Approach to disodred of sexual development

1. Approach to Disorders of sex
development
Dr Bhupendra Kuma Gupta
Dept of Neonatology
IPGME &R SSKM hospital

2. Definition
• Disorders of sex development (DSD) are
heterogeneous group of disorders defined by
atypical development of genetic,gonadal and
anatomic sex

3. Normal genitalia in newborn

4. DSD presentation in the newborn
• Ambiguous genitalia
• Cryptorchidism
• Unilateral cryptorchidism with hypospadias
• Penoscrotal, scrotal or perineal hypospadias
with or without microphallus

5. .
• Apparently female appearance with
clitoromegaly and/or inguinal hernia or
palpable gonad
• Asymmetry of in size, pigmentation or
rugation of labioscrotal folds
• Discordance of external genitalia with
prenatal karyotype

6. NORMAL SEX DEVELOPMENT

7. .
• Undifferentiated gonads develop in the
bilateral genital ridges around 6 weeks of
gestation and begin to differentiate by 7
weeks.
• SRY which encodes the primary testis-
determining transcription factor on the short
arm of the Y chromosome promotes the
gonads to develop into testes.

8. .

9. .
• In the XY gonad SRY expression is initiated by
WT1/GATA4/FOG which leads to the up
regulation of SOX9 expression via synergy with
NR5A1.
• Once SOX9 levels reach a critical threshold
SOX9 auto regulates its own expression.
• In the XX gonad RSPO1/WNT4 represses SOX9
expression.

10. Anatomic sex
• Refers to the external and internal genitalia
• Testis secretes two hormones critical for male
genital formation
• Anti-mullerian hormone produced by Sertoli
cells
• Testosterone produced by Leydig cells

11. Internal genitalia
• AMH causes regression of the mullerian ducts
that would otherwise become uterus,fallopian
tubes, cervix, and upper vagina.
• Testosterone prevents the regression of the
wolffian ducts and promotes their
development into the vas deferens, seminal
vesicles and epididymis.

12. .
• Mullerian duct regression and wolffian duct
development require high local concentrations
of AMH and testosterone respectively.
• Failure of a testis to develop on one side may
result in ipsilateral retention of mullerian
structures and regression of wolffian
structures

13. .

14. External genitalia
• The enzyme 5α-reductase present in high
concentration in genital skin, converts
testosterone to dihydrotestosterone (DHT).
• DHT is the primary hormone responsible for
masculinizing the external genitalia including
the genital tubercle and labioscrotal folds
which form the penis and scrotum
respectively.

15. .
• In the absence of DHT these undifferentiated
structures develop into the clitoris and labia.
• Testicular descent from the abdomen to the
inguinal ring requires insulin-like peptide 3
(INSL3) and descent from the inguinal ring into
the scrotum requires testosterone.
• Formation of normal male internal and
external genitalia under the influence of
testosterone and DHT requires functional
androgen receptors in the target tissues.

16. .

17. Time course
First trimester
• Testicular synthesis of testosterone is
stimulated by activation of the luteinizing
hormone (LH) receptor by human chorionic
gonadotropin (hCG) produced by the placenta.
• The first trimester is the only period during
which the labioscrotal folds are susceptible to
fusion.

18. .
• If a 46,XX fetus is exposed to excess
androgens during the first trimester the
clitoris and labioscrotal folds will virilize and
may appear indistinguishable from a normal
male penis and scrotum although the latter
will be empty

19. Second and third trimesters
• Testicular androgen production is stimulated
by LH from the fetal pituitary and is
responsible for penile growth, scrotal
maturation (rugation, pigmentation and
thinning) and final testicular descent.
• High intrauterine concentrations of
testosterone may influence brain
development possibly affecting later behavior
sexual orientation and gender identity

20. Classification
Chicago consensus 2006
1.46XX DSD
2.46XY DSD
3.Disorder of sex chromosome

21. 46 XX DSD
1.Disorder of ovarian development
2.Maternal or fetal androgen excess
3.Syndromic

22. .

23. 46XY DSD
1.Disodrer of testicular development
2.Disorder of androgen biosynthesis or action

24. .
• .

25. Disorder of sex chromosome
1.Turner syndrome
2.Kleinfelter syndrome
3. Mixed gondal dysgenesis

26. .
Approach to DSD

27. .
History
Maternal drug exposure
• Androgens (testosterone, danazol)
• Drugs that interfere with androgen synthesis
or action (finasteride)
• Maternal virilization during pregnancy due to
poorly controlled maternal CAH, a virilizing
adrenal or ovarian tumor

28. .
• Family history of CAH, hypospadias
cryptorchidism, infertility, pubertal delay,
corrective genital surgery,genetic syndromes,
or consanguinity.
• Death of a male family member from vomiting
or dehydration in early infancy may suggest
undiagnosed CAH

29. Physical examination
• Stretched penile length,presence of chordee
position of the urethral orifice,presence of
vaginal opening ,pigmentation and symmetry
of the scrotum or labioscrotal folds.
• Normal full-term male infant has a penile
length of at least 2.5 cm, measured stretched
from the pubic ramus to the tip of the glans
and usually 1 cm or more in width

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31. .

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34. .
• The normal full-term female infant has a
clitoris <1 cm in length and <0.5 cm in width
• Posterior fusion of the labioscrotal folds is
assessed by determining the anogenital ratio
which is the distance between the anus and
the posterior fourchette divided by the
distance between the anus and the base of
the phallus.
• An anogenital ratio >0.5 indicates first-
trimester androgen exposure

35. .
• Gonadal size, position, and descent should be
noted.
• A gonad below the inguinal ligament is usually
a testis (normal or dysgenetic) but may be an
ovotestis or even a uterus herniating into the
inguinal canal.
• Abnormal genital development with bilateral
nonpalpable gonads should raise immediate
concern for salt wasting CAH

36. Severity of virilization
Prader staging

37. .

38. External masculinization score

39. Associated anomalies
• Denys-Drash syndrome (Wilms tumor and
diffuse glomerulosclerosis)
• WAGR (Wilms tumor, Aniridia, Genitourinary
anomalies and mental Retardation) syndrome
• Other conditions associated with DSD include
smith-lemli-opitz, Robinow, Antley-Bixler and
Goldenhar syndromes, campomelic dysplasia
and trisomy 13

40. .
• .
Neonate with suspected DSD
Gonads palpable
Unilateral BilateralNo
Possible undrevirilised
male XY DSD
Possible mixed gonadal
dysgenesis,ovotesticular DSD
Possible virilised
female XX DSD

41. .

42. .

43. CAH
• The most common DSD presenting in the
neonatal period is a 46,XX infant with CAH.
• The most common form of CAH (>90%) is
deficiency of 21-hydroxylase (21-OHase) caused
by mutations in CYP21A2.
• Rarer forms of CAH due to deficiency of 11β-
hydroxylase or 3β-hydroxysteroid dehydrogenase
• Individuals with CAH typically do not have
testicular tissue and therefore usually have
normally developed mullerian structures and no
wolffian structures

44. .
• Incidence of 21-OHase deficiency is 1:16,000
• Patients with salt wasting out number those
with simple virilizing CAH by 3:1.
• The male:female sex ratio is 1:1
• Females are easily detected at birth due to
abnormal genital development
• Males have normal genitalia and may be
missed on clinical exam (although hyper
pigmentation of the scrotum can be a clue).

45. .
• In an infant with 11-OHase deficiency levels
of 11-deoxycortisol and 11 deoxy
corticosterone are elevated and can cause
hypertension.
• An infant with 3β-HSD deficiency may have
mildly elevated 17-OHP on newborn screen

46. .
• First-line investigation
• Karyotyping/FISH
• Serum electrolytes,RBS
• USG for Mullerian structures and gonads
• Sr 17-OHP

47. Interpretation of 17-OHP
1.Unaffected <15 nmol/L
2.21 hydroxylase deficiency > 300-800 nmol/L
3. 11 beta OH and 3 beta OH deficiency 15-100
nmol/L
Prematurity ,sampling prior to 48 hours of life
and neonatal stress can cause 17-OHP as high as
100 nmol/L

48. Pelvic ultrasonography
• Determine whether uterus is present.
• Testes can often be visualized by ultrasound
but ovaries are less likely to be identified.
• Given the association between urologic and
genital malformations, ultrasonographic
evaluation should include the kidneys, ureters,
and bladder.
• Adrenal hyperplasia can often be found in
babies with CAH but is not diagnostic

49. .
Second line investigations
• Sr testosterone,dihydrotestosterone
• FSH,LH
• AMH
• 11-deoxycortisol
• HCG stimulation test
• Genitogram and laproscopy

50. Management
Gender assignment
• After the preliminary investigations and karyotyping
1. Female assignment 
a. 46 XX and CAH
b. Complete AIS
• Male assignment
a.5 alpha reductase deficiency
b.17 beta HSD 3 deficiency

51. .
For ovotesticular DSD
• Difficult to assign gender in the neonatal
period
• Multiple factors have to be taken into account
including anticipated quality of sexual
function,surgical options,fertility potential

52. CAH management
• These neonates can present as medical
emergency (salt wasting crisis)
• Salt-wasting crises usually develop between the
5th and 14th day of life but can occur as late as 1
month and may occur even in affected infants
whose virilization is not severe.
• Weight, fluid balance, and electrolytes must be
monitored closely with blood samples at least
every 2 days during the first few weeks of life to
detect hyponatremia or hyperkalemia

53. .

54. Definitive treatment DSD
Hormonal treatment
• Testosterone in case of micro phallus
• Pubertal estrogen and progestin in female
gender assignment

55. .
Surgical treatment
• Definitive surgery should only be consider
once psychological factors, adult gender
identity, fertility potential and individual own
preference of sexual activity is ensured and
discussed with reasonable level of surety

56. Prognosis
• Risk of future tumor development and fertility
are two important prognostic factor
• Risk of gonadoblastoma,dysgerminoma and
seminoma is present in XY intra abdominal
gonads
• Fertility may be possible utilising sperm retrieval
and ICSI in pt with functional gonads
• In female ovulation induction and embryo
transfer using donated ova have been used in
CAH and Turner syndrome

57. .
Thank u