Disorder of the sex development A Luczay Sex

Disorder of the sex development A. Luczay

Sex development GENETIC (chromosal) X X X Y GONADAL ovarium testis INTERNAL uterus prostate EXTERNAL female SEX ASSIGNMENT girl boy PSYCHOSOCIAL female GENITAL

DIFFERENTIATION OF THE GONADS PRIMORDIAL GERM CELS ADRENAL MEDULLA ADRENAL CORTEX WOLFFIAN DUCT MÜLLERIAN DUCT MEDULLA BIPOTENTIAL GONAD 46 XY 46 XX DEVELOPING TESTIS DEVELOPING OVARY TUBULUBI SEMINIFERIS CONDUCTING DUCT SPERMATOGONIUMS CORTEX WOLFFIAN DEGENERATION PRIMARY FOLLICLES MÜLLERIAN DUCT REGRESSION FALLOPIAN TUBE

GENITAL DIFFERENTIATION INDIFFERENT STAGE GONAD INDIFFERENT STAGE UROGENITAL FOLD MESONEPHROS LABIOSCROTAL MÜLLERIAN DUCT SWELLING WOLFFIAN DUCT MALE FEMALE GLANS FUSIONED EPIDIDYMIS UROGENITAL TESTIS FOLD OVARY FALLOPIAN VAS DEFERENS TUBE GLANS PENIS SEMINAL VESICLE UTERUS PROSTATE VAGINA FEMALE RAPHE URETHRAL SLIT UROGENITAL FOLD ANUS URETHRAL MEATUS CLITORIS VAGINAL ORIFICE

DISORDERS OF THE EXTERNAL GENITALIA PRADER SINECKER

CLINICAL ASSESSMENTOF INFANTS WITH AMBIGUOUS GENITALIA GONADS PALPABLE NON-PALPABLE NORMAL KARYOTYPE SERUM Te HIGH LOW INCREASED

Classification

SEX CHROMOSOME DSD 45, X Turner syndrome DSD KARYOTYPE : 46, XY DSD KARYOTYPE: 46, XX Disorder of testicular development Disorder of ovarian development 1. Complet Gonadal Dysgenesis (Swyer syndroma) 1. Ovotesticular DSD 2. Partial Gonadal Dysgenesis 2. testis SRY+, SOX 9 duplication 3. Testicular regression 3. gonadal dysgenesis 4. Ovotesticular DSD 47, XXY Klinefelter syndrome Defect in androgen biosynthesis or in androgen action 1. defect in biosynthesis (17 hydroxilase defect, 17 HSD, 5 reductase defect, Star mutation) 2. defect in action (CAIS, PAIS) 45 X/46, XY 46, XX/46, XY Mixed gonadal dysgenesis (ovotesticular DSD) Chimeric ovotesticular DSD 3. LH receptor mutation (Leydig-hypoplasia, aplasia) 4. Persistent Müllerian duct syndrome Androgen over production 1. fetal origin: 21 -OH def. /11 OH def. 2. fetoplacental origin aromatase defektus 3. maternal origin: luteoma, exogén

SEX CHROMOSOME DSD 45, X Turner syndrome DSD KARYOTYPE : 46, XY DSD KARYOTYPE: 46, XX Disorder of testicular development Disorder of ovarian development 1. Complet Gonadal Dysgenesis (Swyer syndroma) 1. Ovotesticular DSD 2. Partial Gonadal Dysgenesis 2. testis SRY+, SOX 9 duplication 3. Testicular regression 3. gonadal dysgenesis 4. Ovotesticular DSD 47, XXY Klinefelter syndrome Defect in androgen biosynthesis or in androgen action 1. defect in biosynthesis (17 hydroxilase defect, 17 HSD, 5 reductase defect, Star mutation) 2. defect in action (CAIS, PAIS) 45 X/46, XY 46, XX/46, XY Mixed gonadal dysgenesis (ovoteticular DSD) Chimeric ovotesticular DSD 3. LH receptor mutation (Leydig-hypoplasia, aplasia) 4. Persistent Müllerian duct syndrome Androgen over production 1. fetal origin: 21 -OH def. /11 OH def. 2. fetoplacental origin aromatase defektus 3. maternal origin: luteoma, exogén

SEX CHROMOSOME DSD 45, X Turner syndrome DSD KARYOTYPE : 46, XY DSD KARYOTYPE: 46, XX Disorder of testicular development Disorder of ovarian development 1. Complet Gonadal Dysgenesis (Swyer syndroma) 1. Ovotesticular DSD 2. Partial Gonadal Dysgenesis 2. testis SRY+, SOX 9 duplication 3. Testicular regression 3. gonadal dysgenesis 4. Ovotesticular DSD 47, XXY Klinefelter syndrome Defect in androgen biosynthesis or in androgen action 1. defect in biosynthesis (17 hydroxilase defect, 17 HSD, 5 reductase defect, Star mutation) 2. defect in action (CAIS, PAIS) 45 X/46, XY 46, XX/46, XY Mixed gonadal dysgenesis (ovoteticular DSD) Chimeric ovotesticular DSD 3. LH receptor mutation (Leydig-hypoplasia, aplasia) 4. Persistent Müllerian duct syndrome Androgen over production 1. fetal origin: 21 -OH def. /11 OH def. 2. fetoplacental origin aromatase defektus 3. maternal origin: luteoma, exogén

Turner syndrome Ø 1/2500 live female birth Ø Hand-food edema in infancy Ø Pterygium colli (neck webbing), Low posterior hairline, Broad chest, short stature Ø Cardiac, renal malformations Ø Karyotype: 45, X

SEX CHROMOSOME DSD 45, X Turner syndrome DSD KARYOTYPE : 46, XY DSD KARYOTYPE: 46, XX Disorder of testicular development Disorder of ovarian development 1. Complet Gonadal Dysgenesis (Swyer syndroma) 1. Ovotesticular DSD 2. Partial Gonadal Dysgenesis 2. testis SRY+, SOX 9 duplication 3. Testicular regression 3. gonadal dysgenesis 4. Ovotesticular DSD 47, XXY Klinefelter syndrome Defect in androgen biosynthesis or in androgen action 1. defect in biosynthesis (17 hydroxilase defect, 17 HSD, 5 reductase defect, Star mutation) 2. defect in action (CAIS, PAIS) 45 X/46, XY 46, XX/46, XY Mixed gonadal dysgenesis (ovotesticular DSD) Chimeric ovotesticular DSD 3. LH receptor mutation (Leydig-hypoplasia, aplasia) 4. Persistent Müllerian duct syndrome Androgen over production 1. fetal origin: 21 -OH def. /11 OH def. 2. fetoplacental origin aromatase defektus 3. maternal origin: luteoma, exogén

Klinefelter syndrome Ø 1/500 -1000 live male birth Ø Small testis, high stature, learning difficulties, gynecomastia in puberty Ø At pubert testicular size increases (~10 ml) Midpuberty: low androgen level Ø Karyotype: 47, XXY

SEX CHROMOSOME DSD 45, X Turner syndrome DSD KARYOTYPE : 46, XY DSD KARYOTYPE: 46, XX Disorder of testicular development Disorder of ovarian development 1. Complet Gonadal Dysgenesis (Swyer syndroma) 1. Ovotesticular DSD 2. Partial Gonadal Dysgenesis 2. testis SRY+, SOX 9 duplication 3. Testicular regression 3. gonadal dysgenesis 4. Ovotesticular DSD 47, XXY Klinefelter syndrome Defect in androgen biosynthesis or in androgen action 1. defect in biosynthesis (17 hydroxilase defect, 17 HSD, 5 reductase defect, Star mutation) 2. defect in action (CAIS, PAIS) 45 X/46, XY 46, XX/46, XY Mixed gonadal dysgenesis (ovotesticular DSD) Chimeric ovotesticular DSD 3. LH receptor mutation (Leydig-hypoplasia, aplasia) 4. Persistent Müllerian duct syndrome Androgen over production 1. fetal origin: 21 -OH def. /11 OH def. 2. fetoplacental origin aromatase defektus 3. maternal origin: luteoma, exogén

Complet gonadal dysgenesis Swyer syndrome Ø Bilateral streak gonads Ø Apparently normal female external genitalia Ø High risk of gonadoblastoma, germinoma Ø Karyotype: 46, XY

SEX CHROMOSOME DSD 45, X Turner syndrome DSD KARYOTYPE : 46, XY DSD KARYOTYPE: 46, XX Disorder of testicular development Disorder of ovarian development 1. Complet Gonadal Dysgenesis (Swyer syndroma) 1. Ovotesticular DSD 2. Partial Gonadal Dysgenesis 2. testis SRY+, SOX 9 duplication 3. Testicular regression 3. gonadal dysgenesis 4. Ovotesticular DSD 47, XXY Klinefelter syndrome Defect in androgen biosynthesis or in androgen action 1. defect in biosynthesis (17 hydroxilase defect, 17 HSD, 5 reductase defect, Star mutation) 2. defect in action (CAIS, PAIS) 45 X/46, XY 46, XX/46, XY Mixed gonadal dysgenesis (ovotesticular DSD) Chimeric ovotesticular DSD 3. LH receptor mutation (Leydig-hypoplasia, aplasia) 4. Persistent Müllerian duct syndrome Androgen over production 1. fetal origin: 21 -OH def. /11 OH def. 2. fetoplacental origin aromatase defektus 3. maternal origin: luteoma, exogén

Parcial gonadal dysgenesis Ø Ambigous genitalia (Leydig cell mass) Ø Partial rest of Müllerian duct Ø Karyotype: 46, XY Ø High risk of gonadoblastoma

SEX CHROMOSOME DSD 45, X Turner syndrome DSD KARYOTYPE : 46, XY DSD KARYOTYPE: 46, XX Disorder of testicular development Disorder of ovarian development 1. Complet Gonadal Dysgenesis (Swyer syndroma) 1. Ovotesticular DSD 2. Partial Gonadal Dysgenesis 2. testis SRY+, SOX 9 duplication 3. Testicular regression 3. gonadal dysgenesis 4. Ovotesticular DSD 47, XXY Klinefelter syndrome Defect in androgen biosynthesis or in androgen action 1. defect in biosynthesis (17 hydroxilase defect, 17 HSD, 5 reductase defect, Star mutation) 2. defect in action (CAIS, PAIS) 45 X/46, XY 46, XX/46, XY Mixed gonadal dysgenesis (ovoteticular DSD) Chimeric ovotesticular DSD 3. LH receptor mutation (Leydig-hypoplasia, aplasia) 4. Persistent Müllerian duct syndrome Androgen over production 1. fetal origin: 21 -OH def. /11 OH def. 2. fetoplacental origin aromatase defektus 3. maternal origin: luteoma, exogén

Steroid Hormone Biosynthesis cholesterol CH 3 C O HO O OH HO Pregnenolone HO dehidroepiandrosterone 17 a-OH-pregnenolone CH 3 C O OH O O O 17 a-OH-progesterone Progesterone O 17 ANDROSTENEDIONE O CH 2 OH C C O O DOC 11 -Dezoxycortisol CH 2 OH C O HO O OCH HO CH 2 OH C O OH O Corticosterone HO O OH CORTIZOL CH 2 OH C O O ALDOSTERONE

17 - hydroxilase defect Ø Rare form of CAH Ø Both testosterone and estrogen synthesis is decreased Ø Hypertension, hypokalemia

SEX CHROMOSOME DSD 45, X Turner syndrome DSD KARYOTYPE : 46, XY DSD KARYOTYPE: 46, XX Disorder of testicular development Disorder of ovarian development 1. Complet Gonadal Dysgenesis (Swyer syndroma) 1. Ovotesticular DSD 2. Partial Gonadal Dysgenesis 2. testis SRY+, SOX 9 duplication 3. Testicular regression 3. gonadal dysgenesis 4. Ovotesticular DSD 47, XXY Klinefelter syndrome Defect in androgen biosynthesis or in androgen action 1. defect in biosynthesis (17 hydroxilase defect, 17 HSD, 5 reductase defect, Star mutation) 2. defect in action (CAIS, PAIS) 45 X/46, XY 46, XX/46, XY Mixed gonadal dysgenesis (ovoteticular DSD) Chimeric ovotesticular DSD 3. LH receptor mutation (Leydig-hypoplasia, aplasia) 4. Persistent Müllerian duct syndrome Androgen over production 1. fetal origin: 21 -OH def. /11 OH def. 2. fetoplacental origin aromatase defektus 3. maternal origin: luteoma, exogén

Complete androgen insensitivity ØX q 11 -12 – AR gene Ø Female external genitalia, good breast development, hairless Ø Low risk of gonadoblstoma (2 -5%)

SEX CHROMOSOME DSD 45, X Turner syndrome DSD KARYOTYPE : 46, XY DSD KARYOTYPE: 46, XX Disorder of testicular development Disorder of ovarian development 1. Complet Gonadal Dysgenesis (Swyer syndroma) 1. Ovotesticular DSD 2. Partial Gonadal Dysgenesis 2. testis SRY+, SOX 9 duplication 3. Testicular regression 3. gonadal dysgenesis 4. Ovotesticular DSD 47, XXY Klinefelter syndrome Defect in androgen biosynthesis or in androgen action 1. defect in biosynthesis (17 hydroxilase defect, 17 HSD, 5 reductase defect, Star mutation) 2. defect in action (CAIS, PAIS) 45 X/46, XY 46, XX/46, XY Mixed gonadal dysgenesis (ovoteticular DSD) Chimeric ovotesticular DSD 3. LH receptor mutation (Leydig-hypoplasia, aplasia) 4. Persistent Müllerian duct syndrome Androgen over production 1. fetal origin: 21 -OH def. /11 OH def. 2. fetoplacental origin aromatase defektus 3. maternal origin: luteoma, exogén

Parcial androgen insensitiviy ØX q 11 -12 Ø The seerity of undervirilisation depend on the receptor sensitivity. Ø High risk of gonadoblastoma

SEX CHROMOSOME DSD 45, X Turner syndrome DSD KARYOTYPE : 46, XY DSD KARYOTYPE: 46, XX Disorder of testicular development Disorder of ovarian development 1. Complet Gonadal Dysgenesis (Swyer syndroma) 1. Ovotesticular DSD 2. Partial Gonadal Dysgenesis 2. testis SRY+, SOX 9 duplication 3. Testicular regression 3. gonadal dysgenesis 4. Ovotesticular DSD 47, XXY Klinefelter syndrome Defect in androgen biosynthesis or in androgen action 1. defect in biosynthesis (17 hydroxilase defect, 17 HSD, 5 reductase defect, Star mutation) 2. defect in action (CAIS, PAIS) 45 X/46, XY 46, XX/46, XY Mixed gonadal dysgenesis (ovoteticular DSD) Chimeric ovotesticular DSD 3. LH receptor mutation (Leydig-hypoplasia, aplasia) 4. Persistent Müllerian duct syndrome Androgen over production 1. fetal origin: 21 -OH def. /11 OH def. 2. fetoplacental origin aromatase defektus 3. maternal origin: luteoma, exogén

Steroid Hormone Biosynthesis cholesterol CH 3 C O HO O OH HO Pregnenolone HO dehidroepiandrosterone 17 a-OH-pregnenolone CH 3 C O OH ANDROSTENEDIONE P 450 c 21 O CH 2 OH C C O 11 -Dezoxycortisol CH 2 OH C O HO O OCH HO CH 2 OH C O OH O Corticosterone HO O OH O DOC CORTIZOL CH 2 OH C O O ALDOSTERONE O O O 17 a-OH-progesterone Progesterone O 17

Cngenital adrenal hyperplasia (21 -OHD) Ø 1/15000 live birth Ø CYP 21 gene mutation Ø 2/3 salt wasting form

SEX CHROMOSOME DSD 45, X Turner syndrome DSD KARYOTYPE : 46, XY DSD KARYOTYPE: 46, XX Disorder of testicular development Disorder of ovarian development 1. Complet Gonadal Dysgenesis (Swyer syndroma) 1. Ovotesticular DSD 2. Partial Gonadal Dysgenesis 2. testis SRY+, SOX 9 duplication 3. Testicular regression 3. gonadal dysgenesis 4. Ovotesticular DSD 47, XXY Klinefelter syndrome Defect in androgen biosynthesis or in androgen action 1. defect in biosynthesis (17 hydroxilase defect, 17 HSD, 5 reductase defect, Star mutation) 2. defect in action (CAIS, PAIS) 45 X/46, XY 46, XX/46, XY Mixed gonadal dysgenesis (ovoteticular DSD) Chimeric ovotesticular DSD 3. LH receptor mutation (Leydig-hypoplasia, aplasia) 4. Persistent Müllerian duct syndrome Androgen overproduction 1. fetal origin: 21 -OH def. /11 OH def. 2. fetoplacental origin aromatase defect 3. maternal origin: luteoma, exogén

Treatment

TS

KS

17 -OH

CGD

CAIS

21 OH

PGD

PAIS