Differential Diagnosis of Ambiguous Genitalia (AG)

Tian Qin-jie

Dept. OB/GYN, PUMCH, CAMS

WHO Collaborating Centre for Training and Research in Human Reproductive Health

Determination of

newborn’s sex mostly

depends on

the appearance of

external genitalia

What’s the most common reason?

How do we find the reasons?

Disorders of Sex Development (DSD)

• Definition: DSDs are congenital conditions in which development of chromosomal, gonadal or anatomic sex is atypical– Pediatrics,2006,Nov

• The incidence of DSD is about 1/1,000 newborns– NIH, USA 2000

New classification of disorders of sex development (1996)

Numbers Ratio

Sex chromosome abnormalities： 187 41.6％ Turner’s syndrome 166

XO/XY gonadal dysgenesis 10

Super female 7

True hermaphroditism 2

46,XX/46,XY gonadal dysgenesis 1

Klinefelter syndrome 1

Gonadal abnormalities 150 33.3%

XX pure gonadal dysgenesis 119

XY pure gonadal dysgenesis 17

True hermaphroditism 11

Testicular regression 3

Sex hormones abnormalities 113 25.1％ Hyperandrogenism 56

Congenital adrenal hyperplasia 55

Excess androgen intake during early pregnancy 1

Hypoandrogenism 14

17-hydroxygenase deficiency 14

Androgen insensitivity syndrome 43

Complete type 15

Partial type 28

Total 450 100.0％

Summary of DSD

• Various types and different etiologies

• Different DSDs might have similar manifestations

• Same DSD might have different manifestation

• Complicated, easily-confused

HOW TO MAKE

A CORRECT

DIAGNOSIS AND

DIFFERENTIAL

DIAGNOSIS?

Key points

• Familiar with each disorders

• Useful clues and procedure

Manifestation of DSD

• AG is one of most common complains– At birth/puberty– 23.3% of DSD, PUMCH, 2001

• Amenorrhea• Underdeveloped breast and/or sexual

hairs• Short status

Basic Knowledge

I. The Differentiation and Development of External Genitalia

• Originates from same structure

• Depends on:– Testis differentiation

• Leydig Cells

– Androgens in genitalia during fetal development• Testosterone 5α -reductase DHT

– Function of androgen receptor (AR)

2. Degree of labium-scrotum fusion related to the timing of androgen

Under influence of high level of androgen – Before gestational 12 weeks

• tend to have more signs of virilism-girl• small penis, hypospadias or partial fusion of scrotum

– After gestational 12 weeks • Girl will only have clitomegaly

Androgen Plays the most important

role in the normal development of external

genitalia

3. Dysfunction of androgen plays the key role in AG

• Androgen excess

• Androgen deficiency

• Failure of gonadal differentiation

Classification of Ambiguous Genitalia－ 2001

Cases (N) Percent (%)

Androgen Excess -46,XX

Congenital adrenal hyperplasia (CAH) 55 52.4

Excessive intake of androgen during

early pregnancy

1 1.0

Androgen Deficiency -46,XY

Partial androgen insensitivity

syndrome (PAIS)

28 26.7

Testicular regression 3 2.9

Failure of gonadal differentiation

True hermaphroditism 13 12.4

45,X/46,XY gonadal dysgenesis 5 4.8

Total 105 100.0

Differential Diagnosis• History:

– familial diseases? – drug used during pregnancy?

• PE:– Height, axillary and pubic hairs, breast de

velopment– Size of clitoris, degree of labial fusion, loca

tion of gonads– Pelvic examination: Vagina? Cervix? Uter

us?

Differential Diagnosis

• Sex chromosome

• Serum T, E2, P; LH, FSH, PRL and 17-hydroxyprogesterone

• hCG test, ACTH test, T test, Dexamethasone test

• Laparotomy and laparoscopic examination -nature of gonads

• SRY gene, AR gene analysis

Flow Chart for

differential diagnosis

Ambiguous Genitalia

Breast Development

46,XX 46,XY

CAH PAIS/17OHDTrue Intersex

Ambiguous Genitalia

45,XO 45,XO/46,XY

Turner’s 45,XO/46,XY Gonadal Dysgenesis

Underdeveloped Genitalia

Height<1.50m

Ambiguous Genitalia

Gonad below Inguinal Canal

Testis Ovotestis

Non-CAH True Intersex

Case Study

1. 43-yr-old, social sex female

2. Complains: AG, Amenorrhea, infertility

3. PE: Absence of cervix and uterus

4. Chromosome: 46,XY

5. T:890.78ng/dl

(male:375-950, female:<50)

E:42.11pg/ml

(male:19-52, female:>75)

6. Diagnosis: PAIS

7. DD: Testicular Regression

17OHD

Summary of Contents• One center: Androgen’s key role• Two cardinal points:

– Organogenesis: male and female– Timing of androgen-12 wks

• Three classification of AG Three most common DSDs

Three clues for DD Height, Breast and Location of gonads