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 Gonadal abnormalities 150 33.3% XX pure gonadal dysgenesis 119 XY pure gonadal dysgenesis 17 11 Testicular regression 3 Sex hormones abnormalities 113 25.1％ Hyperandrogenism 56 Congenital adrenal hyperplasia 55 Excess androgen intake during early pregnancy Hypoandrogenism 14 17-hydroxygenase deficiency 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 Amenorrhea 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 development Size of clitoris, degree of labial fusion, location of gonads Pelvic examination: Vagina? Cervix? Uterus?

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 True Intersex PAIS/17OHD

Underdeveloped Genitalia Height<1.50m Underdeveloped Genitalia Ambiguous Genitalia 45,XO 45,XO/46,XY Turner’s 45,XO/46,XY Gonadal Dysgenesis

Ambiguous Genitalia Gonad below Inguinal Canal Testis Ovotestis Non-CAH True Intersex

Case Study

43-yr-old, social sex female Complains: AG, Amenorrhea, infertility PE: Absence of cervix and uterus Chromosome: 46,XY 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