Approach to a case of

AMBIGUOUS
Disorders GENITALIA
of sexual differentiation
Dr.Yamini Kapileshwarkar MD.(Ped)
Dept.of Pediatrics,
MP SHAH Medical College,
Jamnagar (Gujarat- India)
 A short overview of 2 cases
• A full term normal
delivered baby
presented with mild
respiratory distress,
reticular pattern and
prolonged CRT with signs
of shock.
LabReports
• CBC- WNL
• CRP- 4.5 (negative)
• S.Na+ : 128 mEq/dl
• S.K+ : 5.4 mEq/dL
• RFT: Bl.urea : 64mg/dl, S.creat: 1.1
• ABG: Metabolic Acidosis pH: 7.14
 What Next ??
• 17 Hydroxy Progesterone.- markedly elevated
• Karyotype- 46 XX
• USG abdomen- presence of uterus.
• Baby was resucitated with fluids.
• Started upon initially with injectable hydrocort.
Then on to oral Hydro cortisone + Fludro cortisone.
• Diag: 46XX Female DSD with 21 hydroxylase deff.
 21-hydrxylase deficiency-CAH
Cholesterol

Pregnenolone

Progesterone

17-OH progesterone

Excess leads to viriization

Androgens
21-hydroxylase

Defficiency leads to
Cortisol shock & hyponatremia
 DIAGNOSIS
• Fail to conserve sodium normally

• Infant present at 6-14 days

• progressive wt loss,Vomiting,refusal to
feed,dehydration,shock,pigmentation of
nipple,axilla,umbilicus & genitals(due to increased
ACTH)
 Diagnosis (cont..)
• 17-OHP : high,>50 ng/ml 24 hrs after birth
• 11-DOC elevated in CYP11B1
• Plasma renin activity & aldosterone :d/d b/w
salt wasting & simple –virlizing forms
• S electrolytes every other day until salt
wasting status determined
 MANAGEMENT

• Correction of hypovolemia & hyponatremia

• Cortisol replacement in virlized F :hydrocortisone
20mg/m2/day,q8h dosing
• Wt,fluid balance & electrolytes monitored closely
• Fludrocortisone acetate 0.05-0.2mg/day for
mineralocorticoid replkacement
 Case 2
• A 22 day old baby was
brought by mother for
routine check up as she
found genitals unusual.
• There were no other
complaints.
• Bilateraly the folds had
rounded bodies
palpable.
LabReports
• S.Na+ : 138 mEq/dl
• S.K+ : 4.4 mEq/dL
• 17 hydroxy progesterone - normal
• karyotype- 46XY
• What next ??
• Testosterone / Dihydro testosterone – normal
• Diag: ? Complete Androgen Insensitivity
 Complete Androgen Sensitivity
• Testicular Feminisation (female phenotype)
• 1 in 20-60,000 males, X-linked trait
• In utero loss of androgen, and MIS secretion means loss of
internal genitalia
• 2% of females with an inguinal hernia have Complete androgen
sensitivity
• Usually diagnosed with amenorrhea, absence of pubic hair or
hormonal profile
• Gonadectomy and Oestrogen replacement therapy
 Revised Nomenclature And Classification
Previous Revised
Female 46,XX DSD
pseudohermaphrodite

Male pseudohermaphrodite 46,XY DSD

True hermaphrodite Ovotesticular DSD

XX male 46,XX testicular DSD
XY sex reversal 46,XY complete gonadal
dysgenesis
• Sex chromosome DSD
– 45,X (Turner syndrome and variants)
– 47,XXY (Klinefelter syndrome and variants)
– 45,X/46,XY (mixed gonadal dysgenesis, ovotesticular DSD)
– 46,XX/46,XY (chimeric, ovotesticular DSD)
• 46,XY DSD
– Disorders of testicular development (complete and partial gonadal dysgenesis)
– Disorders of androgen synthesis (complete and partial androgen insensitivity,
disorders of antimüllerian hormone [AMH]/receptor, androgen biosynthesis
defect)
– Other (severe hypospadias, cloacal exstrophy)
• 46,XX DSD
– Disorders of ovarian development (ovotesticular DSD, testicular DSD, gonadal
dysgenesis)
– Androgen excess (fetal [eg, congenital adrenal hyperplasia (CAH)],
• Normal Sexual Differentiation -3 stages
1. Establishment of chromosomal sex- (XY, SRY, TDF, Y)
 2. Gonadal development
SRY-gene (TDF)
Short arm of Y chromosome
Present Absent
Bipotential
Gonad

Receptors 2 X chromosomes
For H -Y antigen

TESTES OVARY
3. Differentiation of internal ducts & genitalia
Mullerian duct → Female internal organs
Wolffian duct → Male internal Organs
 46,XX • Gonads: 2 ovaries
disorders of sexual evelopment • Mullerian duct structures normal
(Previous female
• Wolffian duct structure absent
pseudohermaphroditism)
• Virlization of external genitalia
• Most common form of genital
ambiguity :female with CAH due 21-
OH deficiency(>90%)
• before 12 wks:LS fusion +clitorial
enlargement
• Overall, CAH is the most frequent
cause of ambiguous genitalia in the
newborn, constituting approximately
60% of all intersex cases.
 46,XX
disorders of sexual evelopment
EXCESS FETAL ANDROGENS EXCESS MATERNAL ANDROGENS

Congenital adrenal hyperplasia • Maternal androgen secreting

• 21 -hydrxylase deficiency
• 11-hydroxylase deficiency
• 3ß-hydroxysteroid
dehydrogenase deficiency
tumours (ovary, adrenal)
• Maternal ingestion of
androgenic drugs
(XY- FEMALE)
 XY- FEMALE (Male pseudohermaphroditism)
Failure to produce Failure to utilize
testosterone testosterone
• Pure XY gonadal • 5-alpha-reductase
dysgenesis (swyer’s deficiency
syndrome)
• Anatomical testicular • Androgen receptor
failure (testicular deficiency
regression syndrome) * Complete androgen
• Leydig-cell agenesis Insensitivity (TFS)
• Enzymatic testicular * Incomplete androgen
failure Insensitivity
Etiology

• Defects in testicular dev

• Deficiency of testicular hormones

• Defect in androgen action

 Partial Androgen Sensitivity
(Reifenstein’s Syndrome)

• Incomplete male pseudohermaphroditism

• Ambiguous genitalia
• Incomplete: normal testosterone, LH and
testosterone/DHT ratio
 True hermaphroditism
OvotesticularDSD

• Very rare
• 90% present with ambiguous genitalia
• 2/3 raised as M
• All have urogenital sinus & most cases have uterus
• Chromosomal pattern 46,XX  75%
mosaic (XX/XY) > 46,XY
• Has both ovarian & testicular
tissue
• 1-Lateral testis on one
side & ovary on the other
• 2-Unilateral ovotestis on
one side & normal gonads on
the other
• 3-Bilateral 2 ovotestis
 Partial/Mixed gonadal dysgenesis
• 2nd most common cause of ambiguous genitalia
in the newborn
• 45,X/46,XY  M phenotype/ deficient virilization
• Testis on one side & streak gonads on the other
• Testis is dysgenetic/non sperm producing
• Unilat unicornuate uterus on the streak gonad side
• Varying degrees of inadequate musculinization
• 46XY
• Bilateral dysgenetic testes
• Uterus is present
• Inadequate virilization & cryptorchidism
• Wide range of phenotypes
• Sex of rearing F
 AMBIGUOUS GENITALIA AT BIRTH

Any one of the following :

• A small, hypospadiac phallus
and unilaterally undescended
gonad.
• An enlarged phallus with
The external genital organs bilaterally impalpable gonads.
look unusual, making it
impossible to identify the • An enlarged phallus and a
sex of the newborn from vagina in the same infant.
its outward appearance.
 Evaluation of a case
• History ( family, maternal , sibling)

• Thorough physical examination

• USG

• Rapid Karyotype
 Diagnostic tests within hours
•Baseline serum electrolytes, RFT
•Hormones
•17 hydroxyprogesterone,
•plasma renin activity,
•testosterone, dihydrotestosterone , T :DHT ratio
•gonadotropins & AMH
•Vesicourethrogram/genitogram:
•reveal vagina with cervix at its apex or utricle (MD remnant)
GENDER ASSIGNMENT
• extremely distressing for the parents
• profound pressure on the medical team to announce
gender .....however
• Postpone making a gender assignment until
sufficient information is available & the results of
investigation has enabled the most appropriate
choice of the sex of rearing
• The choice must be the result of full discussion
between parents & medical team
Management & Treatment Options Goals

• Gender assignment & identify sex of rearing

• Surgical reconstruction

• Parental counselling & prediction of fertility

• It requires multidisciplinary team including:
 Endocrinologist TREATMENT
 Gynecologist
 Surgeon
 Ped urologist
 Psychologist
 Geneticist
 Radiologist
• Psychological support for the parents

• Gender assignment

• Medical treatment

• Surgical treatment