2. Definition
When the external genitalia do not appear completely male or
completely female .
Incidence:1in 2000 live births
Most cases present in newborn period
Social and medical emergency
3. When to suspect
Micropenis: Stretched penile
length<2.5cm in a term newborn
Asymmetry of labioscrotal folds
A penis with B/L nonpalpable testis
U/L cryptorchidism with hypospadias
Perineoscrotal or penoscrotal
hypospadias with or without microphallus
even if testes are descended.
Apparently female external genitalia with
clitoromegaly or inguinal hernia
Overtly abnormal genitals like cloacal
exstrophy
Discordance of external genitalia with
prenatal karyotype.
4. Disorder of Sexual Differentiation(DSD)
Also known as disorder of sexual development (Nelson) is
defined as a congenital condition in which development of
chromosomal,gonadal & anatomical sex is different.
Preferred over older terminology such as ambiguous
genitalia, pseudohermaphroditism and intersex
Atypical development of genetic, gonadal and phenotypic sex
Includes disorders grouped under 4 major headings
46,XX virilized female
46,XY undervirilized male
Gonadal differentiation and chromosomal disorders
6. Incidence
The exact data on the incidence and prevalence of
conditions causing ambiguous genitalia are limited.
Congenital adrenal hyperplasia accounts for most of the
cases
Incidence of CAH 1 in 15000, AIS 1 in 20,000 (Avery’s
disease of newborn 9th ed)
7. Incidence-India
Etiology and clinical profile of ambiguous genitalia studied (n=109)
1) Genetic females with virilisation or FPH –27.5 %(n=30)
Congenital adrenal hyperplasia (CAH) was the underlying cause in all cases
of FPH
Salt wasting form - 23/30
Simple virilising form – 7/30
2) Genetic males undervirilised or MPH –52.3 %(n=57)
Androgen insensitivity syndrome - 28% (16/57)
5- alpha reductase deficiency - 23%(13/57) .
3) Disorder of gonadal differentiation- 10.1%(n=11)
Gonadal dysgenesis – 9/11
True hermaphrodite – 2/11
4) Syndromic form of ambiguous genitalia- 1.8% (n=2)
Rajesh R. Joshi, Sudha Rao, Meena Desai. Etiology and clinical profile of ambiguous genitalia-an
overview of 10 years experience. Indian Pediatrics, 2006;43:974-979.
8. Embryology
Sexual differentiation-3 stages
1. Determination of chromosomal sex (at conception)
2. Gonadal differentiation (at 6-7 wks of gestation)
3. Phenotypic sex determination (at 8-12 wks of gestation)
Stage 1 depends upon sex chromosome complement of
fertilizing sperm
Stage 2 depends upon SRY gene of Y chromosome
Stage 3 depends upon testosterone and Mullerian Inhibiting
Factor (MIF)
9. Gonad develops from
Somatic cells (arise from mesonrphric cells and coelomic
epithelium)- sertoli cells/granulosa cells
Germ cells (arise from yolk sac and migrate to genital ridge)Leydig cell/theca cell
10. Embryology
Testicular development is guided by TDF which is encoded
by the SRY gene on the short arm of the Y chromosome.
Under the influence of the TDF ,germ cells in the genital ridge
differentiate into Sertoli cells which secrete MIS (causes
regression of the mullerian ducts) and Leydig cells which
produce testosterone (promotes maturation of spermatogonia
and regulates male phenotype).
12. Embryology
In the absence of the Y chromosome , gonads differentiate
into ovaries at around 11-13 weeks gestation.
Absence of MIS leads to persistence of mullerian
structures which develop into:
Fallopian tubes
Uterus
Cervix
Vagina
15. Embryology
In males DHT leads to development of these three structures
into :
Glans penis
Scrotum
Penile shaft
In absence of DHT, these structures develop into
Clitoris
Labia majora
Labia minora
16. Embryology
True hermaphroditism have both testicular and ovarian tissue
in the gonads.
In patients with pure gonadal dysgenesis,both gonads are
streak gonads.
Patients with mixed gonadal dysgenesis have a testis on one
side and a streak gonad on the other
17.
18. History
Maternal drug ingestion esp. in 1st trimester
(androgen, antiandrogen, progestins, antiseizure medication.)
H/O virilization in mother may suggest androgen producing
tumour (adrenal or ovarian,) placental aromatase
deficiency,CAH.
Past h/o early death of infants may suggest a previously missed
androgenital deficiency
Family h/o affected sibling or family member
(CAH, hypospadias, infertility, delayed puberty
, cryptorchidism, consanguinity)
Neonatal death.
19. External genitalia Examination
Streched penis length,
width of corpora,
presence of chordee,
position of the urethral meatus,
presence of vaginal opening
pigmentation &symmetry of scrotum
&labioscrotal fold
Anogenital ratio>0.5 is an indicator of
1st trimester androgen exposure.
CAH with ambiguous genitalia
20. External genitalia Examination
Gonadal size ,position & descent should be noted a gonad
below inguinal ligament is ususally a testis.
Abnormal genital development with cliteromegaly or
apparently well formed penis with an empty scrotum should
raise concern of virilised female with CAH.
Bimanual rectal exam may reveal mullerian strucures cervix or
uterus in midline.
Associated anomalies should be noted.
(WAGR, SMITH-LEMLI-OPITZ, ROBINOW,GOLDENHAR
SYNDROME)
Ambiguous genitalia in CAH
23. Algorithm for evaluation of 46,XX DSD
Ambiguous genitalia
46 XX Karyotype
Uterus present
17 Hydroxy progesterone
Normal
Ovotestis on USG
Biopsy:
Ovarian folicles &
testicular tubules
Hermaphroditism
(Bisexual gonads)
Increased
CAH
Normal
Matrnal virilization/
Exogenous androgen exposure
Maternal virilizing disorders:
Medications: Progestins
Tumors (adrenal/ovarian)
Luteomas of pregnancy
Aromatase deficiency
24. Algorithm for evaluation of 46,XY DSD
Ambiguous genitalia
Karyotype 46 XY
USGlvis
Pelvis
No uterus
Uterus present
hCG stimulation test
N/ T & DHT:
AIS(Ar mutation
analysis)/
Idiopathic
Normal T & DHT
: 5 alpha reductase
deficiency
Gonadal biopsy:
•True hermaphordite
•Persistent mullerian duct
syndrome
T and DHT:
LH/FSH :partial gonadal dysgenesis,
leydig cell hypoplasia
Precursor steroids : T-biosynthesis
defect
25. Ultrasonography
Identify müllerian structures- uterus, ovaries, fallopian tubes
and upper half of vagina
Allows visualization of a neonate's adrenal glands - enlarged in
infants with congenital adrenal hyperplasia (CAH) - have a
cribriform appearance.
Normal ultrasonographic findings of the adrenal glands do not
exclude a diagnosis of CAH.
26. Genitography
Helps to determine ductal anatomy.
In a neonate with ambiguous genitalia, a catheter can be
inserted into the urethra - Contrast is injected to outline the
internal ductal anatomy.
Findings - normal urethral anatomy, a müllerian remnant in a
male, a common urogenital sinus, or normal female internal
genitalia
CT and MRI - may help identify internal anatomy
Endoscopic examination of genitourinary tract .
27. Genetic Evaluation
KARYOTYPE
FISH
Presence of SRY
X and Y probes for gonadal biopsies
Specialized molecular genetic tests
Mutation analysis of 21-hydroxylase gene
Androgen receptor sequencing
Y chromosome microdeletions
29. hCG stimulation test
Evaluation of gonadal axis in children
Dynamic & reliable test for leydig cell evaluation in boys
Assess testosterone secretion by testes
500 IU of hCG given i/m daily for 3 days
Serum testosterone, DHT, DHEA, androsteedione, LH & FSH
are measured at baseline and then 24 hr after 3rd day
Collection of 24 hr urine before & after three doses of hCG
used in analysis of steroid profile to detect testosterone
biosynthesis defect
30. Interpretation
2 to 20 times rise in testosterone
1)adequate rise indicates presence of functioning testes
2)if rise is blunted –enzymatic defect in testosterone synthesis,
gestational loss of testicular tissue, LH receptor mutation
3) ↑ T:DHT ratio(>20:1)- 5 alpha reductase def
Raised LH,FSH denotes anorchia or primary gonadal failure
Increased precursor steroid denotes biosynthesis defect
31. GnRH stimulation test
Assess the pituitary function and degree of pubertal maturation
in DSD
Evaluation of B/L cryptorchidism (along with hCG stimulation
test)
Method: Serum LH, FSH, estradiol, testosterone and SHBG
collected, followed by 2.5mcgm/kg GnRH iv is given, then
above samples collected at 30 and 60 min.
32. Interpretation
In normal cases FSH&LH values rise at 30 min and later
decline at 60 min
Initially there is predominant FSH response with progressive
increase in LH response with pubertal maturation
In primary gonadal failure the basal gonadotropins are
elevated with exaggerated response to GnRH
34. DSD Team Participants
Pediatrician
Medical Geneticist
Pediatric Urologist
Pediatric Endocrinologist
Gynecologist
Pediatric Psychologist
Cytogeneticist
Social Worker
35. General guidelines for gender
assignment
Try to match the baby’s sex assignment to the chromosomal
and gonadal sex if possible
Try to anticipate pubertal development
Consider future function when planning surgeries
Try to preserve fertility
Respect the opinions of well-informed parents
37. 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
38. Reconstructive surgery
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
39. Reconstructive surgery
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
40. Hormone therapy
Depending on severity of condition, hormone therapy alone
may be enough to correct the initial hormonal imbalance.
Ability of the gonads to produce appropriate hormones for sex
of rearing is a factor in sex assignment.
Advantageous to retain a gonad appropriate to the assigned sex
if it is likely to function adequately.
41. 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
42. 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
45. Congenital Adrenal Hyperplasia
Incidence – 1 in 12000
Most common cause of ambiguous genitalia in female newborn
Autosomal recessive inheritance
No sex prediliction
21-hydroxylase deficiency - common cause of CAH
Young women may present with symptoms of polycystic
ovarian syndrome
46. CAH due to 21-OH deficiency
Classic salt wasting
Classic simple
virilizing
Males
Females
Males
Females
Age at dx
Birth-6mo
Birth-1mo
2-4 yr
Birth-2yr
External
genitalia
Normal
Ambiguous
Normal
Ambiguous
Nonclassic
Males
Females
Child to adult
Normal
Usually
normal; may
have
clitoromegal
y
Aldosterone
Low
Normal
Normal
Cortisol
Low
Low
Normal
17-OHP
Basal>20,000 ng/dL
Basal> 10,000 – 20,000
ng/dL
ACTH stimulated 1,500 –
10,000 ng/dL
% of normal
0
1-2
20-50
21-OH
activity
Pediatrics Endocrinology, Mechanisms, Manifestations and Management, Ora H. Pescovitz, Erica A.
Eugster, 2004 by Lippincott Williams & Wilkins.
47. Management
Medical –
Stablisation of general condition
Correction of electrolyte abnormalities
After stabilisation – replacement of glucocorticoid and / or
mineralocorticoids depending on the general condition
Glucocorticoid replacement :
Hydrocortisone – 10-15mg/m2/d
Prednisolone – 2.5-6mg/m2/d
Mineralocorticoid replacement :
9 fluorohydrocortisone – 0.1-0.2mg/d
48. Management
Surgical –
Females with severe virilisation – early recession of clitoris
followed by vaginoplasty
Mild virilisation – medical treatment is adequate
NEWBORN SCREENING PROGRAMME
50. 5 alpha reductase deficiency
Autosomal recessive
Male have small phalus or ambiguous genitalia with with
perineoscrotal hypospadias,bifid scrotum, inguinal,labio/scrotal
testis.
Mullerian structures regress & wolffian duct derivaties
present.
At puberty they present with primary amenorrhoea and may
experience virilization
Diagnosis is done by increased testosteron to DHT ratio .
51. Treatment
Medical management –
Males – testosterone enanthenate 25 mg i.m. monthly X 3mths
may increase penile length
Females - estrogen replacement therapy should be initiated at a
bone age of 12 years or once an increase in gonadotropins is
observed
Dose is tailored to reach adult replacement levels over a 3-4
year range
52. Surgical treatment
Females
Feminizing genitoplasty - gonadectomy, restructuring of the
labioscrotal folds into labia, and reduction or recession of the
phallus
Males
Urethroplasty (Perineoscrotal hypospadias repair is typically a
multistage procedure.)
Repair of bifid scrotum
Chordee repair
Orchiopexy
53. Androgen insensitivity syndrome(AIS)
Also known as Androgen receptor defects
M/c form of male DSD
Frequency 1/20,000 genetic males
X linked recessive disorder
Two types
complete AIS
Partial AIS(k/a Reifenstein syndrome)
54. Clinical presentation
Extreme failure of virilization
Genetic male invariably reared as female since birth
Testes may be intra-abdominal/inguinal
AMH causes regression mullerian ducts.
Normal breast (due to peripheral aromatization of testosterone)
Primary amenorrhoea
Absent pubic hair
55. Investigation
Serum Gonadotropins
LH & FSH leading to testosterone &estrogen
hCG stimulation test (Twofold or greater increase in
testosterone level in response to HCG suggests normal
functioning testicular tissue and helps rule out a defect in
testosterone biosynthesis)
56. Treatment
Remove inguinal hernias
Gonadectomy before or immediately after completion of
puberty (increased risk of gonadoblastoma)
Estrogen replacement
Vaginal reconstruction or vaginoplasty may be needed
Supportive counseling for infertility
Genetic counseling for family members