Dr. Aftab Ahmad Siddiqui

1. OUTLINE HUMAN SEX
DIFFERENTIATION, APPROACH
TO AN INFANT WITH
AMBIGUOUS GENITALIA
Presentor- Dr. Bikramjit Singh
Jafra
Moderator- Dr. C.P. Sachdev

2. CONTENTS
1. Embryology of sexual development
2. Definition
3. Revised classification of DSD
4. Approach to a child with DSD
5. Investigations
6. Management
7. Take home message

3. EMBRYOLOGY OF SEXUAL
DEVELOPMENT

4. NORMAL SEXUAL
DIFFERENTIATION
• Stage 1-Establishment of
chromosomal sex at
fertilization(46,xx or
46,XY) (at conception)
• Stage 2-Development of
undifferentiated gonads
into testes or ovaries, (at
6-7 wks of gestation)
• Stage 3-Subsequent
differentiation of internal
ducts & external genitalia
(at 8-12 wks of
gestation)
• Depends upon sex
chromosome
complement of fertilizing
sperm
• Depends upon SRY gene
of y chromosome
• Depends upon
testosterone and
mullerian inhibiting
factor (mif)

5. • Dev. of female gonads is an active process –requires
– Chromosome complement of 46,XX
– Genetic factors such as DAX1
– Signaling molecule WNT-4
• Dev. Of male phenotype –requires
– Y chromosome
– An intact SRY gene
– Other genes such as SOX9, SF1, WT1 etc
• Aberrant recombinations result in
– X chromosomes carrying SRY, resulting in XX males, or
– Y chromosomes that have lost SRY, resulting in XY females

8. SUMMARY

9. DISORDERS OF SEXUAL
DEVELOPMENT

10. • Defined as a congenital condition in which development of
chromosomal, gonadal & anatomical sex is different
• Normally, the chromosomal, gonadal and
anatomic sex are in consonance with each other
• Term DSD- Preferred over older terminology such as
ambiguous genitalia, pseudohermaphroditism and intersex
• ATYPICAL OR AMBIGUOUS GENITALIA- is any case
in which the external genitalia do not appear
completely male or completely female

11. • DSD is problem of 3 G’s:-
– Genetic Sex (CHROMOSOMAL SEX)
– Gonadal Sex
– Genital Sex (PHENOTYPE SEX)
• About 1 in 4,500 infants is born with
abnormalities of the external genitalia

12. PROPOSED REVISED
NOMENCLATURE

13. PROPOSED DSD CLASSIFICATION

14. APPROACH
 History
 General physical examination
(presence of any dysmorphism)
 Gonadal examination
 Rectal examination
 Genital anatomy
 Investigation
 Management

15. H/o
• Antenatal:
– Virilization in mother may suggest androgen producing
tumor (arrhenoblastoma) or placental aromatase deficiency
– Maternal drug h/o esp. in 1st trimester (virilization)
• Birth History:
– IUGR
– Congenital malformations
• Family h/o:
– Consanguinity (AR), Unexplained neonatal death, (CAH)
Ambiguous genitalia, Infertility or unexpected changes at
puberty may suggest a genetically transmitted trait

16. • h/o FTT, poor feeding and vomiting in
early infancy- CAH
• Genito urinary malformations
• Hirsutism, amenorrhea, gynaecomastia
(AIS), Infertility
Adolescent Pt
• When ambiguity first noted?
• Any pubertal signs?

17. GENERAL PHYSICAL EXAMINATION
• Dysmorphic features (syndromes,
chromosomal) ..
• Vitals
• Anthropometry, SMR
• In adolescent -Precocious/ delayed puberty,
hirsutism,
• Hyper pigmentation of the skin due ↑↑ ACTH
• Inguinal masses/hernia ..
• Skeletal malformation ..

18. GONADAL EXAMINATION
• Gonadal size/texture
• Symmetry
• Position and descent (scrotal, inguinal,
abdominal, absent)
• Palpation commencing from ASIS down
the full length of inguinal canal
RECTAL EXAMINATION
• To palpate for presence or absence of
the uterus

19. EXTERNAL GENITALIA
EXAMINATION
In phenotypic males –Phallus
• Length and diameter phallus
• Micropenis - <-2.5 SD (<1.9 cm in term) ..
• Site of the urethral opening
• One/two orifices on the perineum
In phenotypic female- Clitoris
• >9mm cliteromegaly
• Truly enlarged clitoris is identified by the
presence of palpable corporal or erectile tissue
• In premature babies clitoris may appear enlarged
due to the relatively underdeveloped labia majora

21. Labioscrotal folds
• Assess degree of fusion – fusion
progresses from posterior to anterior
direction
• Rugosity or hyperpigmented
Anogenital ratio
• Ratio of distance between anus and
posterior fourchette divided by
distance between anus and clitoris.

22. • >0.5 s/o
– Virilization
– Some post. labial
fusion

23. Classification by Prader of the various degrees of
masculinization of the external genitalia in females
with CAH

24. INVESTIGATIONS
Multiple steps to be performed simultaneously
(mojor change- use karyotype as the starting point)
1. Karyotype, with rapid determination of sex
chromosomes (in many centers this is available within
24-48 hr)
2. Internal anatomy of patients with ambiguous genitalia
can be defined with 1 or more of the following studies:
a) Voiding cystourethrogram
b) Endoscopic examination of the genitourinary tract
c) Pelvic ultrasound; renal and adrenal ultrasound
d) Pelvic CT or MRI
e) Exploratory laparoscopy & gonadal biopsy

25. INVESTIGATIONS cont..
3. Other blood tests
a) Screen for CAH: cortisol biosynthetic precursors
and adrenal androgens (particularly 17-
hydroxyprogesterone and androstenedione for 21-
hydroxylase deficiency, the most common form)
b) Screen for androgens and their biosynthetic
precursors
c) Screen for gonadal response to gonadotropin in
patients suspected of having testicular gonads:
stimulation with injections of hCG; measure
testosterone and DHT before and after hCG
d) Molecular genetic analyses for SRY and other Y-
specific loci
e) Gonadotropin levels

28. QUES…
CASE- 1
• A full term normal delivered baby presented with mild
respiratory distress, reticular pattern &prolonged CRT with
sign of shock
• LAB reports-
– CBC-WNL
– CRP-negative
– S. Na- 128 meq/dl
– S. K- 5.4 meq/dl
– RFT- blood urea-64mg/dl
– S. Creat- 1.1
– ABG shows- met. Acidosis
– pH-7.14

29. QUES…
• KARYOTYPE = 46XX
• USG ABDOMEN = Presence of uterus
• Other tests =17 OH PROGESTERONE =
Markedly elevated
• DIAGNOSIS= 46XX FEMALE DSD WITH 21
HYDROXYLASE DEFICIENCY
• Baby was resuscitated with fluids ;
Started upon initially with injectable
hydrocort; Then on oral hydrocort &
fludrocort…

30. QUES…
CASE- 2
• A 22 day old baby was brought by mother for
routine checkup as she found unusual genitals. no
other complaints.bilaterally the folds had palpable
round body.
• Lab test- S. Na- 138; S. K – 4.4

31. QUES…
• Karyotype 46XY
• USG- Testes
• 17 Hydroxyprogesterone- N
• Testosterone/DHT ratio= normal
• Increased LH;Testosterone; & Androgen levels
• DIAGNOSIS= Complete androgen insensitivity
• Also called testicular feminisation (female
phenotype)

32. MANAGEMENT OF DSD

33. STEPS TOWARDS Mx OF DSD
1. Gender assignment
2. Sx correction of the ambiguous
genitalia
3. Hormonal T/T
4. Psychosocial support
It requires multidisciplinary team

34. GENDER ASSIGNMENT
Factors influencing gender assignment
include
1. Diagnosis
2. Genital appearance
3. Surgical options
4. Need for lifelong replacement therapy
5. Potential for fertility
6. Views of family
7. Circumstances relating to cultural
practices

35. GENDER ASSIGNMENT cont..
• Girls with CAH are fertile & must always
be assigned a female sex.
• In cases which can not be fertile, gender
assignment will depend on
– The appearance of the external genitalia
– The potential for normal sexual functioning
• True hermaphroditism  F
– Since ovarian function may be preserved &
may be fertile

36. GENDER ASSIGNMENT cont..
• Great care should be taken in
declaring a male sex considering
– Potential for reconstructive surgery
– Probability for pubertal virilization
– Response of the external genitalia to
exogenous & endog. T
– Pt with small phallus & poor response to
androgens may be reared as F

37. GENDER ASSIGNMENT cont..
• 5α-reductase M sex assignement 
pubertal virilization  penile growth
(subnormal) & male sexual identity
• Inborn errors of T biosynthesis F
effective M reconstructive surgery is
highly unlikely
• Complete Androgen Insensitivity  F
Partial A I  preferably F ..

38. RECONSTRUCTIVE SURGERY
• Goals
Cosmetic
 to make a boy’s or a girl’s genitalia look natural
 restoring sexual function
• May need repeated surgeries later in life

39. RECONSTRUCTIVE SURGERY cont..
• For girls : sexual function of organs is often not compromised
despite any ambiguous appearance.
• Depending on severity options are :
Uncovering vagina hidden under skin
Removing excess masculine tissue around the
clitoris(clitoral reduction) – done once hormone
replacement therapy has begun
Testis should be removed soon after birth if female sex of
rearing is decided ..

40. RECONSTRUCTIVE SURGERY cont..
• For boys : surgery is complicated but often successful. It
includes :
Lengthening of the incomplete penis
 Undescended testis that is to be retained is best brought
down into the scrotum at the time of initial gonadal biopsy
Correction of chordee and urethroplasty in boys with
hypospadias is usually performed between 6 and 18 months
of age

41. RECONSTRUCTIVE SURGERY cont..
• For pt with DSD who have Y-
chromosome material and
intraabdominal gonads-gonadectomy

42. HORMONE THERAPY
• Hypogonadism is common with
– Dysgenetic gonads
– Defects in sex steroid biosynthesis
– Resistance to androgens
• Hormonal induction of puberty
– Replicates the normal pubertal maturation
– Induces secondary sexual characteristics
– Growth spurt
– Optimal bone mineralization
– Psychosocial maturation

43. HORMONE THERAPY cont..
Dx
• In M
– IM depot injections of testosterone esters
– Oral testosterone undecanoate
– Transdermal preparations
• Pt. with PAIS may need
– Supraphysiological doses of testosterone ..
• F with hypogonadism
– Estrogen- to induce pubertal changes and menses
– Progestin is added
• After break through bleeding develops or
• Within 1–2 y of continuous estrogen

44. WHAT TO TELL PARENTS..??

45. PSYCHOSOCIAL SUPPORT TO
PARENTS
• Show the baby to the parents
• Counsel both parents together
• Do not commit- unless sure
What to tell the parents?
• The baby is healthy but the external genitalia is incompletely
developed & tests are necessary to determine the sex
• There are other babies with similar condition
• A No. of treatable conditions can result in atypical genetalia
• Reassurance that a good outcome can be anticipated
• How long the process of investigation will take ? Around 3-4 Wk
• Give them appt times & names of the people who will see them
• To talk about their fears of future sexual identity & sexual
orientation of their child  preferably with psychologist or social
worker
• Support when it comes to facing their friend & relatives

46. PREDICTION OF FERTILITY
• Ovaries are generally functional but
testicular tissue is generally dysgenetic
• XX patients with CAH have a reasonably
high probability of being fertile since
they have a uterus and 2 normal ovaries
• Women with 46,XX ovotesticular DSD are
occasionally fertile

47. • Pts with gonadal dysgenesis, partial AIS, 17-
OHD are infertile either because testis are
abnormal or there is no uterus
• If child has no chance of fertility and genitalia
are sufficiently well developed to function as
male, male sex of rearing is advised
• Pts with ovotesticular DSD should be raised as
female after removing the testicular tissue
and leaving the ovary in place

48. TAKE HOME MESSAGE
• DSD is a medical emergency and social
emergency
• Rule out CAH in a child who is not
growing well and presents with adrenal
crisis
• Multidisciplinary approach
• Phenotypic sex- guides investigations
• Do not commit sex/gender of rearing
unless sure

49. THANK YOU