3. Introduction
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• Sex differentiation is a complex process that involves
many genes.
• The key to sexual dimorphism is the Y chromosome,
which contains the testis-determining gene called
the SRY gene on its short arm.
• under SRY influence, male development occurs; in
its absence, female development is established.
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4. • Although the sex of the embryo is determined
genetically at the time of fertilization, the gonads do
not acquire male or female morphological
characteristics until the seventh week of
development.
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5. Definitions
• A group congenital conditions associated with
atypical development of internal and external
genitalia.
• Formerly, called intersex disorders
• ambiguous genitalia, describes genitalia that do not
appear clearly male or female
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10. 1) Sex Chromosome DSD
• Sex chromosome DSDs typically arise from an
abnormal number of sex chromosomes.
• turner and Klinefelter syndromes are most
frequently encountered.
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11. Turner syndrome(XO)
• is caused by de novo loss or severe structural
abnormality of one X chromosome in a phenotypic
female.
• is the most common form of gonadal dysgenesis
that leads to POF.
• Half patients have a 45,X chromosome complement
and the other half exhibit mosaicism (eg, 45X/46XX).
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12. • Maternal age is not a predisposing factor
• Turner syndrome occurs in approximately 1 in
5,000 female live births.
• In 75% of patients, the lost sex chromosome is of
paternal origin.
• 95–99% of 45,X conceptions are miscarried.
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15. Klinefelter syndrome
• phenotypically male.
• most common cause of hypogonadism and infertility in
males.
• 80% have a male karyotype with an extra chromosome X-
47,XXY.
• 20% have multiple sex chromosome aneuploidies (48,XXXY;
48,XXYY;49,XXXXY), mosaicism (46,XY/47,XXY).
• Errors in paternal nondisjunction in meiosis I account for
half the cases.
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16. Clinical features
Hypogonadism and hypogenitalism
gynecomastia
taller stature
Infertility in almost all
Decreased IQ
Behavioral/psychiatric problems
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17. Ovotesticular DSD
• Formerly called true hermaphroditism
• is found in all three DSD categories
• an ovary, testis, or ovotestis may be paired.
• Most common karyotype is 46XX
• In the sex chromosome DSD group, ovotesticular DSD
may arise rom a 46,XX/46,XY karyotype.
• The phenotypic appearance ranges rom undervirilized
male to ambiguous genitalia to turner stigmata.
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18. Mixed gonadal dysgenesis
• one type of ovotesticular DSD.
• one gonad is streak and the other is a normal or a
dysgenetic testis.
• Most have mosaic karyotype 45X/46XY.
• 46,XY karyotype is found in 15%.
• The phenotypic appearance is wide ranging, but all
patients have uterus, vagina and most have FT at
least on the side of the streak.
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19. 2) 46,XY DSD
• formerly called male pseudo hermaphroditism.
• Insufficient androgen exposure of a fetus destined to
be a male.
• testes are frequently present.
• have a small phallus that is inadequate for sexual
function.
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20. • etiology
• abnormal testis developmentgonadal
dysgenesis
• abnormal androgen production or action.
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21. 46,XY Gonadal Dysgenesis
• Under development of gonad.
• This spectrum of abnormal gonad underdevelopment
includes:
• Pure(complete)
• partial
• mixed
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22. pure gonadal dysgenesis
• Formerly named Swyer syndrome
• Results from a mutation in SRY or in another gene
with testis-determining effects (DAX1, SF-1, CBX2)
• This leads to underdeveloped dysgenetic gonads
that fail to produce androgens or AMH.
• creates a normal prepubertal female phenotype and
a normal müllerian system due to absent AMH.
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23. Partial gonadal dysgenesis
• defines those with gonad development intermediate
between normal and dysgenetic testes.
• Depending on the percentage of underdeveloped
testis, wolffian and müllerian structures and genital
ambiguity are variably expressed.
• at leat one gonad is dysgenetic or streak.
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24. Abnormal Androgen Production or
Action
• In some cases, 46,XY DSD may stem from
abnormalities in:
(1) AMH function
(2) testosterone biosynthesis,
(3) luteinizing hormone (LH) receptor function,
(4) androgen receptor action.
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25. Isolated deficiency MIS
• Also called persistent mullerian duct syndrome(PMDS)
• a rare disorder in which there is no production of MIS.
• the genitalia are normal for a male, but there are
varying degrees of remnants of the muIIerian system.
• The most common presentation is a phenotypic male
with an inguinal hernia on one side and impalpable
contralateral gonad.
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26. Androgen insensitivity syndrome [AIS].
• there is a lack of androgen receptors or failure of
tissues to respond to receptor DHT complexes.
• Consequently, androgens produced by the testes
are ineffective in inducing differentiation of male
genitalia.
• these patients have testes and MIS is present.
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27. Complete androgen insensitivity
syndrome [CAIS]
• Also called testicular feminization syndrome.
• appear as phenotypically normal females at birth
• often present at puberty with primary
amenorrhea.
• vagina is shortened or blind ending; and the
uterus and FT are absent.
• testes are frequently found in the inguinal or IabiaI
regions, but spermatogenesis does not occur.
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28. Partial androgen insensitivity
syndrome [PAIS]
• ambiguous genitalia may be present, including
clitoromegaly or a small penis with hypospadias.
• Testes are usually undescended in these cases.
• associated with varying degrees of virilization
and genital ambiguity.
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29. 5-a-Reductase deficiency
• inability to convert testosterone to DHT.
• Without DHT, external genitalia do not develop
normally and may appear male but underdeveloped
with hypospadias, or may appear female with
clitoromegaly.
• Extreme virilization at puberty due to direct action of
testestrone.
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30. Deficient testosterone biosynthesis,
• Any defect in the production of testosterone from
cholesterol leads to ambiguous genitalia and
symptoms of CAH.
• hCG/LH receptor abnormalities within the testes
can lead to Leydig cell aplasia/hypoplasia and
impaired testosterone production.
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31. 3) 46,XX DSD
• Individuals with 46,XX DSD are females that
have been exposed to excessive amounts of
androgenic compounds that masculinize the
external genitalia causing them to be
ambiguous.
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33. Abnormal Ovarian Development
• Disorders of ovarian development in those with a
46,XX complement include:
• gonadal dysgenesis,
• testicular DSD,
• ovotesticular DSD.
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34. 46,XX Gonadal dysgenesis
• similar to turner syndrome, streak gonads develop.
• These lead to hypogonadism, prepubertal normal
female genitalia, and normal müllerian structures,
but other turner stigmata are absent.
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35. 46,XX Testicular DSD
• Defects may stem from SRY translocation onto one X
chromosome.
• SRY guides the gonad to develop along testicular lines.
• Production of AMH prompts müllerian system regression.
• androgens promote development of the wolffian system
and external genitalia masculinization.
• Spermatogenesis, is absent due to a lack o certain genes
on the long arm of the Y chromosome.
• Diagnosed at puberty or infertility evaluation.
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36. Androgen Excess
• Previously termed female pseudohermaphroditism.
• Excessive fetal androgen exposure may result in
discordant between gonadal gene and phenotypic
appearance of external genitalia.
• 3 commonly affected structures by
• Clitoris
• Labioscrotal folds
• Urogenital sinus
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37. • Sources of excess androgen
• maternal: virilizing tumors, drugs
• Placental: placental aromatase deficiency
• Fetal: CAH
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38. Congenital adrenal hyperplasia
• most common cause of ambiguous genitalia(60% of DSD).
• Individuals are genetically female [46,XX], but excessive
androstenedione produced by the adrenal glands results
in masculinization of the external genitalia.
• salt-losing adrenal crisis (hyponatremia, hyperkalemia,
and failure to thrive)
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39. Etiology
• 21-hydroxylase deficiency : 95% of the case
• Other less common cause
• deficiency of 11-B—hydroxylase
• deficiency of 17—a-hydroxylase
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40. • Defective conversion of 17-hydroxyprogesterone to
11-deoxycortisol accounts for 95% of CAH.
• This conversion is mediated by 21-hydroxylase, the
enzyme encoded by the CYP21A2 gene.
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41. Clinical features
• Female infants with classic 21-hydroxylase
deficiency are born with ambiguous genitalia
• Males with the classic non-salt-losing form who
are not identified by neonatal screening typically
present at two to four years of age with early
virilization (pubic hair, growth spurt, adult body
odor).
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43. Approach DSD
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• At birth, gender assignment of the normal newborn usually
involves a simple assessment of the external genitalia.
• a multidisciplinary DSD team that includes a pediatric
endocrinologist, geneticist, pediatric gynecologist, pediatric
urologist, and psychologist or therapist.
• DSD evaluation incorporates hormone level measurement,
imaging, cytogenetic studies, and in some cases
endoscopic, laparoscopic, and gonadal biopsy.
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44. History
• Prenatal exposure to androgens (eg, progesterones,
danazol , testosterone).
• Family history of females who are childless or have
amenorrhea (androgen insensitivity).
• Family history of unexplained infant deaths(CAH).
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45. Physical examination
• Inspection and palpation of the genitalia.
• The labioscrotal folds and inguinal region should be
palpated for gonads,
• number of urogenital openings documented.
• Measures of the phallus/clitoris
• associated non genital anomalies or dysmorphic
features should be documented
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may involve the gonads, internal duct system, or external genitalia.
the greater the aneuploidy, the more severe the mental impairment and dysmorphism..The most common aneuploidy in humans
undiagnosed until they reach adulthood because many patients are phenotypically normal until puberty. Puberty commences at the normal age, but the testes remain small. Patients develop secondary sex characters late.
These are defined by the amount of normal testicular tissue and by karyotype.
Can also be classed as chromosomal DSD if its mosic ..45x/46xy
Herniorraphy reveals a uterus and FT in the hernia sac.
Vas deferens presents bilaterally ,usually running close to the uterus because testis produce reference range testestrone.
, the paramesonephric system is suppressed, and uterine tubes and uterus are absent.
Failure to identify an internal mullerian structure in phenotypic female with an inguinal hernia should always raise the possibility of CAIS.
is an increased risk of testicular tumors, these girls develop breasts during pubertal maturation due to abundant androgen to-estrogen conversion
Dx high testestrone to DHT ratio
structures commonly affected by elevated androgen levels or ovarian development disorders are the clitoris,labioscrotal folds, and urogenital sinus.
In individuals without SRY translocation, other genes with testis-determining effects are most likely present or activated.
In affected individuals, the ovaries and female internal ductal structures such as the uterus, cervix, and upper vagina are present.
Thus, patients are potentially fertile.The external genitalia, however, are virilized to a varying degree depending on the amount and timing of androgen exposure.
. Rarely, genital ambiguity may be so profound that inappropriate sex assignment is made at birth.
