviduct & no uterus
- Testis are present either within the abdomen or in
the ingiunal canal