disorder of the sex development
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Disorder of the sex Disorder of the sex developmentdevelopment
Disorder of the sex Disorder of the sex developmentdevelopment
A. LuczayA. Luczay
Sex developmentSex development
GENETICGENETIC X XX X X YX Y(chromosal)(chromosal)
GONADALGONADAL ovariumovarium testis testis
GENITALGENITAL INTERNAL INTERNAL uterusuterus prostateprostate
EXTERNAL EXTERNAL femalefemale male male
SEX ASSIGNMENTSEX ASSIGNMENT girlgirl boyboy
PSYCHOSOCIALPSYCHOSOCIAL female female malemale
PRIMORDIAL GERM CELS
DIFFERENTIATIONOF THE GONADS
DIFFERENTIATIONOF THE GONADS
ADRENAL MEDULLA ADRENAL CORTEX
WOLFFIAN DUCT
MÜLLERIAN DUCTMEDULLA
CORTEXBIPOTENTIAL GONAD
46 XY 46 XX
DEVELOPING TESTIS DEVELOPING OVARY
TUBULUBI SEMINIFERIS
CONDUCTING DUCT
MÜLLERIAN DUCT REGRESSIONSPERMATO-
GONIUMS
PRIMARY FOLLICLES
WOLFFIAN DEGENERATION
FALLOPIAN TUBE
GENITAL DIFFERENTIATIONGENITAL DIFFERENTIATIONINDIFFERENT STAGE
GONAD
MESONEPHROS
MÜLLERIAN DUCT
WOLFFIAN DUCT
OVARY
FALLO-PIAN
TUBE
UTERUS
VAGINA
FEMALE
EPIDIDYMIS
TESTIS
VAS DEFERENS
SEMINAL VESICLE
PROSTATE
MALE
INDIFFERENT STAGE
UROGENITAL FOLD
LABIOSCROTAL
SWELLING
MALEFEMALE
GLANS
URETH-RAL SLIT
FUSIONED UROGENITAL FOLD
UROGENI-
TAL FOLD
ANUS
GLANS PENIS
RAPHE
URETHRAL MEATUS CLITORIS
VAGINAL ORIFICE
DISORDERS OF THE EXTERNAL DISORDERS OF THE EXTERNAL GENITALIAGENITALIA
PRADER SINECKER
CLINICAL ASSESSMENTOF CLINICAL ASSESSMENTOF INFANTS WITH AMBIGUOUS INFANTS WITH AMBIGUOUS
GENITALIAGENITALIA
SERUM Te HIGH LOW
GONADS PALPABLE NON-PALPABLE
NORMAL NORMAL INCREASED
KARYOTYPE
ClassificationClassification
SEX CHROMOSOME DSD DSD KARYOTYPE : 46,XY DSD KARYOTYPE: 46,XX
Disorder of testicular development
Disorder of ovarian development
45,X Turner syndrome 1. Complet Gonadal Dysgenesis
(Swyer syndroma)
1. Ovotesticular DSD
2. Partial Gonadal Dysgenesis
2. testis SRY+, SOX9 duplication
3. Testicular regression 3. gonadal dysgenesis
4. Ovotesticular DSD
47, XXY Klinefelter syndrome
Defect in androgen biosynthesis or in androgen action
Androgen over production
1. defect in biosynthesis (17hydroxilase defect, 17 HSD, 5reductase defect, Star mutation)
1. fetal origin: 21-OH def./11OH def.
2. fetoplacental origin aromatase defektus
3. maternal origin: luteoma, exogén
2. defect in action (CAIS, PAIS)
45X/46,XY Mixed gonadal dysgenesis (ovotesticular DSD)
46,XX/46,XY Chimeric ovotesticular DSD
3. LH receptor mutation (Leydig-hypoplasia,
aplasia) 4. Persistent Müllerian
duct syndrome
SEX CHROMOSOME DSD DSD KARYOTYPE : 46,XY DSD KARYOTYPE: 46,XX
Disorder of testicular development
Disorder of ovarian development
45,X Turner syndrome 1. Complet Gonadal Dysgenesis
(Swyer syndroma)
1. Ovotesticular DSD
2. Partial Gonadal Dysgenesis
2. testis SRY+, SOX9 duplication
3. Testicular regression 3. gonadal dysgenesis
4. Ovotesticular DSD
47, XXY Klinefelter syndrome
Defect in androgen biosynthesis or in androgen action
Androgen over production
1. defect in biosynthesis (17hydroxilase defect, 17 HSD, 5reductase defect, Star mutation)
1. fetal origin: 21-OH def./11OH def.
2. fetoplacental origin aromatase defektus
3. maternal origin: luteoma, exogén
2. defect in action (CAIS, PAIS)
45X/46,XY Mixed gonadal dysgenesis (ovoteticular DSD)
46,XX/46,XY Chimeric ovotesticular DSD
3. LH receptor mutation (Leydig-hypoplasia,
aplasia) 4. Persistent Müllerian
duct syndrome
SEX CHROMOSOME DSD DSD KARYOTYPE : 46,XY DSD KARYOTYPE: 46,XX
Disorder of testicular development
Disorder of ovarian development
45,X Turner syndrome 1. Complet Gonadal Dysgenesis
(Swyer syndroma)
1. Ovotesticular DSD
2. Partial Gonadal Dysgenesis
2. testis SRY+, SOX9 duplication
3. Testicular regression 3. gonadal dysgenesis
4. Ovotesticular DSD
47, XXY Klinefelter syndrome
Defect in androgen biosynthesis or in androgen action
Androgen over production
1. defect in biosynthesis (17hydroxilase defect, 17 HSD, 5reductase defect, Star mutation)
1. fetal origin: 21-OH def./11OH def.
2. fetoplacental origin aromatase defektus
3. maternal origin: luteoma, exogén
2. defect in action (CAIS, PAIS)
45X/46,XY Mixed gonadal dysgenesis (ovoteticular DSD)
46,XX/46,XY Chimeric ovotesticular DSD
3. LH receptor mutation (Leydig-hypoplasia,
aplasia) 4. Persistent Müllerian
duct syndrome
Turner syndromeTurner syndrome1/2500 live female birth1/2500 live female birthHand-food edema in infancyHand-food edema in infancyPterygium colli (neck webbing), Pterygium colli (neck webbing),
Low posterior hairline, Broad Low posterior hairline, Broad chest, short staturechest, short stature
Cardiac, renal malformationsCardiac, renal malformationsKaryotype: 45,XKaryotype: 45,X
SEX CHROMOSOME DSD DSD KARYOTYPE : 46,XY DSD KARYOTYPE: 46,XX
Disorder of testicular development
Disorder of ovarian development
45,X Turner syndrome 1. Complet Gonadal Dysgenesis
(Swyer syndroma)
1. Ovotesticular DSD
2. Partial Gonadal Dysgenesis
2. testis SRY+, SOX9 duplication
3. Testicular regression 3. gonadal dysgenesis
4. Ovotesticular DSD
47, XXY Klinefelter syndrome
Defect in androgen biosynthesis or in androgen action
Androgen over production
1. defect in biosynthesis (17hydroxilase defect, 17 HSD, 5reductase defect, Star mutation)
1. fetal origin: 21-OH def./11OH def.
2. fetoplacental origin aromatase defektus
3. maternal origin: luteoma, exogén
2. defect in action (CAIS, PAIS)
45X/46,XY Mixed gonadal dysgenesis (ovotesticular DSD)
46,XX/46,XY Chimeric ovotesticular DSD
3. LH receptor mutation (Leydig-hypoplasia,
aplasia) 4. Persistent Müllerian
duct syndrome
Klinefelter syndromeKlinefelter syndrome
1/500-1000 live male birth1/500-1000 live male birth Small testis, high stature, learning Small testis, high stature, learning
difficulties, gynecomastia in pubertydifficulties, gynecomastia in puberty At pubert testicular size increases (At pubert testicular size increases (~~10 10
ml)ml)
Midpuberty: low androgen levelMidpuberty: low androgen level Karyotype: 47,XXY Karyotype: 47,XXY
SEX CHROMOSOME DSD DSD KARYOTYPE : 46,XY DSD KARYOTYPE: 46,XX
Disorder of testicular development
Disorder of ovarian development
45,X Turner syndrome 1. Complet Gonadal Dysgenesis
(Swyer syndroma)
1. Ovotesticular DSD
2. Partial Gonadal Dysgenesis
2. testis SRY+, SOX9 duplication
3. Testicular regression 3. gonadal dysgenesis
4. Ovotesticular DSD
47, XXY Klinefelter syndrome
Defect in androgen biosynthesis or in androgen action
Androgen over production
1. defect in biosynthesis (17hydroxilase defect, 17 HSD, 5reductase defect, Star mutation)
1. fetal origin: 21-OH def./11OH def.
2. fetoplacental origin aromatase defektus
3. maternal origin: luteoma, exogén
2. defect in action (CAIS, PAIS)
45X/46,XY Mixed gonadal dysgenesis (ovotesticular DSD)
46,XX/46,XY Chimeric ovotesticular DSD
3. LH receptor mutation (Leydig-hypoplasia,
aplasia) 4. Persistent Müllerian
duct syndrome
Complet gonadal dysgenesisComplet gonadal dysgenesisSwyer syndromeSwyer syndrome
Bilateral streak gonadsBilateral streak gonads Apparently normal female external Apparently normal female external
genitaliagenitalia High risk of gonadoblastoma, High risk of gonadoblastoma,
germinomagerminoma Karyotype: 46,XYKaryotype: 46,XY
SEX CHROMOSOME DSD DSD KARYOTYPE : 46,XY DSD KARYOTYPE: 46,XX
Disorder of testicular development
Disorder of ovarian development
45,X Turner syndrome 1. Complet Gonadal Dysgenesis
(Swyer syndroma)
1. Ovotesticular DSD
2. Partial Gonadal Dysgenesis
2. testis SRY+, SOX9 duplication
3. Testicular regression 3. gonadal dysgenesis
4. Ovotesticular DSD
47, XXY Klinefelter syndrome
Defect in androgen biosynthesis or in androgen action
Androgen over production
1. defect in biosynthesis (17hydroxilase defect, 17 HSD, 5reductase defect, Star mutation)
1. fetal origin: 21-OH def./11OH def.
2. fetoplacental origin aromatase defektus
3. maternal origin: luteoma, exogén
2. defect in action (CAIS, PAIS)
45X/46,XY Mixed gonadal dysgenesis (ovotesticular DSD)
46,XX/46,XY Chimeric ovotesticular DSD
3. LH receptor mutation (Leydig-hypoplasia,
aplasia) 4. Persistent Müllerian
duct syndrome
Parcial gonadal dysgenesisParcial gonadal dysgenesis
Ambigous genitalia Ambigous genitalia (Leydig cell (Leydig cell mass)mass)
Partial rest of Müllerian ductPartial rest of Müllerian duct Karyotype: 46,XYKaryotype: 46,XY High risk of gonadoblastoma High risk of gonadoblastoma
SEX CHROMOSOME DSD DSD KARYOTYPE : 46,XY DSD KARYOTYPE: 46,XX
Disorder of testicular development
Disorder of ovarian development
45,X Turner syndrome 1. Complet Gonadal Dysgenesis
(Swyer syndroma)
1. Ovotesticular DSD
2. Partial Gonadal Dysgenesis
2. testis SRY+, SOX9 duplication
3. Testicular regression 3. gonadal dysgenesis
4. Ovotesticular DSD
47, XXY Klinefelter syndrome
Defect in androgen biosynthesis or in androgen action
Androgen over production
1. defect in biosynthesis (17hydroxilase defect, 17 HSD, 5reductase defect, Star mutation)
1. fetal origin: 21-OH def./11OH def.
2. fetoplacental origin aromatase defektus
3. maternal origin: luteoma, exogén
2. defect in action (CAIS, PAIS)
45X/46,XY Mixed gonadal dysgenesis (ovoteticular DSD)
46,XX/46,XY Chimeric ovotesticular DSD
3. LH receptor mutation (Leydig-hypoplasia,
aplasia) 4. Persistent Müllerian
duct syndrome
Steroid Hormone Steroid Hormone BiosynthesisBiosynthesis
dehidroepiandrosteroneHO
O
O
O
17-OH-progesterone
cholesterol
ALDOSTERONE
Pregnenolone
Progesterone
11-Dezoxycortisol
CorticosteroneCORTIZOL
17OH-pregnenolone
C
HO
CH3
O
C
O
CH3
O
DOC
C
O
CH2OH
O
C
O
CH2OH
OHO
O
C
CH2OH
OHO
OCH
OHC
HO
CH3
O
OHC
O
CH3
O
OHC
O
CH2OH
O
HOC
O
CH2OH
OOH
17
ANDROSTENEDIONE
17-17- hydroxilase defect hydroxilase defect
Rare form of CAH Rare form of CAH Both testosterone and estrogen Both testosterone and estrogen
synthesis is decreasedsynthesis is decreased Hypertension, hypokalemiaHypertension, hypokalemia
SEX CHROMOSOME DSD DSD KARYOTYPE : 46,XY DSD KARYOTYPE: 46,XX
Disorder of testicular development
Disorder of ovarian development
45,X Turner syndrome 1. Complet Gonadal Dysgenesis
(Swyer syndroma)
1. Ovotesticular DSD
2. Partial Gonadal Dysgenesis
2. testis SRY+, SOX9 duplication
3. Testicular regression 3. gonadal dysgenesis
4. Ovotesticular DSD
47, XXY Klinefelter syndrome
Defect in androgen biosynthesis or in androgen action
Androgen over production
1. defect in biosynthesis (17hydroxilase defect, 17 HSD, 5reductase defect, Star mutation)
1. fetal origin: 21-OH def./11OH def.
2. fetoplacental origin aromatase defektus
3. maternal origin: luteoma, exogén
2. defect in action (CAIS, PAIS)
45X/46,XY Mixed gonadal dysgenesis (ovoteticular DSD)
46,XX/46,XY Chimeric ovotesticular DSD
3. LH receptor mutation (Leydig-hypoplasia,
aplasia) 4. Persistent Müllerian
duct syndrome
Complete androgen Complete androgen insensitivityinsensitivity
X q11-12 – AR geneX q11-12 – AR gene Female external genitalia, good Female external genitalia, good
breast development, hairlessbreast development, hairless Low risk of gonadoblstoma (2-5%)Low risk of gonadoblstoma (2-5%)
SEX CHROMOSOME DSD DSD KARYOTYPE : 46,XY DSD KARYOTYPE: 46,XX
Disorder of testicular development
Disorder of ovarian development
45,X Turner syndrome 1. Complet Gonadal Dysgenesis
(Swyer syndroma)
1. Ovotesticular DSD
2. Partial Gonadal Dysgenesis
2. testis SRY+, SOX9 duplication
3. Testicular regression 3. gonadal dysgenesis
4. Ovotesticular DSD
47, XXY Klinefelter syndrome
Defect in androgen biosynthesis or in androgen action
Androgen over production
1. defect in biosynthesis (17hydroxilase defect, 17 HSD, 5reductase defect, Star mutation)
1. fetal origin: 21-OH def./11OH def.
2. fetoplacental origin aromatase defektus
3. maternal origin: luteoma, exogén
2. defect in action (CAIS, PAIS)
45X/46,XY Mixed gonadal dysgenesis (ovoteticular DSD)
46,XX/46,XY Chimeric ovotesticular DSD
3. LH receptor mutation (Leydig-hypoplasia,
aplasia) 4. Persistent Müllerian
duct syndrome
Parcial androgen Parcial androgen insensitiviyinsensitiviy
X q11-12X q11-12 The seerity of undervirilisation The seerity of undervirilisation
depend on the receptor sensitivity.depend on the receptor sensitivity. High risk of gonadoblastomaHigh risk of gonadoblastoma
SEX CHROMOSOME DSD DSD KARYOTYPE : 46,XY DSD KARYOTYPE: 46,XX
Disorder of testicular development
Disorder of ovarian development
45,X Turner syndrome 1. Complet Gonadal Dysgenesis
(Swyer syndroma)
1. Ovotesticular DSD
2. Partial Gonadal Dysgenesis
2. testis SRY+, SOX9 duplication
3. Testicular regression 3. gonadal dysgenesis
4. Ovotesticular DSD
47, XXY Klinefelter syndrome
Defect in androgen biosynthesis or in androgen action
Androgen over production
1. defect in biosynthesis (17hydroxilase defect, 17 HSD, 5reductase defect, Star mutation)
1. fetal origin: 21-OH def./11OH def.
2. fetoplacental origin aromatase defektus
3. maternal origin: luteoma, exogén
2. defect in action (CAIS, PAIS)
45X/46,XY Mixed gonadal dysgenesis (ovoteticular DSD)
46,XX/46,XY Chimeric ovotesticular DSD
3. LH receptor mutation (Leydig-hypoplasia,
aplasia) 4. Persistent Müllerian
duct syndrome
Steroid Hormone Steroid Hormone BiosynthesisBiosynthesis
dehidroepiandrosteroneHO
O
O
O
17-OH-progesterone
cholesterol
ALDOSTERONE
Pregnenolone
Progesterone
11-Dezoxycortisol
CorticosteroneCORTIZOL
17OH-pregnenolone
C
HO
CH3
O
C
O
CH3
O
DOC
C
O
CH2OH
O
C
O
CH2OH
OHO
O
C
CH2OH
OHO
OCH
OHC
HO
CH3
O
OHC
O
CH3
O
OHC
O
CH2OH
O
HOC
O
CH2OH
OOH
17
ANDROSTENEDIONEP450c21
Cngenital adrenal Cngenital adrenal hyperplasiahyperplasia(21-OHD)(21-OHD)
1/15000 live birth1/15000 live birth CYP21 gene mutationCYP21 gene mutation 2/3 salt wasting form2/3 salt wasting form
SEX CHROMOSOME DSD DSD KARYOTYPE : 46,XY DSD KARYOTYPE: 46,XX
Disorder of testicular development
Disorder of ovarian development
45,X Turner syndrome 1. Complet Gonadal Dysgenesis
(Swyer syndroma)
1. Ovotesticular DSD
2. Partial Gonadal Dysgenesis
2. testis SRY+, SOX9 duplication
3. Testicular regression 3. gonadal dysgenesis
4. Ovotesticular DSD
47, XXY Klinefelter syndrome
Defect in androgen biosynthesis or in androgen action
Androgen overproduction
1. defect in biosynthesis (17hydroxilase defect, 17 HSD, 5reductase defect, Star mutation)
1. fetal origin: 21-OH def./11OH def.
2. fetoplacental origin aromatase defect
3. maternal origin: luteoma, exogén
2. defect in action (CAIS, PAIS)
45X/46,XY Mixed gonadal dysgenesis (ovoteticular DSD)
46,XX/46,XY Chimeric ovotesticular DSD
3. LH receptor mutation (Leydig-hypoplasia,
aplasia) 4. Persistent Müllerian
duct syndrome
TreatmentTreatment
TSTS
KSKS
17 17 -OH -OH
CGDCGD
CAISCAIS
21 OH21 OH
PGDPGD
PAISPAIS
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