Disorders of sex

development

10/09/2022 by dr wondmeneh R1 1
outline
• Introduction

• Definition

• Classification

• Specific types of DSD

• Approach to patient
10/09/2022 by dr wondmeneh R1 2
 Introduction
• 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.

10/09/2022 by dr wondmeneh R1 3
• 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.

10/09/2022 by dr wondmeneh R1 4
 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

10/09/2022 by dr wondmeneh R1 5
10/09/2022 by dr wondmeneh R1 6
Incidence

• Rates vary and approximate 1 in every 1000 to 4500

live births.

10/09/2022 by dr wondmeneh R1 7
Classification

• Former classification

(1) Gonadal dysgenesis

(2) Male Pseudohermaphroditism

(3) Female pseudohermaphroditism

(4) true hermaphroditism

10/09/2022 by dr wondmeneh R1 8
Current classification

10/09/2022 by dr wondmeneh R1 9
1) Sex Chromosome DSD

• Sex chromosome DSDs typically arise from an

abnormal number of sex chromosomes.

• turner and Klinefelter syndromes are most

frequently encountered.

10/09/2022 by dr wondmeneh R1 10
 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).

10/09/2022 by dr wondmeneh R1 11
• 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.

10/09/2022 by dr wondmeneh R1 12
Clinical feature

10/09/2022 by dr wondmeneh R1 13
10/09/2022 by dr wondmeneh R1 14
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.

10/09/2022 by dr wondmeneh R1 15
Clinical features

Hypogonadism and hypogenitalism

gynecomastia
taller stature
Infertility in almost all
Decreased IQ
Behavioral/psychiatric problems

10/09/2022 by dr wondmeneh R1 16
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.

10/09/2022 by dr wondmeneh R1 17
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.

10/09/2022 by dr wondmeneh R1 18
 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.

10/09/2022 by dr wondmeneh R1 19
• etiology

• abnormal testis development\gonadal

dysgenesis

• abnormal androgen production or action.

10/09/2022 by dr wondmeneh R1 20
 46,XY Gonadal Dysgenesis

• Under development of gonad.

• This spectrum of abnormal gonad underdevelopment
includes:

• Pure(complete)

• partial

• mixed

10/09/2022 by dr wondmeneh R1 21
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.

10/09/2022 by dr wondmeneh R1 22
 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.

10/09/2022 by dr wondmeneh R1 23
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.

10/09/2022 by dr wondmeneh R1 24
 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.

10/09/2022 by dr wondmeneh R1 25
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.

10/09/2022 by dr wondmeneh R1 26
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.

10/09/2022 by dr wondmeneh R1 27
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.

10/09/2022 by dr wondmeneh R1 28
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.

10/09/2022 by dr wondmeneh R1 29
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.

10/09/2022 by dr wondmeneh R1 30
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.

10/09/2022 by dr wondmeneh R1 31
Etiology

• abnormal ovarian development

• excess androgen exposure.

10/09/2022 by dr wondmeneh R1 32
Abnormal Ovarian Development

• Disorders of ovarian development in those with a

46,XX complement include:

• gonadal dysgenesis,

• testicular DSD,

• ovotesticular DSD.

10/09/2022 by dr wondmeneh R1 33
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.

10/09/2022 by dr wondmeneh R1 34
 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.

10/09/2022 by dr wondmeneh R1 35
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

10/09/2022 by dr wondmeneh R1 36
• Sources of excess androgen

• maternal: virilizing tumors, drugs

• Placental: placental aromatase deficiency

• Fetal: CAH

10/09/2022 by dr wondmeneh R1 37
 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)

10/09/2022 by dr wondmeneh R1 38
Etiology
• 21-hydroxylase deficiency : 95% of the case
• Other less common cause

• deficiency of 11-B—hydroxylase
• deficiency of 17—a-hydroxylase

10/09/2022 by dr wondmeneh R1 39
• 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.

10/09/2022 by dr wondmeneh R1 40
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).

10/09/2022 by dr wondmeneh R1 41
10/09/2022 by dr wondmeneh R1 42
Approach DSD

• 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.

10/09/2022 by dr wondmeneh R1 43
 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).

10/09/2022 by dr wondmeneh R1 44
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

10/09/2022 by dr wondmeneh R1 45
10/09/2022 by dr wondmeneh R1 46
10/09/2022 by dr wondmeneh R1 47
10/09/2022 by dr wondmeneh R1 48
Investigations
• Karyotyping
• R/O CAH and adrenal insufficiency
• Imaging

10/09/2022 by dr wondmeneh R1 49
Refrences

10/09/2022 by dr wondmeneh R1 50
 Thanks

10/09/2022 by dr wondmeneh R1 51