A simplified approach to disorders of sexual differentitation

1. DSD
MAJ PULKIT AGARWAL1

2. NORMAL SEXUAL DIFFERENTIATION
Three steps-
1. Establishment of chromosomal sex at
fertilization(46,XX or 46,XY)
2. Development of undifferentiated gonads into testes
or ovaries
3. Subsequent differentiation of internal ducts &
external genitalia as a result of endocrine functions
associated with the gonad present
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3. HOW TO ASSIGN GENDER
• Genetic Sex (Karyotype)
• External Genitalia
• Gonads/reproductive organs
• Psychosocial
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4. 4

5. 5

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7. DISORDERS OF SEXUAL DIFFERENTIATION
• When the external genitalia do not have the
typical anatomic appearance of normal male
or female genitalia.
• Infants with ambiguous genitalia have genes
of either a male or female, but with some
additional characteristics of opposite sex.
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8. 9

9. CAUSES OF DSD
• 46XX DSD
• 46XY DSD
• Disorders of Gonadal Differentiation
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10. 46,XX DSD
• Previously known as female-
pseudohermaphrodites
• Normal ovaries
• Internal female organs are present
• Variable degrees of virilisation of the external
genitalia
• Causes
– CAH
– Placental Aromatase Deficiency
• Both mother and infant are virilised
– Maternal Androgen excess
• Maternal CAH, Virilizing tumors, drugs 11

11. CAH
• 21 Hydroxylase deficiency in >90% (mutation in
CYP21A2)
• 11 β Hydroxylase or 3 β Hydroxysteroid
dehydrogenase deficiency is rare
• Easily detected in females
• Males: hyperpigmentation of scrotum
• Salt wasting: simple virilizing = 3:1 (d/f by PRA
and Aldosterone level)
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12. 13

13. 46 XY DSD
• Incomplete masculinization in a male
• Causes
– Testicular unresponsiveness to hCG & LH
– Disorders of testosterone synthesis
• 17 α hydroxylase deficiency, 17-20 lyase deficiency etc
– Disorders of testosterone metabolism
• 5 α reductase deficiency
– End organ resistance
• PAIS, CAIS
– Vanishing testes syndrome
– Lack of AMH receptor ( Persistent Mullerian Duct
Syndrome)
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14. GONADAL DIFFERENTIATION DISORDERS
• Ovotesticular DSD (True hermaphroditism)
– 46XX (70%), 46 XY (10%), mosaics
– Internal structures may be mullerian or wolffian
depending upon local presence of testosterone/AMH
– Histology of gonads is diagnostic: should contain both
testicular and follicle containing ovarian tissue
• Mixed Gonadal Dysgenesis (MGD)
– 45X/46 XY
– Testes on one side, streak gonad/dysgenetic testes on
other side
– Asymmetric external genitalia + single palpable testis,
but can vary widely 15

15. • 46XY Complete Gonadal Dysgenesis (CGD)
– Swyer Syndrome
– Complete sex reversal
– Abnormal functioning of SRY leads to incomplete
testicular differentiation
– B/l streak gonads, internal structures are female
– Raised as females, usually diagnosed at puberty
• 46XX Testicular DSD
– Phenotypically male, fail to attain puberty due to
inadequate testosterone secretion
– Translocation of SRY to X chromosome
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16. 17

17. Gonadal and chromosomal
characteristics of DSD
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18. EVALUATION
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19. HISTORY
Family history
• CAH:Neonatal death (male baby with
vomiting/dehydration)
• Hypospadias/ cryptorchidism
• Infertility/Pubertal delay
• Consanguinity
Pregnancy history
-Placental aromatase deficiency allows fetal adrenal
androgens to virilize both mother & fetus
-Androgen secreting tumors
– Medication: Androgens, antiandrogens (finesteride,
spironolactone), estrogens
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20. PHYSICAL EXAMINATION
General Examination
– Dysmorphic features
– Evidence of salt wasting skin turgor, poor tone,
dehydration, low BP, vomiting, poor feeding
– Hyper pigmentation
– In adolescent evidence of hirsutism/ virilization
Tanner staging
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21. External Genitalia
• Phallus
– Stretched length (>2.5 cm in male term infant/ < 1cm
clitoris in female term infant)
– Chordee
– Position of orifice
• Labioscrotal folds
– Separated or fused fusion is an androgen effect
– Skin texture rugosity suggests exposure to androgens
– Color of the skin ↑↑ pigmentation may be evidence
for CAH
– Vaginal opening 22

22. Gonadal Examination
• Palpate labioscrotal tissue & inguinal canal for
presence of gonads
• Note No. of gonads, size, symmetry, position.
• Palpable gonads below the inguinal canal are almost
always testicles
• Ovotestis may be present as inguinal hernia
Rectal exam
• To palpate for presence or absence of the uterus
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23. - Complete
masculinisation
- Normal looking
hyperpigmented male
genitalia
(but no palpable testes)
A 46,XX patient
known to have
congenital adrenal
hyperplasia due to 21
α-hydroxylase
deficiency
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24. 5α-Reductase
deficiency
Boys with a small phallus
Bifid scrotum
Urogenital sinus with
perineal hypospadias, and
a blind vaginal pouch
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25. Pigmented, short,
curved phallus, central
urogenital slit,
and separated
labioscrotal testis
A 46,XY patient known
to have congenital
adrenal hyperplasia due
to 3β-hydroxy
dehydrogenase
deficiency
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26. Androgen Insensitivity Syndromes
Partial androgen insensitivity with
descended testes in bifid labioscrotal folds
Less severe partial androgen insensitivity with
severe hypospadias and maldescent of testes
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27. INVESTIGATIONS
 First Line
• Karyotype
• Electrolytes
• RFT
• 17 OHP & Testosterone
 Chromosome analysis
• FISH (SRY)
 USG pelvis, KUB
 MRI
 Genitogram/ cystoscopy
 Rarely laporoscopy & gonadal biopsy
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28. • Hormonal assays
 17 OHP
• Done after 48-72 hrs of life (normally elevated in
the 1st 2 days of life)
• False positive: prematurity, LBW, acute illness
• Normal =82-400 ng/dl
• >400 CAH
• 200-300 ACTH stimulation test
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29. 17OHP
Normal/
slight
increase
Elevated
17OHP
Increased
CAH rare
forms
Normal
CAH 21 OH
Normal
17OHP
Gonadal
Dysgenesis/
Ovotesticular
DSD/ Non CAH
DSD
Elevated
CAH 21 OH
ACTH
Intermediates
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30. • 21-hydroxylase def: ↑↑ 17-OHP
• Normal 17-OHP + 46XX  ACTH stim test
check (11-deoxycorticosterone, 11-
deoxycortisol, 17-hydroxypregnenolone ) to
detect other adrenal enzymatic defects
• 11OH: 11 deoxycortisol, 11
deoxycorticosterone ↑
• 3β HSD: 17OHP ↑, 17 OH Pregnenolone ↑↑
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31. Testosterone
Normal/ Slight
Increase
No increase,
normal T:DHT
?PAIS
Phallus increase
<2+/- 0.6
Very high
CAIS
Low
No change
Gonadal
dysgenesis/LH
receptor mutation/
Gest loss of
testes/defect of
Testosterone synth
T:DHT >20:1
5 α reductase def
T:DHT<0.8:1
17 β HSD
deficiency
HCG stimulation
HCG stimulation
Monthly
testosterone
x 3 months
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34. THANKS
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