Disorders of sexual development (DSD) refer to congenital conditions where chromosomal sex, gonadal sex, and anatomical sex are incongruent. DSD results from atypical development of chromosomal, gonadal or anatomical sex. Evaluation involves assessing family history, physical exam, karyotype, internal anatomy by ultrasound, and hormone levels. Management includes counseling, treatment of medical issues, determining gender of rearing, and surgery. The goal is to optimize health outcomes and psychosocial well-being for individuals with DSD.

2. • Genetic sex - chromosomes
• Anatomical sex - internal and external
genitalia
• Sexual identity - one's identity as male or
female.
Introduction

3. Definition
• Disorder of sexual development (DSD) : a
congenital discrepancy between genetic
(chromosomal ), gonadal and phenotypic sex
(external genitalia).
• The term DSD has replaced earlier used
derogatory terms like ambiguous genitala and
intersex.

4. • Pointers DSD include:
o atypical genitalia,
o peno-scrotal bypospadias,
o bilateral inguinal masses in girls (extreme
undervirilization in a boy),
o cryptorchidism in boys (extreme virlization in
girls) &
o primary amenorrhea.
DSD evaluation is not required in isolated
micropenis, penile hypospadias or prominent
clitoris.

5. Epidemiology
• Based on these criteria 1 in 3000-4000
neonates have DSD.
• The incidence of DSD in Saudi Arabia has been
estimated at 1:2,500 live births; whilst in
Egypt, it has been estimated at 1:3,000 live
births.

6. PATHOPHYSIOLOGY
• Sexual development entails development of
internal and external genital organs guided by
genetic sex.
• This involves development of gonads, production
of hormones and their action and development
of gender identity.
• Gender determination happens at conception
with XX karyotype predicting female and XY
karyotype male development.

7. XX XY
Mesoderm
(urogenital ridge) Bi-potential gonad
4-6 weeks
WTI and NRSAI genes
SRY NRSA1 gene
FOXL2 and DAX1
SOX9
6 weeks
(5ARDII)
12 weeks
Genetic sex
Gonadal sex
Phenotypic sex
genital tubercle and urogenital
sinuses
mullerian and wolfian duct
Renal adrenal
7 weeks
Estrogen
12 weeks
Estrogen

8. Adrenal glands
• Normally, the adrenal glands are responsible for
producing three different hormones:
• 1. corticosteroids,
• 2. mineralocorticoids(regulate salt and water) and
• 3. androgens, which are male sex hormones.

10. • Placental aromatase protects female fetus
and pregnant mother from androgenic effect
of DHEAS produced by fetal adrenals.
• Fetus is protected from maternal androgens
by the placental 17 beta hydroxysteroid
dehydrogenase II (17BSD II) enzyme that
converts testosterone to androstenidione.
Placenta

12. Pathophysiology
• A. Female infants Virilization:
• They have a 46,XX karyotype, are SRY-negative, and
have exclusively ovarian tissue.
• B. Inadequate virilization of male infants:
• This problem is caused by inadequate androgen
production or incomplete end organ response to
androgen.
• C. Disorders of gonadal differentiation
• True hermaphroditism. The presence of both a testis
and an ovary (or ovotestes) in the same individual
• D. Chromosome abnormalities, syndromes, and
associations.

13. ETIOLOGY
• Disorders of sexual development are
caused by abnormal gonadal
differentiation, development or function.
• Karyotype based classification helps in
understanding the etiology of DSD and
planning work-up and manager.

14. • XX DSD is the commonest form of DSD.
• This is placental, ovarian or adrenal
androgen excess.
XX DSD

15. • Adrenal etiology:
• 21 hydroxylase deficiency (21OHD), 11 hydroxylase
deficiency (11OHD), 3BHSD.
• Aromatase deficiency and P450 oxidoreductase (POR)
deficiency are associated with maternal virlization in
pregnancy.
• Maternal causes:
• Transplacental passage of androgens before 12 weeks of
gestation due to luteoma of pregnancy, androgen producing
tumor and androgen exposure in the mother causes genital
ambiguity.
• Gonadal dysgenesis:
• XX maleness is caused by SRY gene insertion in 90% cases.
• The men have normal sexual development and puberty but
small testis and azoospermia.
• SOX3, SOX9 and SOX10 over expression also causes XX
maleness.

17. XY DSD
• XY DSD represents a wide range of disorders of
testicular development, androgen production and
action .
• Disorders of gonadal development have variable
presentation with or without palpable gonads and
mullerian structures.
• Steroidogenic defects have palpable gonads without
mullerian structures reflecting normal AMH secretion.
• Despite significant advances in understanding the
pathophysiology a large number of these cases remain
unclassified.

19. • Disorders of testicular development:
• These disorders are caused by defects in
genes involved in the development of the bi-
potential gonad (WT1 and NR5A1), testis
(SRY and SOX9) and ovary (DAX1 over
expression).
• Testicular regression due to fetal vascular
insult results in anorchia.
• Mullerian structures are absent as testicular
regression usually occurs after 6 weeks of
gestation.
• These children present with small phallic size
and no palpable gonads.

21. • Disorders of testosterone production:
• These disorders are characterized by low testosterone
and high gonadotropin levels.
• Mullerian structures are absent as AMH production
is normal.
• Combined adreno-testicular defect: can present
with salt wasting (SLO, StAR, SCC, POR and 3BHSD
deficiency) or mineralocorticoid excess (17
hydroxylase deficiency).
• Isolated testicular steroidogenic defect due to
17BHSD III deficiency is associated with high
androstenedione and low testosterone level.
• LHCGR (Luteinizing Hormone/Choriogonadotropin
Receptor) defect is characterized by low testosterone
deficiency, elevated LH and normal FSH levels.
• The presentation is usually as female external
appearance with palpable gonads.

23. • Disorders of testosterone action:
• DHT mediates androgen effect on external
genitalia while testosterone maintains
wolfian structure.
• 5ARDII deficiency is associated with low
DHT despite high testosterone levels.
• Wolfian structures are normal due to
preserved testosterone effect but external
genitalia range from normal female to
phenotypic male.

24. • Androgen insensitivity syndrome (AIS) is
characterized by high DHT and testosterone
levels.
• The phenotype depends on the level on androgen
resistance.
• Complete AIS represents the extreme form of the
disease with no testosterone effect.
• Aromatization of testosterone during puberty
results in feminization.
• Neonatal presentation with palpable gonads is
characteristic.
• Mullerian structures are absent as AMH action is
normal.

26. • Inefficient AMH action:
• Decreased production or action of AMH
results in persistent mullerian duct
syndrome.
• The condition is associated with
undescended testis, inguinal hernia and
vas deferens entwined in mullerian
structure.
• The condition is associated with infertility
and testicular torsion.

27. SEX CHROMOSOME DSD
• Ovo-testicular DSD is characterized by the
presence of testicular (as confirmed by
seminiferous tubules) and ovarian (as confirmed
by oocytes) tissue in the same individual.
• Gonads could be in the form of ovary and testis
on different sides or ovo-testis.
• Genital asymmetry points to the condition.
• Karyotype is variable from 46 XX to 46 XX/XY and
46 XX/47 XXY.

28. ASSESSMENT
• DSD represents a medical and social emergency.
• The initial evaluation of the infant with
ambiguous genitalia should include:
• History
• physical examination
• evaluation of the sex chromosomes.
• assessment of internal anatomy by ultrasound
• Measurement of adrenal and gonadal steroid
secretion.
APPROACH

29. HISTORY
• Virlization in mothers during pregnancy (suggesting
aromatase and oxidoreductase deficiency or luteoma of
pregnancy) and intake of androgenic agents (progestogens,
valproate) should be noted.
• Family history of sibling death, consanguinity, infertility (in
maternal aunts indicative of X linked AIS) and delayed
puberty should be enquired.
• Genital ambiguity at birth is indicative of steroidogenic
defects, partial ÁIS or gonadal dysgenesis.
• Failure to thrive, pigmentation and salt wasting crisis
suggests congenital adrenal hyperplasia.
• Girls with primary amenorrhea and inguinal masses most
likely have complete AIS or 17BHSD deficiency.

30. EXAMINATION
• Careful examination would help exclude normal
variants like clitoromegaly due to lack of
suprapubic fat, apparent micropenis due to
buried penis, penile hypospadias and labial
adhesion.
• Further examination should include identification
of gonads, extent of labio-scrotal fusion, genital
symmetry, number of urogenital openings and
phallic size.
• Round, smooth gonads palpable below the
inguinal ring are usually testis.

31. • Ovo-testis is an irregular structure higher up
around the inguinal canal.
• Rarely globular swelling around the inguinal
region may represent prolapsed fallopian
tube.
• Careful palpation of the inguinal canal in
squatting position may be required to localize
gonads.
• Mullerian structures can be identified using
per rectal examination or pelvic ultrasound.

32. • Identification of gonads and mullerian structures
allows preliminary classification of DSD.
• Mullerian structures without palpable gonads
indicates androgen excess in a girl while palpable
gonad without mullerian structures should raise
the possibility of androgen deficiency in a boy.
• Presence of both gonads and mullerian
structures suggests gonadal dysgenesis or
inefficient AMH action.
• Absent mullerian structures and gonads could be
due to abdominal gonads or testicular regression
syndrome.

34. • Extent of labio-scrotal fusion is assessed using
prader staging where stage I indicates normal
female development and stage V normal male
appearance.
• Prader Staging was developed for virlizing
CAH and External Masculization score is more
appropriate for XY DSD.

35. • Penile length less than 2 cm and clitoral size
more than 1 cm are considered abnormal.
• The extent of labio-scrotal fusion is assessed
using anogenital ratio (ratio of distance between
anus and anterior forchette to that between anus
and posterior forchette).
• Levels greater than 0.5 suggests virlization.
• The site and number of uro-genital openings are
important for surgical management.
• Genital asymmetry points to ovo testicular DSD
or mixed gonadal dysgenesis.

36. DIAGNOSTIC WORK-UP
• Diagnostic work-up is aimed at classification
of DSD and involves ascertainment of genital
sex and work-up to pinpoint the cause.

37. • Initial assessment:
• Initial assessment depends on the time of
presentation and likely clinical diagnosis.
• Evaluation of the sex chromosomes(Karyotype)
• Assessment of internal anatomy by pelvic
ultrasound.
• Serum electrolytes.
• MRI abdomen and pelvis may be required in older
children.
• Measurement of adrenal and gonadal steroid
secretion.
• Testosterone level.
• Gonadal biopsy may be considered.

41. MANAGEMENT
• Management of DSD includes
• treatment of life threatening conditions,
• parental education,
• decision about gender of rearing and
• initiation of specific treatment.
• Multi-disciplinary team including :
• Paediatric Endocrinologist, Paediatric Surgeon,
Geneticist and social worker is required.

42. • IMMEDIATE MANAGEMENT:
• Serum electrolytes and blood glucose should
be monitored and steroid replacement
initiated in children with congenital adrenal
hyperplasia.

43. • COUNSELLING:
• Parental counselling should include detailed
information about sexual development, the
possible etiology in the child, probable gender of
rearing, long term implications including fertility
issues and need for medical and surgical
management.
• The counselling should be done in a phased
manner.
• Gender specific terms (he, she), neutral titles (it)
and layman language should be avoided.

44. • SPECIFIC MANAGEMENT:
• Specific management includes
• Steroid replacement in congenital
adrenal hyperplasia,
• Testosterone in children with biosynthetic
defects and topical DHT cream in 5ARDII.
• Gonadectomy and estrogen replacement
is indicated in complete AIS.

45. • GENDER OF REARING:
• Decision regarding gender of rearing should be taken only
after extensive evaluation.
• This is important given the significant psychosocial impact of
hormonal milieu.
• Key considerations include sexual and reproductive prospects
and feasibility of reconstruction.
• Most children with XX DSD have a prospect of fertility and
should be reared as females.
• Children with simple virilising form of CAH often present at a
late stage with male gender identity and appearance.
• Male gender of rearing with hysterectomy may be considered
in this setting.
• Male gender of rearing is recommended in most individuals
with XY DSD with the exception of complete AIS where
female gender is desirable.

47. • Surgical management:
• Clitoroplasty for XX DSD is done before one year of
age.
• Early vaginoplasty has a risk of vaginal stenosis
mandating resurgery.
• Vaginoplasty should therefore be done after puberty
with regular dilatations subsequently.
• Severely virilised individuals with XX DSD wanting
male gender of identity should undergo hysterectomy
and oophorectomy, Multi-step correction for
hypospadias and chordee is requirec in XY DSD.
• Prosthetic testis may be considered in boys with
anorchia.

48. • Consideration for gonadectomy:
• An important cause of concern in a child
with gonadal dysgenesis is the risk for
development of gonadal neoplasm
(Gonadoblastoma); XY dysgenesis with
abdominal testis.
• The risk is very low for complete AIS and
gonadal biopsy after puberty could be
sufficient.

50. THANKS FOR YOUR ATTENTION