Sexual Differentation Disorders-1

ATATURK UNİVERSİTY MEDICAL FACULTY
Department of Medical Genetics
Sexual Differentiation
Disorders
2
Vakasorusu
Doç.Dr.Çiğdem Yüce Kahraman gel!rm!s
Sex Development
• Chromosomal sex: the karyotype (46,XX, 46,XY, or variants).
• Gonadal sex: the presence of a testis or ovary after the process of sex
determination.
• Phenotypic (anatomic) sex: the appearance of the external genitalia and
internal structures after the process of sex differentiation.
• Psychosexual development (“brain sex”): an unpredictable outcome of
several biologic factors, as well as environmental and social influences.
Sexual Differentiation and Determination
• The sex of an individual is determined by the X and Y chromosomes.

• The presence of an intact Y chromosome leads to maleness regardless of
the number of X chromosomes present.
• Absence of a Y chromosome results in female development.
• Although the sex chromosomes are present from conception, differentiation

into a phenotypic male or female does not commence until approximately 6
weeks.
• Up to this point both the müllerian and Wolffian duct systems are present
and the embryonic gonads, although consisting of cortex and medulla, are
still undifferentiated.
• From 6 weeks onwards, the embryo develops into a female unless the testis-
determining factor (TDF) initiates a sequence of events that prompt the
undifferentiated gonads to develop into testes.
The Testis-Determining Factor—SRY

• In 1990 it was shown that the testis-determining factor or gene is located on
the short arm of the Y chromosome close to the pseudo-autosomal region.
• This gene is now referred to as being located in the sex-determining region of
the Y chromosome (SRY).
• It consists of a single exon that encodes a protein of 204 amino acids that
include a 79-amino-acid HMG box, indicating that it is likely to be a
transcription regulator.
Partial Sex-Linkage
• Partial sex-linkage has been used in the past to account for
certain disorders that appear to exhibit autosomal dominant
inheritance in some families and X-linked inheritance in others.
• This is now known to be likely to be because of genes carried on
that portion of the X chromosome sharing homology with the Y
chromosome, and which escapes X-inactivation. During meiosis,
pairing occurs between the homologous distal parts of the short
arms of the X and Y chromosomes, the so-called pseudo-
autosomal region. As a result of a cross-over, a gene could be
transferred from the X to the Y chromosome, or vice versa,
allowing the possibility of male-to-male transmission.
• The latter instances would be consistent with autosomal
dominant inheritance. A rare skeletal dysplasia, Leri-Weil
dyschondrosteosis, in which affected individuals have short
stature and a characteristic wrist deformity (Madelung
deformity), has been reported to show both autosomal
dominant and X-linked inheritance. The disorder has been
shown to be due to deletions of, or mutations in, the short
stature homeobox(SHOX) gene, which is located in the
pseudoautosomal region.
Madelung deformity
Feet!oen
=> leads to SHOX DYSCHONDROSIS

>
-
SRUM, S
SRY-Type HMG Box (SOX) Genes
en
A family of genes known as the SOX genes shows homology with SRY by sharing a 79-
amino-acid domain known as the HMG (high-mobility group) box. This HMG domain
activates transcription by bending DNA in such a way that other regulatory factors
can bind with the promoter regions of genes that encode for important structural
proteins. These SOX genes are thus transcription regulators and are expressed in
specific tissues during embryogenesis. For example, SOX1, SOX2, and SOX3 are
expressed in the developing mouse nervous system. the most !mportant
• In humans it has been shown that loss-of-function mutations inO SOX9 on

chromosome 17 cause campomelic dysplasia.
• This very rare disorder is characterized by bowing of the long bones, sex
reversal in chromosomal males, and very poor long-term survival. In-situ
hybridization studies in mice have shown that SOX9 is expressed in the
developing embryo in skeletal primordial tissue, where it regulates type II
collagen expression, as well as in the genital ridges and early gonads.>-
skelet
d!splaz!s
• SOX9 is now thought to be one of several genes that are expressed downstream of
SRY in the process of male sex determination.
• Mutations in SOX2 (3q26) have been shown to cause anophthalmia or
microphthalmia, but also a wider syndrome of esophageal atresia and genital
hypoplasia in males: the anophthalmia-esophageal-genital syndrome.
i
Genetic model of sex determination in

humans. The formation of the
undifferentiated/bipotential gonad is
controlled by several genes acting
simultaneously, such as WT1, SF1 and Lim1.
⑳ Primary sex determination is based on the
presence of the Y chromosome and its main
sex-determining gene, SRY. In this case, SOX9,
⑳ FtzF1/SF1 and AMH expression divert the
L
O >
-
Antogel!st
etk
goster!rler
.
gonad and the reproductive tract towards the

male phenotype. This differentiation process is
regulated by several other genes, including
DAX1, GATA4, FOXL2 and, possibly, DMRT1 and
2 (not shown in the figure). In females, SRY
absence allows gonadal development towards
⑳ a female phenotype, mediated by genes such
Ant!- ...
Hormone
as DAX1, Wnt4 and SF1, resulting in aromatase
upregulation. The exact role of stra8 (not
shown) in this process remains to be clarified.
Molecular patterns of sex determination in the animal kingdom: a
comparative study of the biology of reproduction.
Manolakou P, Lavranos G, Angelopoulou R - Reproductive biology and
endocrinology : RB&E (2006)
i
Evidence that the SRY gene is the primary factor that determines
maleness comes from several observations
SRY sequences are present in XX males. These are infertile phenotypic males
who appear to have a normal 46,XX karyotype.
• Mutations or deletions in the SRY sequences are found in many XY females.
These are infertile phenotypic females who are found to have a 46,XY
karyotype.
In mice the SRY gene is expressed only in the male gonadal ridge as the testes
are developing in the embryo.
• Transgenic XX mice that have a tiny portion of the Y chromosome containing
the SRY region develop into males with testes.
• From a biological viewpoint (i.e., the maintenance of the species), it

would clearly be impossible for the SRY gene to be involved in
crossing over with the X chromosome during meiosis I.
• Hence SRY has to lie outside the pseudoautosomal region.
• However, there has to be pairing of X and Y chromosomes, as
otherwise they would segregate together into the same gamete
during, on average, 50% of meioses.
• Nature’s compromise has been to ensure that only a small portion
of the X and Y chromosomes are homologous, and therefore pair
during meiosis I.
• Unfortunately, the close proximity of SRY to the pseudoautosomal
region means that, occasionally, it can get caught up in a
recombination event.
• This almost certainly accounts for the majority of XX males, in
whom molecular and fluorescent in-situ hybridization studies show
evidence of Y-chromosome sequences at the distal end of one X-
chromosome short arm.
The distal short arms of the X and Y

chromosomes exchange material
during meiosis in the male. The
region of the Y chromosome in
which this crossover occurs is called
the pseudoautosomal region. The
SRY gene, which triggers the process
leading to male gonadal
differentiation, is located just
outside the pseudoautosomal
region. Occasionally, the crossover
occurs on the centromeric side of O
d
the SRY gene, causing it to lie on an X
olmas!na
X chromosome instead of on the Y rogmen

vor
SRY's
chromosome. An offspring receiving

this X chromosome will be an XX
male, and an offspring receiving the
Y chromosome will be an XY female.
>
-
F!shle ton!s! konur.
i
/
XX Males, XY Females, and the Genetic Basis of Sex Determination

The distal short arms of the X and Y chromosomes exchange material during
meiosis in the…
• During normal meiosis in the male, crossover occurs between the tip of the
short arm of the Y chromosome and the tip of the short arm of the X
chromosome. These regions of the X and Y chromosomes contain highly
similar DNA sequences. Because this resembles the behavior of autosomes
during meiosis, the distal portion of the Y chromosome is known as the
pseudoautosomal region. It spans approximately 2.5 Mb.
• Just centromeric of the pseudoautosomal region lies a gene known as SRY
(sex-determining region on the Y). This gene, which is expressed in
embryonic development, encodes a product that interacts with other genes
to initiate the development of the undifferentiated embryo into a male
(including Sertoli cell differentiation and secretion of müllerian-inhibiting
substance). The SRY gene product is a member of the highmobility group
(HMG) family of DNA-bending transcription factors. By bending DNA, the
protein is thought to promote DNA–DNA interactions that trigger events in
the developmental cascade leading to male differentiation. In particular,
the protein encoded by SRY interacts antagonistically with that of DAX1,
which represses genes that promote differentiation of the embryo into a
male. In the absence of SRY, DAX1 continues to repress these genes, and a
female embryo is created.
• Expression of SRY triggers off a series of events that involves other genes such
as SOX9 (17q24), leading to the medulla of the undifferentiated gonad
developing into a testis, in which the Leydig cells begin to produce
testosterone.
This leads to stimulation of the Wolffian ducts, which form the male internal
genitalia, and also to masculinization of the external genitalia.
• Masculinization of the external genitalia is mediated by dihydrotestosterone,
which is produced from testosterone by the action of 5α-reductase.
The Sertoli cells in the testes produce a hormone known as müllerian inhibitory
factor, which causes the müllerian duct system to regress.
• In campomelic dysplasia, resulting from mutated SOX9, ambiguous genitalia is
common in cases with a 46,XY karyotype.
• Ambiguous genitalia, or sex reversal, is also frequent in cases of deletion
9p24.3 syndrome. This is probably due to haploinsufficiency for the
DMRT1 gene, a transcriptional regulator expressed in Sertoli cells,
spermatogonia, and spermatocytes.
↳ erkek
-
O
st!mulat!on
• In the absence of normal SRY expression, the cortex of the

undifferentiated gonad develops into an ovary.
• The müllerian duct forms the internal genitalia. The external genitalia fail
to fuse and grow as in the male, and instead evolve into normal female
external genitalia. This normal process of female development is
sometimes referred to rather chauvinistically as the ‘default’ pathway. = Fem
Without the stimulating effects of testosterone, the Wolffian duct system

regresses.
• Normally sexual differentiation is complete by 12 to 14 weeks’ gestation,
although the testes do not migrate into the scrotum until late pregnancy.
Abnormalities of sexual differentiation are uncommon but they are
important causes of infertility and sexual ambiguity.
&O -Bu
!k! neml!
k!s!rl!k
Classification of DSD
>
- genell!kle
durumunda hastahaneye
basvurulur
.
Discordance between the chromosomal sex and the appearance of the external
genitalia. The current system for the classification of DSD was introduced in the
Chicago Consensus in 2005. There are three broad groups:
-sex chromosome DSD
-46,XX DSD
-46,XY DSD.
Sex chromosome DSD
Sex chromosome DSD includes conditions such as
-47,XXY (Klinefelter syndrome and variants),
-45,X (Turner syndrome and variants),
-45,X/46,XY (mixed gonadal dysgenesis)
-46,XX/46,XY (chimerism).
These are often identified antenatally, frequently as an incidental finding, with
confirmation of the diagnosis after birth. Antenatal diagnosis allows for focused
evaluation of the other complications often associated with these disorders, for
example, cardiac anomalies in Turner syndrome. It also provides the opportunity to
offer counselling to families prior to the birth.
46,XX DSD MC CAH
46,XX DSD encompasses disorders of gonadal development, such as

gonadal dysgenesis and disorders secondary to androgen excess.
Androgen excess during pregnancy may be endogenous (secondary to
an adrenal adenoma, dermoid cyst, Sertoli-Leydig tumor, sex cord
stromal tumor or metastatic carcinoma) or exogenous (secondary to
danazol, progestins or potassium sparing diuretics). Exogenous steroids
taken during pregnancy can also cause posterior fusion of the labia,
clitoral enlargement, and increased degrees of androgenization.
!m!
The commonest known genetic condition that leads to 46,XX DSD is CAH-
Congen!tal
↳
Adenal
due to 21α-hydroxylase deficiency and this occurs in approximately one

Hyperplas a
in 10,000 to one in 14,000 infants.

Rarer conditions include 46,XX testicular DSD which refers to a male
with testes and male genitalia, and 46,XX ovotesticular DSD which refers
to individuals that have both ovarian and testicular tissue in the gonads,
usually as ovotestes, but less commonly as separate gonads.
i
46,XY DSD
M!
Als
46,XY DSD has three broad categories:

-disorders of gonadal development,
-disorders in androgen synthesis or action and
-other causes, including hypogonadotropic hypogonadism,
> !nmem!s
--------
cryptorchidism, and isolated hypospadias.

test!s
, ↑
I
~
-
----
-
~
Girls with 46,XY DSD will most likely have androgen

insensitivity syndrome (AIS), gonadal dysgenesis or a
biochemical disorder of androgen synthesis.
46,XY DSD females (mostly AIS) is clearer, with mutations in
the AR gene found in over 80% of individuals.
Disorders of Steroid Metabolism
•The disorders of steroid metabolism include a

number of autosomal recessive inborn errors of
the biosynthetic pathways of cortisol. Virilization
>?
-
of a female fetus may occur together with salt loss

in infants of either sex from a deficiency of the
hormone aldosterone. In addition, defects of the
androgen receptor result in lack of virilization of
chromosomally male individuals.
↳ DSD
-
m
N
-
⑳
A e
- gr!le
>ens!k
Learn
Both
Congenital Adrenal Hyperplasia

(Adrenogenital Syndrome) DOC :

D!agnos!s of
Cho!ce
• The diagnosis of congenital adrenal hyperplasia (CAH) should

be considered in any newborn female - infant presenting with
virilization of the external genitalia, because this is the most
common cause of ambiguous genitalia in female newborns. 21-
Hydroxylase deficiency accounts for more than 90% of cases.
Approximately 25% have the salt-losing form, presenting in the
second or third week of life with circulatory collapse,
hyponatremia, and hyperkalemia. Less commonly, CAH is a result
of deficiency of the enzymes 11β-hydroxylase or 3β-
dehydrogenase, and very rarely occurs as a result of deficiencies
of enzymes 17α-hydroxylase and 17,20-lyase.
• Desmolase deficiency is very rare, with all pathways blocked,
causing a reversed phenotype of ambiguous genitalia in males,
and severe addisonian crises. Males with the rare 5α-reductase
deficiency are significantly under-masculinized but do not suffer
other metabolic problems and are likely to be raised as females.
At puberty, however, the surge in androgen production is
sufficient to stimulate growth of the phallus, making gender
identity and assignment problematic.
Virilized external genitalia in a

female with congenital adrenal
hyperplasia
Affected females with classic CAH are virilized from accumulation of the
adrenocortical steroids proximal to the enzyme block in the steroid
biosynthetic pathway, many of which have testosterone-like activity.
However, they have normal müllerian-derived internal organs. The
> uterus , ovor-
-
possibility of CAH should not be forgotten, of course, in male infants Y um etc
vor
.
oma
presenting with circulatory collapse in the first few weeks of life. d!sar!s!nda
pen!s vor.
• Affected infants, in addition to requiring urgent correct assignment of

gender, are treated with replacement cortisol, along with
fludrocortisone if they have the salt-losing form. Virilized females may
require plastic surgery later. Steroid replacement is lifelong and should
be increased during intercurrent illness or stress, such as surgery.
Menarche in girls with salt-losing CAH is late, menstruation irregular,
and they are subfertile.
Androgen Insensitivity Syndrome > pr!mer ammonher a

-
durumunda
get r l yor
.
Individuals with the androgen insensitivity syndrome have female external genitalia
and undergo breast development in puberty. They classically present either with
primary amenorrhea or with an inguinal hernia containing a gonad that turns out to be
a testis. Inguinal hernia is uncommon in girls and if present, especially if bilateral,
androgen insensitivity syndrome should be considered. There is often scanty
secondary sexual hair and investigation of the internal genitalia reveals an absent
uterus and fallopian tubes with a blind-ending vagina. Chromosome analysis reveals a
normal male karyotype, 46,XY.
• Androgen production by the testes is normal but androgen does not bind normally
because of an abnormal androgen receptor —the androgen receptor gene on the X
chromosome is mutated. This can be functionally assayed in skin fibroblasts. Some
individuals have incomplete or partial androgen insensitivity, and under-virilization is
variable. Affected subjects may have a female sexual orientation and are sterile.
Testes must be removed because of an increased malignancy risk, and estrogen given
for secondary sexual development and prevention of long-term osteoporosis.
i
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Sexual Differentation Disorders-1

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ATATURK UNİVERSİTY MEDICAL FACULTY

Department of Medical Genetics

Sexual Differentiation and Determination

• The sex of an individual is determined by the X and Y chromosomes.

• Although the sex chromosomes are present from conception, differentiation

The Testis-Determining Factor—SRY

=> leads to SHOX DYSCHONDROSIS

• In humans it has been shown that loss-of-function mutations inO SOX9 on

Genetic model of sex determination in

gonad and the reproductive tract towards the

• From a biological viewpoint (i.e., the maintenance of the species), it

The distal short arms of the X and Y

X chromosome instead of on the Y rogmen

chromosome. An offspring receiving

XX Males, XY Females, and the Genetic Basis of Sex Determination

• In the absence of normal SRY expression, the cortex of the

Without the stimulating effects of testosterone, the Wolffian duct system

46,XX DSD MC CAH

46,XX DSD encompasses disorders of gonadal development, such as

due to 21α-hydroxylase deficiency and this occurs in approximately one

in 10,000 to one in 14,000 infants.

46,XY DSD has three broad categories:

cryptorchidism, and isolated hypospadias.

Girls with 46,XY DSD will most likely have androgen

Disorders of Steroid Metabolism

•The disorders of steroid metabolism include a

of a female fetus may occur together with salt loss

Congenital Adrenal Hyperplasia

(Adrenogenital Syndrome) DOC :

• The diagnosis of congenital adrenal hyperplasia (CAH) should

Virilized external genitalia in a

possibility of CAH should not be forgotten, of course, in male infants Y um etc

• Affected infants, in addition to requiring urgent correct assignment of

Androgen Insensitivity Syndrome > pr!mer ammonher a

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