The document discusses disorders of sex development (DSD) including: 1. There is a community in the Dominican Republic where some males are born looking like girls but grow a penis at puberty, known as "Guevedoces", meaning "penis at twelve". This is likely due to 5α-reductase deficiency. 2. The presentation, etiology, pathogenesis, and management of various DSD conditions are reviewed including congenital adrenal hyperplasia, androgen insensitivity syndrome, and defects in testicular development. 3. Evaluation of a child with ambiguous genitalia involves a thorough history, examination, and targeted investigations to determine the diagnosis and guide management.

2. Dominican Republic is the 2nd largest
Caribbean nation after cuba

3. There is a small community in Dominican Republic
where some males are born looking like girls and grow
penis at puberty.
They are known as “ Guevedoces” means “penis at twelve” .

4. Quiz : What is the probable disorder ?
a) 21 α - hydroxylase deficiency
b) 5 α - reductase deficiency
c) Androgen insensitivity syndrome
d) Leydig cell aplasia

5. Seminar on
Disorder of Sexual
Differentiation
Presented by
Dr. Jahangir Alam
MBBS, DCH, FCPS
Child Specialist, CMH Dhaka cantonment.

6. Introduction
• The birth of a new baby is one of the most
dramatic events in a family, and the first question
is usually "is it a boy or a girl?" The newborn
infant with ambiguous genitalia is a surprise for
the doctors as well as for the parents .
• The nomenclature for such baby as 'intersex',
'hermaphrodite', and 'pseudohermaphrodite' is
out of date. So, the Chicago Consensus held in
2005 recommended new terminology based on
the umbrella term disorders of sex
differentiation (DSDs)

7. We shall discuss the topic in two parts
1st part 2nd part
1) Definition of DSD and
atypical genitalia
1) Approach to DSD
2) Incidence 2) Investigation
3) Sexual differentiation 3) Prenatal diagnosis
4) Hormonal influence on
sexual differentiation
4) Newborn screening
5) Etiologic classification of
DSD
5) Management
6) Pathogenesis 6) Follow up

8. Definition
• Disorder of sexual differentiation (DSD) :
DSD defines a condition “in which development of
chromosomal, gonadal or anatomical sex is
atypical”.
• Atypical/Ambiguous genitalia:
Atypical genitalia may be defined in a broad sense,
in any case in which external genitalia do not
appear completely male or completely female.

9. Incidence
There are limited data on the incidence of DSD.
• Overall incidence of DSDs is one in 5,500 live birth
• Congenital adrenal hyperplasia (CAH) and mixed
gonadal dysgenesis constituting approximately over
50% of all cases
• The incidence of CAH worldwide is 1:15,000
• Mixed gonadal dysgenesis is 1:10,000
Ref : Am J Hum Biol 2000;12:151-66.
: J Sex Res 2002;39:174-8

10. Revised nomenclature
Previous name Currently accepted
Intersex Disorders of sex differentiation (DSD)
Male pseudohermaphrodite 46,XY DSD
Undervirilization of an XY male 46,XY DSD
Undermasculinization of an XY male 46,XY DSD
46,XY intersex 46,XY DSD
Female pseudohermaphrodite 46,XX DSD
Overvirilization of an XX female 46,XX DSD
Masculinization of an XX female 46,XX DSD
46,XX intersex 46,XX DSD
True hermaphrodite Ovotesticular DSD
Gonadal intersex Ovotesticular DSD
XX male or XX sex reversal 46,XX testicular DSD
XY sex reversal 46,XY complete gonadal dysgenesis

11. Normal sexual differentiation
Undifferentiated gonad
SRY gene in Y chromosome Absence of
SRY gene in X chromosome
testis
Ovaries
testosterone
Absence of
testosterone and AMH
Antimullerian
hormene(AMH)
DHT
Glans
penis
Scrotum
Regression of Mullerian
Epididymis
Vas difference
Ejaculatory duct
Wollfian duct
Fallopian tubes
Uterus
Cervix
Vagina

13. Etiologic Classification of DSD
A. 46,XX DSD
1) Androgen Exposure
a) 21-Hydroxylase deficiency
b) 11β-Hydroxylase deficiency
c) 3β-Hydroxysteroid dehydrogenase II deficiency
d) Aromatase (P450arom or CYP19) deficiency
e) Glucocorticoid receptor gene mutation
f) Virilizing ovarian tumor
g) Virilizing adrenal tumor
h) Androgenic drugs
2) Disorder of Ovarian Development
a) XX gonadal dysgenesis
b) Testicular DSD (SRY+, SOX9 duplication)
3) Undetermined Origin

14. B. 46,XY DSD
1) Defects in Testicular Development
a) Denys-Drash syndrome
b) WAGR syndrome
c) XY pure gonadal dysgenesis (Swyer syndrome)
2) Deficiency of Testicular Hormones
a) Leydig cell aplasia
b) Lipoid adrenal hyperplasia deficiency;
c) 3β-HSD II deficiency
d) 17-Hydroxylase/17,20-lyase deficiency
3) Defect in Androgen Action
a) 5α-reductase II deficiency
b) Androgen insensitivity syndrome(AIS)

15. C. Ovotesticular DSD
1) XX
2) XY
3) XX/XY chimeras
D. Sex Chromosome DSD
1) 45,X (Turner syndrome and variants)
2) 47,XXY (Klinefelter syndrome and variants)
3) 45,X/46,XY (mixed gonadal dysgenesis, sometimes a
cause of ovotesticular DSD)

16. Pathogenesis

17. Congenital Adrenal Hyperplasia
1. 46 XX DSD
a) 21α-Hydroxylase (21 α-OH) deficiency
b) 11β-Hydroxylase (11β-OH) deficiency
c) 3β-Hydroxysteroid dehydrogenase II (3β- HSD II)
deficiency
2. 46 XY DSD
a) 3β-HSD II deficiency
b) 17-Hydroxylase (17α-OH) /17,20-lyase
deficiency

18. Cholesterole
Pregnenolone
Testosterone
DHT
DHEA
Androstenedione17-OH Progesterone
17-OH Pregnenolone
Deoxycortisol
Cortisol
Progesterone
Deoxycorticosterone
Corticosterone
Aldosterone Estradiole
11β-OH
21α-OH
17α-OH 17,20
lyase
3β-HSD
FIG: MAJOR PATHWAYS OF STEROID BIOSYNTHESIS

19. Cholesterole
Pregnenolone
Testosterone
DHT
DHEA
Androstenedione17-OH Progesterone
17-OH Pregnenolone
Deoxycortisol
No
Cortisol
Progesterone
Deoxycorticosterone
No
Aldosterone Estradiole
21α-OH
Na- ↓
K- ↑
Cl- ↓
Renin-↑
Hypo-
Glycaemia
&
ACTH-↑
Ambiguous
Genitalia
in girls
21α-HYDROXYLASE DEFICIENCY

20. Cholesterole
Pregnenolone
Testosterone
DHT
DHEA
Androstenedione17-OH Progesterone
17-OH Pregnenolone
Deoxycortisol
No Cortisol
Progesterone
Deoxycorticosterone
Corticosterone
No Aldosterone Estradiole
11β-OH
11β- HYDROXYLASE DEFICIENCY
Salt Retention
&
Hypertension
Hypo-
Glycaemia
&
ACTH-↑
Ambiguous
Genitalia
in girls

21. Cholesterole
Pregnenolone
Testosterone
No DHT
DHEA
Androstenedione17-OH Progesterone
17-OH Pregnenolone
Deoxycortisol
No Cortisol
Progesterone
Deoxycorticosterone
Corticosterone
No Aldosterone
No Estradiole
3β-HSD
3β- HSD DEFICIENCY
Na- ↓
K- ↑
Cl- ↓
Renin -↑
Hypo-
Glycaemia
&
ACTH-↑
Ambiguous
Genitalia
in both sex

22. Cholesterole
Pregnenolone
Testosterone
DHT
DHEA
Androstenedione17-OH Progesterone
17-OH Pregnenolone
Deoxycortisol
No Cortisol
Progesterone
Deoxycorticosterone
Corticosterone
Aldosterone
Estradiole
17α-OH 17,20
lyase
17α- HYDROXYLASE DEFICIENCY
Hypertension
K+ - ↓
Renin- ↓
Hypo-
Glycaemia
&
ACTH-↑
Sexual
Infantilism
In male

23. Aromatous deficiency
(+) Gonadotropin
Androgen
estrogen
aromatase
FSH Ovarian cyst
Cliteromegaly & Labial Fusion

24. Glucocorticoid Receptor Gene Mutation:
Defective glucocorticoid receptor (GR)
Reduced sensitivity to target tissue to glucocorticoid
↑↑Mineralocorticoid
Ambiguous genitalia in female
Male may be undervirilized
HTN
Hypokalemia

25. Defects in testicular
differentiation
• Due to deletion of short arm of Y chromosome or
SRY gene in XY fetus.
• Phenotype is female and Mullerian ducts are well
developed because of absence of AMH.
• Usually associated with various syndrome -
a) Denys-Drash syndrome: Nephropathy + ambiguous
genitalia + bilateral Wilms tumor
b) WAGR syndrome: Wilms tumor + aniridia +
genitourinary malformation + retardation
c) Campomelic syndrome: anterior bowing of femur
and tibia + small bladeless scapula + small thoracic
cavity + ambiguous genitalia.

26. Defects in testicular
differentiation contd…
d) Swyer syndrome( XY pure gonadal dysgenesis):
affected patient born with normal female
phenotype but at puberty breast development
and menarche failed to occur.
e) XY gonadal agenesis syndrome : testicular
tissue was active long enough during fetal life
but degeneration seems to occurs between 8th
and 12th fetal week. So testis are absent but the
male phenotype are complete. Also known as
“vanishing testes syndrome”

27. Defects in testicular hormone
• Leydig cell aplasia:
– Usually have female phenotype due to decrease
or absent testosterone, but mild virilization may
be present
– But uterus & fallopian tubes are absent due to
normal production of AMH.
– There are no secondary sexual changes at puberty,
pubic hair may be normal.

28. Androgen insensitivity
syndrome(AIS)
1. Complete AIS:
a. Extreme failure of virilization
b. Genetic male(XY) appears as female at birth with
unambiguous female external genitalia.
c. But vagina is shallow with blind pouch and uterus is
absent due to production of AMH from testis.
d. At puberty breast develops due to peripheral
conversion of testosterone to estrogen
e. But menstruation does not occurs
f. Discovery of testis in inguinal canal is first clue of
diagnosis

29. Androgen insensitivity
syndrome(AIS)
2. Partial AIS:
a. Unlike complete AIS, individual(XY) with partial AIS
presents with ambiguos genitalia.
b. Abundent pubic hair at puberty implies partial
resistance.
c. Some may be associated with various syndrome like
a. Reifenstein syndrome
b. Gilbet-Dreyfus syndrome
d. This is an X-linked recessive disorder, so family
history of cryptorchid relative is suggestive.
hCG stimulation test in necessary to differentiate
between leydig cell aplasia and AIS

30. 17-Ketosteroid Reductase(17β-HSD)
deficiency
• This enzymatic defect in fetus give rise to male with
complete or near complete female phenotype.
• But mullerian ducts are absent
• At puberty androstenedione converts to testosterone
at peripheral tissue and these patients
spontaneously adopt a male gender role.
Androstenedione Testosterone DHT
17β-HSD 5α-Reductase

31. 5α-reductase deficiency(SRD)
• So, boys born with ambiguous genitalia due to
impaired musculinization of male external genitalia.
• At puberty, testosterone dependent pubertal change
occurs such as
– Phallus enlargement
– Descent of inguinal testis
– Spermatogenesis
Androstenedione Testosterone DHT
17β-HSD 5α-Reductase

32. Ovotesticular DSD
(true hermaphrodite)
• In ovotesticular DSD, both ovarian and testicular
tissues are present, either in same or in opposite
gonad.
• Genotype
• 46XX - 70%
• 46XY - 10%
• 46XX/46XY- 20%
• Affected patients have ambiguous genitalia, varying
form of normal female with only slight enlargement of
the clitories to almost normal male external genitalia.
• Most frequently gonads are bilaterally ovotestis, if
unilateral contralateral gonad usually ovary but may be
a testis,

33. Approach to a child with
DSD

34. Presenting complaints

35. At birth
1. Ambiguous genitalia
a) In genotypic (XX) female
• Cliteromegaly
• Labial fusion- complete/ partial
• Labioscrotal fold
• concealed vagina
• Some affected female mistakenly presumed to
be male with hypospadiasis and cryptorchidism
b) In genotypic (XY) male:
• Small phallus
• Bifid scrotum
• Hypospadiasis
• pigmentation
• Unilateral/bilateral cryptorchidism

36. 2. Salt wasting crisis:
a) Anorexia
b) Vomiting
c) Dehydration
d) Weakness
3. Increased skin pigmentation
4. Syndromic features
a) Turner syndrome
b) Klinefelter syndrome
c) Antley-Bixler syndrome

37. Infancy/childhood
• Nephrotic syndrome - Denys-Drash syndrome
• Unexplained obesity - WAGR syndrome

38. At puberty
Further Virilization at puberty and failed to go
into puberty- Aromatase deficiency
Normal female phenotype failed menarche and
breast development at puberty- XY pure gonadal
dysgenesis, leydig cell aplasia,
Breast development normal but no menstruation
and no sex hair- AIS
No secondary sexual changes but pubic hair may
be normal- Leydig cell aplasia, partial AIS
Virilization occurs at puberty, phallus enlarges
and testis decend- 5α-Reductase deficiency.
Breast development in boys

39. History
• Family history:
– Consanguinity-- ↑↑the risk of autosomal recessive
disorders like CAH
– Sibling affected--- CAH (autosomal recessive)
– H/o of neonatal death with ambiguity-- may suggest a
missed diagnosis of CAH
– H/o infertility or amenorrhea– 46xx DSD
• Maternal history of –
– Androgen secreting tumors
– maternal H/o of of taking Progestins, Androgens etc.

40. Examination
• Dysmorphic features .
• Evidence of salt wasting skin turgor, poor tone,
dehydration, low/high BP, increased HR
• Hyper pigmentation of the skin due ↑↑ ACTH
• Hypertension: glucocorticoid receptor gene mutation,
CAH
• Abdominal masses
• Palpable gonad in groin or scrotal or labial fold
• Rectal examination: May reveal the cervix and uterus,
confirming internal Müllerian structures

41. Pigmentation

42. Examination of external genitalia
Size and degree of differentiation of the phallus / Clitoris
Glans - Well formed/Poorly formed
 Hypospadias
Fusion of Labioscrotal folds – Complete/ Partial
Pigmentation of Labioscrotal folds suggest the possibility
CAH
Scrotum- Well developed Or Poorly developed.
Search for palpable gonad/Testes.

43. Examination of External genitalia

44. Investigation

45. For critically ill patient
Investigation 21α-OH
deficiency
11β-OH
deficiency
3β-HSD
deficiency
17α OH
deficiency
S.
Electrolyte
S. Na- ↓↓
S. K - ↑↑
S. Na- ↑↑
S. K- ↓↓
S. Na- ↓↓
S. K - ↑↑
S. Na- ↑↑
S. K- ↓↓
Blood Sugar ↓↓ ↓↓ ↓↓ ↓↓

46. For determination of sex
To see internal anatomy
• Abdominal & pelvic USG to see
– Uterus
– Gonadal location
– Ovarian mass
– Kidney (wilms tumor)
– Adrenal gland - hyperplasia.
• Pelvic CT/ MRI

47. For determination of sex chromosome –
• Karyotyping
• FISH (florescent in situ hybridization) for Y
chromosome material
• PCR analysis of the SRY gene on the Y
chromosome

48. To detect the etiology
• Screen for CAH
a) 17 OHP- ↑↑
b) ACTH - ↑↑
c) S. cortisol- ↓↓
d) Androstenedione
Note: if both S. ACTH & S. cortisol both are elevated
indicates generalized glucocorticoid resistant.
• Screen for androgens and their biosynthetic
precursors

49. • Gonadotropin level (LH, FSH)
• Testosterone level
• Screen for gonadal response to gonadotropin
(testosterone response to HCG)
• to differentiate leydig cell aplasia
with AIS
• 5-α reductase deficiency(SRD)
• Ovotesticular DSD
• Testosterone:DHT ratio : >17 in SRD

50. PRENATAL DIAGNOSIS
1) In 1st trimester : Chorionic villus sampling
(DNA analysis)
2) In 2nd trimester : Amniocentesis (by DNA
analysis & 17- OHP).

51. NEWBORN SCREENING
By detection of 17-OHP in dried
blood spot.

52. Management

53. It requires multidisciplinary team including:
Endocrinologist
Gynecologist
Surgeon
Pediatric urologist
Psychologist
Geneticist
Radiologist
But paediatrician will play the pivotal role

54. Steps of treatments are
a. Initial management of shock and electrolyte
imbalance if required.
b. Counseling
c. Psycho-social and emotional support
d. Sex assignment
e. Medical management
f. Surgery
g. Follow up

55. Counseling
1) It is a psychosocial emergency that can be alleviated
by quick sex assignment and management.
2) So counseling should begin as soon as possible by
professional counselors trained in sex and gender
issues.
3) Genetic counseling about-
i. Recurrence in future pregnancy
ii. Antenatal diagnosis.
iii. Antenatal management.

56. Counseling contd…
4) Mother should informed
about life long treatment
with steroid
5) Dose of hydrocortisone
should be increased double
or triple in case of infection
or stress.
6) Bearing of Steroid Card
always with the patient who
are getting steroid
supplements.

57. Sex assignment
Assignment of gender has to be on an individual basis, and
the decision may need to include cultural considerations.
General guidelines are-
• Raise nearly all XX infants with functional ovaries as
female
• Raise most ambiguous XY infants with testes as male
unless
• external genitalia are more female than male
• marked androgen insensitivity is present
• testes are absent or defective
• Raise infants with mixed gonadal tissue, true
hermaphroditism, or other chromosomal abnormalities
as the sex most consistent with external genitalia

58. Immediate management of shock
 Correction of hypoglycemia, hypovolemia, and
hyponatremia by-
– I/V infusion of 5% glucose in 0.9% saline
@ 20 ml/kg bolus repeated if required
– I/V hydrocortisone sodium succinate
@ 10 mg for infant / 25mg for toddler/ 50mg for older
children
 Correction of hyperkalemia with
– I/V calcium,
– Sodium bicarbonate,
– Kayexalate
– I/V infusion of glucose & insulin

59. Medical management
Disease Management
CAH Steroid replacement therapy
a) Glucocorticoid replacement by
hydrocortisone
b) Mineralocorticoid replacement by
Fludrocortisone
c) For 3β-HSD deficiency I/M testosterone in
early infancy to increase the size of phallus
d) For female with 17-α OH deficiency require
estrogen replacement therapy & for male
require androgen or estrogen based on sex
of raring.
e) Anti-hypertensive therapy for 11β-OH
deficiency and 17-α OH deficiency

60. Medical management contd….
Disease Management
Aromatase
deficiency
Low dose estradiole replacement
CAIS Replacement with estrogen after removal of
testis
PAIS Testosterone enanthate/Androgen therapy
Ovotesticular
DSD
I/M testosterone for 3 month for both
diagnostic and as well as treatment
Newer
treatment for
CAH
4 drug regimen
-Hydrocortisone
-Fludrocortisone
-Testolactone
-Flutamide

61. Surgical management
After appropriate sex assignment has been made
following surgery can be done –
1) Feminizing genitoplasty (to be raised as female)
a) Clitoral resection
b) Labioplasty
c) Vaginoplasty
d) Gonadectomy
2) Masculine reconstruction (to be raised as male)
a) Orchiopexy,
b) hypospadias repair
c) Removal of retained müllerian duct structures.
Timing of surgery : between 2 and 6 months of age*
* Ref: American academy of pediatrics

62. Antenatal management
The main goal of prenatal diagnosis is to facilitate
appropriate prenatal treatment:
Mother with pregnancies at risk of CAH are given-
Dexamethasone 20µg/Kg prepregnancy maternal
weight daily in 2/3 divided doses.
Started at 6 weeks of pregnancy
Therapy is continued if affected fetus is female
diagnosed by chorionic villus sampling.

63. Complication
• Infertility
• Ovarian cyst
• Gonadoblastoma
• Nephrotic syndrome
• Growth retardation
• Mental retardation
• Psychosocial stress

64. Follow up
1. By following clinical parameter
a. Pulse
b. Blood pressure
c. Anthropometry
d. Pubertal development
2. By following investigation
a. Serum electrolyte
b. Plasma renin activity
c. Serum ACTH level
d. Serum testosterone & Estrogen level
e. FSH & LH
f. Bone age by X-ray

65. Conclusion
DSD with ambiguous genitalia required prompt
investigation and early gender assignment. The
complexity of the problem requires a
multidisciplinary team working together. Affected
patients and the parents should be provided with
full information to make an appropriate choice
for gender assignment. The aims of management
in a newborn with DSD should be the provision of
a stable gender identity with psychological
support to the family, potential sexual function
and fertility.

66. Quiz : What is the probable disorder ?
a) 21 α - hydroxylase deficiency
b) 5 α - reductase deficiency
c) Androgen insensitivity syndrome
d) Leydig cell aplasia

67. Answer
a) 21 α - hydroxylase deficiency
b) 5 α - reductase deficiency
c) Androgen insensitivity syndrome
d) Leydig cell aplasia
√

68. ConclusionThank you
Beautiful Bangladesh