AMBIGUOUS GENITALIADisorders of sexual differentiation

Approach to a case of

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

21-hydroxylaseAndrogens

Cortisol

Defficiency leads to shock & hyponatremia

Excess leads to viriization

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

• 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.

Case 2

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 pseudohermaphrodite

46,XX DSD

Male pseudohermaphrodite 46,XY DSD

True hermaphrodite Ovotesticular DSD

XX male 46,XX testicular DSD

XY sex reversal 46,XY complete gonadaldysgenesis

• 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, gonadaldysgenesis)

– 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

Bipotential

Gonad

2 X chromosomesReceptors

For H -Y antigen

OVARYTESTES

Present Absent

3. Differentiation of internal ducts & genitalia

Mullerian duct → Female internal organs

Wolffian duct → Male internal Organs

46,XXdisorders of sexual evelopment

(Previous female pseudohermaphroditism)

• Gonads: 2 ovaries

• Mullerian duct structures normal

• Wolffian duct structure absent

• Virlization of external genitalia

• Most common form of genital ambiguity :female with CAH due 21-OH deficiency(>90%)

• before 12 wks:LS fusion +clitorialenlargement

• Overall, CAH is the most frequent cause of ambiguous genitalia in the newborn, constituting approximately 60% of all intersex cases.

46,XXdisorders of sexual evelopment

EXCESS FETAL ANDROGENS

Congenital adrenal hyperplasia

• 21 -hydrxylase deficiency

• 11-hydroxylase deficiency

• 3ß-hydroxysteroid

dehydrogenase deficiency

EXCESS MATERNAL ANDROGENS

• Maternal androgen secreting tumours (ovary, adrenal)

• Maternal ingestion of androgenic drugs

(XY- FEMALE)

XY- FEMALE (Male pseudohermaphroditism)

Failure to produce

testosterone

• Pure XY gonadaldysgenesis (swyer’ssyndrome)

• Anatomical testicular failure (testicular regression syndrome)

• Leydig-cell agenesis

• Enzymatic testicular failure

Failure to utilize

testosterone

• 5-alpha-reductase deficiency

• Androgen receptor deficiency

* Complete androgen Insensitivity (TFS)

* Incomplete androgen 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

The external genital organs look unusual, making it impossible to identify the sex of the newborn from its outward appearance.

Any one of the following :

• A small, hypospadiac phallus and unilaterally undescendedgonad.

• An enlarged phallus with bilaterally impalpable gonads.

• An enlarged phallus and a vagina in the same infant.

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

TREATMENT• It requires multidisciplinary team including:

Endocrinologist

Gynecologist

Surgeon

Ped urologist

Psychologist

Geneticist

Radiologist

• Psychological support for the parents

• Gender assignment

• Medical treatment

• Surgical treatment