Consultation - Multispecialty

Evaluation of a child with

Ambiguous Genitalia

NICU - 1 day old baby with ambiguous genitalia

Pierre E. Williot, MD, FRCSC, FAAP, FACS

Pediatric Urologist
The Womens and Childrens Hospital of Buffalo
Clinical Associate Professor of Urology
University of Buffalo
Buffalo, New York, USA

Born at 39 wks via normal vaginal delivery

Uncomplicated pregnancy
Prenatal Ultrasound :
Female foetus
No abnormalities detected,
Week of test performed unknown

White Identification card

Vital signs within normal limits

No abnormal facial appearance

Abdomen: soft, no HSM, no masses

Ambiguous genitalia

4 7 weeks

9 11 weeks

No history of fertility problems or spontaneous

abortions in self or family
No ingestion of drugs

- Labio
Labio--scrotal folds
- Intermediate size phallus
- No palpable gonad
- Single meatus at the base of the phallus

Gonads
-Non palpable :
- No testicles
- Undescended testicles
-Palpable (Unilateral)
- Inguinal
I
i l : Testicle,
T ti l Dysgenetic
D
ti Gonad,
G
d
Ovo testis, Ovary
- In labiolabio-scrotal fold : Most likely a testicle

12 + weeks

- Palpable (Bilateral)
- Most likely testicles

Boy or girl ?
Na : 135 Cl : 107 K : Hemolysed
BUN : 17 Creat : 0.91
Glucose : 67

Differential diagnosis :
- 46,, XX DSD (Hypervirilized
( yp
female - Female p
pseudohemarphrodite)
p
)

Temp : 36.6 F.
Pulse : 124 RR : 24 BP : 68/39 mmHg
O2 : 100% at room air

- 46, XY DSD (Hypovirilized male - Male pseudohermaphrodite)

- 45, X/46, XY MGD DSD (Mixed gonadal dysgenesis)
- 46, XX or 46, XY or 46, XX/46, XY Ovotesticular DSD
(Hermaphrodite)

DSD squad team

- Neonatologist
- Pediatric Endocrinology
- Pediatric Urology
- Psychology
y
gy
- Geneticist

Genetic
Karyotype :
XX, XY, Mosaicism
Other chromosomic anomalies
(translocations, etc ) including SRY
Other syndromes

Investigation
- Genetic
- Biochemical
- Hormonal
- Radiologic
- Endoscopic - Surgical
- Psychologic

Biochemical / Hormonal
Electrolytes
Evaluation of the Cholesterol metabolites pathways
Evaluation of the HypothalamoHypothalamo- pituitary
pituitary-- gonadal axis
Stimulation studies
MIS
Normal values varies with age!

Insure proper hormonal balance (CAH)

Induction of puberty, Adult followfollow-up

Radiologic
Ultrasonography : Renal + Pelvic
Radiologic : Sinusography - VCUG
MRI : Pelvic structures (rarely done)

Role of the Psychologist

- Coordinator of the DSD team
- Liaison between parents and medical team members
- Educate parents as to typical development and differentiation
of the sexual/reproductive system.
- Educate parents as to how their infant/childs sexual/reproductive
system differs from the typical
- Educate parents to understand the need for the various medical
tests and procedures performed
- Answer all questions, address fears
- Provide synopsis of medical evaluation, diagnosis, treatment
and a roadmap of future medical/psychologic issues
- Long term follow up.

Initial discussions
- Meetings with both parents
Psychology - Urology - Endocrinology
- Proper terminology
your child
child- phallus - labio
childlabio--scrotal swellings, gonads, etc
- your
- We have to wait for the tests results before making any
recommendations.
- We are aware of the stressful situation and will do everything
to promptly get the answers and to communicate with
them the results of the investigation.
- It can take a long time to get the results of some of the tests.
- We work as a team.

Bladder

Vagina
Urethra

NORMAL DEVELOPMENT
MALE
DEVELOPMENT
Testes

Leydig Sertoli
Cells
Cells
T
5-R

Primitive Gonadal Cells

sry

(No sry)

No T

Epididymis, vas
deferens, ejaculatory
duct, seminal vesicles
Prostate, penis,
scrotum, genital skin

MIS
T

Praders classification

Ovaries

~day 56
Male-specific

MIS

DHT
Duct regression

FEMALE
DEVELOPMENT

Mllerian
D t
Ducts
Wolffian
Ducts

(No MIS)
(No T)

No MIS

Uterus, uterine tubes,

vagina (upper 1/3)

Duct regression

DHT Urogenital Sinus (No DHT) Vagina, labia, clitoris

and Tubercle

Hormonal involvement in sexual differentiation. MIS: Mullerian inhibiting substance; sry:

sex-determining region of Y chromosome. Primordial genital duct system: Mllerian
(female), Wolffian (male)

Laboratory Values
Day 1.5

K 5.4
Normal 17 OHOH-progesterone

Congenital Adrenal Hyperplasia

G F R
46, XY DSD
46, XX DSD

46, XY DSD

Laboratory Values
Day 1.5

K 5.4
Normal 17 OHOH-progesterone
Testosterone 165
DHT 54 (normal for males, high if female)
FSH 1.3
LH 0.3

46, XY DSD
46, XX DSD

Endocrine studies

2 windows of opportunity to measure

Testosterone
Immediately after birth (100ng/dl)
LH surge - Beginning
B i i off the
th 4th weekk off life
lif
Postnatal Testosterone surge at 2 months

Laboratory Values
Day 1.5

K 5.4
Normal 17 OHOH-progesterone
Testosterone 165
DHT 54 (normal for males, high if female)
FSH 1.3
LH 0.3

A few

46, XY

days later (8(8-9)

9)-- Karyotype : 45 XO

Day 11
-Long discussion with the family - Urology/Psychology
- Review of external appearance - ambiguous
- Review of radiologic findings - Vagina + Uterus + Horseshoe kidney
- Review of Laboratory tests and karyotype
- Normal testosterone level with 45, XO sex chromosomes
- External genital ambiguity due to the presence of testosterone
g karyotype
y yp results on 100 cells +/+/- SRY p
probe
- Need for SRY - Awaiting
- Parents comfortable with Female sex of rearing
- did research on the topic
- Questions about sexuality, fertility, menstrual cycle, size of phallus
- Need for laparoscopy + gonadectomy explained
- To do soon: decrease Testosterone influence on phallic size
- Risk of gonadal tumor
- Possibility of preserving a normal ovary if present
(Ovotesticular DSD --- but this is not compatible with 45,XO)
- Discussion of unknown factors : Sexual orientation, gender identity

Day 18
- Meeting with the family - Endocrinology/Psychology
- Review of all up to date findings
- Clarification of any information that might confuse the parents
- Confirmation of surgery
- Answering all questions from Parents

26 days
- Mom called re : swelling in the groin
- Examination : left palpable Gonad with left inguinal herniae

Karyotype

Majority of cells 45,XO

13/100 cells 46
46, XY(abnormal)

Evaluation under G.A. (day 36)

Cystoscopy - Laparoscopy

- Low confluence of the vagina

- Normal urethra and bladder
- Single vagina
- Single normal cervix

Testicle
Adrenal rest

Epididymis

Fallopian tube

Right

Streak

Left - Testicular Tissue

Streak

Left Testis High

Left

Left testis and streak

Left

Left

Genetic evaluation of the gonads

Right gonad : No growth - analysis not possible
Left gonad : 45,X/46,X, idic(Y)(pteridic(Y)(pter->q11.2::q11.2>q11.2::q11.2->pter)
(Abdnormal Y chromozome - Yq
Yq--terminus lost on both
alleles)

Diagnostic

What next ?
- Long term psychologic followfollow-up for the child
and family

45, X/46, XY(abnormal) MGD DSD

- Clitoridal reduction ?
- Induction of puberty/menstrual cycle
- Eventual vaginoplasty
- Egg donation

CAH : PrePre-natal Dx and Therapy.

Work--up of ambiguous genitalia

Work
Uterus on
Pelvic US ?

Yes

No

Gonads
Palpable?

High
17OH?
No

Yes

Yes

N
No
Karyotype

XX

XX - CAH
DSD

XX,XY
XX /XY

Mixed
Gonadal
dysgenesis

Ovotesticular
DSD

At 15 - 18 Weeks : Stop dexa. if male or un

un--affected
female (only one/eight ftus needs it!)
Outcome :
1/3 : neonate with normal genitalia
1 /3 : significantly virilized
1 /3 : some virilization

XO/XY

XY DSD

Autosomal Recessive mode of transmission

Dexamethasone started before the 10th week of
gestation can prevent female pseudopseudohermaphroditism by CAH.

Type IV CAH
or Non CAH
DSD

10

Pre--Natal Therapies
Pre
Dexamethasone update:
Start at 8 weeks - Diagnosis made at 12 weeks
Mysteries:
- How come dexamethasone is effective when
ACTH cannot be demonstrated in the fetal pituitary ?
- Treated babies are born with a responsive pituitary axis,
no Cushingoid features and normal birth weight
(Fetal resistance to dexamethasone!)
- What are the unwanted effects of prenatal dexamethasone
on the affected and non affected children?

Preimplantation Genetic Diagnosis

- During In Vitro Fertilization
- For single gene Mendelian traits

Glans
Corpus
Cavernosum

Glans

Labia Minora
Labia Majora

Uro-genital
Uro
genital sinus
Urethra
Vagina

Reclined mobilized
uro-genital sinus

11

12