2. • discrepancy between external genitalia, gonadal and
chromosomal sex are classified as having a disorder of
sex development
• "disorders of sex development" (DSD) Manifestations
may include:
• bilateral cryptorchidism
• perineal hypospadias with bifid scrotum
• clitoromegaly
• posterior labial fusion
• phenotypic female appearance with a palpable gonad
• hypospadias and unilateral nonpalpable gonad
3. DSDs also include infants with
discordant genitalia and sex
chromosomes
• Turner syndrome (45,XO) and Klinefelter
syndrome
• 46,XY infants with palpable gonads and
simple hypospadias or microphallus, although
undervirilized, do not have truly ambiguous
genitalia
4. NORMAL SEX DEVELOPMENT
• Before 7 week both XX and XY fetuses have
similar reproductive structure
• After 7 week, fetuses bearing a Y chromosome
begin developing testes,
• thereby becoming sexually distinct from fetuses
without a Y chromosome.
• ovarian development also requires active genetic
pathways
• gonadal differentiation and function determines
the genital phenotype.
5. Multiple genes contribute to normal
sexual differentiation
• mutations in these genes can lead to various DSDs :
• Genes involved in gonadal development
• SRY
• SOX9
• SF-1
• DHH
• DAX-1
• WT-1
• WAGR syndrome
• Denys-Drash syndrome
• Frasier syndrome
6. Internal genitalia
• Wolffian (mesonephric) and Müllerian
(paramesonephric) ducts develop in both sexes
• In males, at approximately the seventh week of
gestation, testicular Sertoli cells begin secreting
Müllerian-inhibiting substance (MIS, also called
Müllerian-inhibiting hormone, and AMH, anti-
Müllerian hormone), which induces Müllerian duct
regression [ 19 ].
• In females, the lack of testosterone leads to Wolffian
duct regression and, in response to the lack of
MIS, permits Müllerian duct maturation into
oviduct, uterus, cervix, and upper vagina,
7. External genitalia
• The external genitalia become sexually distinct
at approximately the ninth week of
gestation, after Leydig cells have produced
sufficient testosterone to permit peripheral
synthesis of DHT
• 46,XY infants who lack 5-alpha-reductase type
2 are born with normally functioning testes
but undervirilized external genitalia.
8. • Male external genital morphogenesis is complete
by 12 to 16 weeks
• By 12 weeks, the non-hormone-dependent
separation of vagina and urethra is complete in
females
• Excess androgen exposure before this separation
can cause labial fusion and development of a
phallic urethra or urogenital sinus, but later
exposure causes only clitoral enlargement
and masculinization/scrotalization of labial folds.
9. CLINICAL FEATURES
• Penile length:In a term infant, at birth, the
normal penile length is ≥2.5 cm, and normal
penile diameter is ≥0.9 cm
• (micropenis) may be caused by
decreased testosterone/DHT exposure in the
second or third trimester and by deficiencies
of growth hormone or gonadotropin.
10. • Gonads : presence and position of the gonads
• In a 46,XY child, bilateral nonpalpable testes may arise
from isolated cryptorchidism, anorchia, or occur in
conjunction with persistent Müllerian duct syndrome.
In a 46,XX child, virilizing congenital adrenal
hyperplasia (CAH) should be ruled out.
• Gonads palpable below the inguinal ligament (eg, in
the labioscrotal folds) ( picture 5 ) are usually testes
• Asymmetry of the gonads or other genitalia may
indicate gonadal dysgenesis or development of both
gonadal structures namely ovary and testis, termed
ovotesticular DSD
11. • Urethral opening; A single opening at the
base of the phallus :
• an incompletely fused penile urethra
• a virilized urogenital sinus
• these findings must be confirmed either
bycystoscopy/vaginoscopy or radiographically,
12. • Clitoral size:Normal clitoral width in a neonate
ranges from 2 to 6 mm.
• lengths of more than 9 mm are unusual in
normal infants
13. Virilization :Female virilization standards for
CAH have been established by Prader based
upon the degree of virilization of the
urogenital sinus and the external genitalia
14. For assessing the development of external
genitalia in 46,XY children with DSD, the
Quigley scales have been widely used
15. • Anogenital ratio:is independent of gestational
age and body size
• distance between the anus and posterior
fourchette divided by the distance between
the anus and the base of the clitoris [ 29 ].
• A ratio of >0.5 suggests virilization with some
posterior labial fusion.
16. DIAGNOSTIC APPROACH
• A diagnosis of a disorder of sex development (DSD) should be
considered in infants who have:
• Bilaterally nonpalpable testes ( picture 1 ).
• Microphallus (stretched penile length less than 2.5 cm in a full-term
infant); microphallus without associated hypospadias is not
"ambiguous," but may be a marker of other disorders.
• Perineal hypospadias with bifid scrotum ( picture 2 ).
• Clitoromegaly (clitoral width >6 mm or clitoral length >9 mm)
( picture 3A-B ).
• Posterior labial fusion (anogenital ratio >0.5) ( picture 4 ).
• Gonads palpable in the labioscrotal folds ( picture 5 ).
• Hypospadias and unilateral nonpalpable gonad ( picture 6A-B ).
• Discordant genitalia and sex chromosomes ( picture 7 ).
17. INITIAL EVALUATION
• History:
• Prenatal exposure to androgens
(eg, progesterones, danazol , testosterone) or endocrine disrupters
( phenytoin , aminoglutethimide).
• Maternal virilization in pregnancy (placental aromatase
deficiency, luteoma).
• Family history of females who are childless or have amenorrhea
(androgen insensitivity).
• Family history of unexplained infant deaths (congenital adrenal
hyperplasia).
• History of consanguinity (or homogeneous population) (recessive
disorders, eg, CAH or disorders of androgen biosynthesis).
(See "Diagnosis and treatment of disorders of the androgen
receptor" .)
18. INITIAL EVALUATION
• Physical examination:
• inspection and palpation of the genitalia
• associated nongenital anomalies or dysmorphic
features should be documented
• Infants with congenital gonadotropin-releasing
hormone deficiency also may have cleft lip or
palate and other midline defects
• Infants with Smith-Lemli-Opitz syndrome
• Individuals with P450 oxidoreductase deficiency
19. Laboratory tests
• determination of sex chromosomes and
assessment of gonadal and adrenal steroids.
•
• karyotype:peripheral leukocytes, gonadal tissue
• Based on karyotype classification of the infant
into:
• XX DSD
• XY DSD
• Mixed sex chromosome DSD
20. • 17-hydroxyprogesterone should be measured promptly
in all infants with nonpalpable gonads
• serum electrolytes
• Next, evaluation for the SRY gene
• All infants with ambiguous genitalia should also be
tested for less common types of CAH
• Measurement of cortisol and ACTH
• measurement of Müllerian inhibiting substance (MIS)
or inhibin B and the testosterone response to
administration of hCG
• FISH probe for the SRY gene
21. Imaging
• Ultrasonography of the abdomen and pelvis
• Retrograde urethrogram
• cystoscopy/vaginoscopy
• laparoscopic visualization with gonadal biopsy
22. 46 XX DSD
• differential diagnosis:
• (CAH) 21-alpha-hydroxylase (CYP21A2) ,11-beta-
hydroxylase deficiencies and 3-beta-hydroxysteroid
dehydrogenase deficiency
• gestational hyperandrogenism, XX virilization, with
normal female internal anatomy Causes include
maternal luteoma or theca-lutein cysts, and placental
aromatase enzyme deficiency.
• testicular DSD,
• ovotesticular DSD
• Other causes:SRY translocation, SOX9 duplication
23. Algorithm for evaluation of an infant
with ambiguous genitalia and a 46,XX
karyotype (SRY-negative)*
