Disorder of the sex development Rickets A. Luczay

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

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

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

DISORDERS OF THE EXTERNAL GENITALIA SINECKER PRADER

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

Classification

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 (17hydroxilase defect, 17 HSD, 5reductase defect, Star mutation) 1. fetal origin: 21-OH def./11OH 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 (17hydroxilase defect, 17 HSD, 5reductase defect, Star mutation) 1. fetal origin: 21-OH def./11OH 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 (17hydroxilase defect, 17 HSD, 5reductase defect, Star mutation) 1. fetal origin: 21-OH def./11OH 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 syndrome 1/2500 live female birth Hand-food edema in infancy Pterygium colli (neck webbing), Low posterior hairline, Broad chest, short stature Cardiac, renal malformations Karyotype: 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 (17hydroxilase defect, 17 HSD, 5reductase defect, Star mutation) 1. fetal origin: 21-OH def./11OH 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 syndrome 1/500-1000 live male birth Small testis, high stature, learning difficulties, gynecomastia in puberty At pubert testicular size increases (~10 ml) Midpuberty: low androgen level 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 (17hydroxilase defect, 17 HSD, 5reductase defect, Star mutation) 1. fetal origin: 21-OH def./11OH 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 dysgenesis Swyer syndrome Bilateral streak gonads Apparently normal female external genitalia High risk of gonadoblastoma, germinoma Karyotype: 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 (17hydroxilase defect, 17 HSD, 5reductase defect, Star mutation) 1. fetal origin: 21-OH def./11OH 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 dysgenesis Ambigous genitalia (Leydig cell mass) Partial rest of Müllerian duct Karyotype: 46,XY 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 (17hydroxilase defect, 17 HSD, 5reductase defect, Star mutation) 1. fetal origin: 21-OH def./11OH 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 Biosynthesis dehidroepiandrosterone HO O 17a-OH-progesterone cholesterol ALDOSTERONE Pregnenolone Progesterone 11-Dezoxycortisol Corticosterone CORTIZOL 17a-OH-pregnenolone C CH3 DOC CH2OH OCH OH 17 ANDROSTENEDIONE

17- hydroxilase defect Rare form of CAH Both testosterone and estrogen synthesis is decreased Hypertension, 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 (17hydroxilase defect, 17 HSD, 5reductase defect, Star mutation) 1. fetal origin: 21-OH def./11OH 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 insensitivity X q11-12 – AR gene Female external genitalia, good breast development, hairless 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 (17hydroxilase defect, 17 HSD, 5reductase defect, Star mutation) 1. fetal origin: 21-OH def./11OH 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 insensitiviy X q11-12 The seerity of undervirilisation depend on the receptor sensitivity. 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 (17hydroxilase defect, 17 HSD, 5reductase defect, Star mutation) 1. fetal origin: 21-OH def./11OH 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 Biosynthesis dehidroepiandrosterone HO O 17a-OH-progesterone cholesterol ALDOSTERONE Pregnenolone Progesterone 11-Dezoxycortisol Corticosterone CORTIZOL 17a-OH-pregnenolone C CH3 DOC CH2OH OCH OH 17 ANDROSTENEDIONE P450c21

Cngenital adrenal hyperplasia (21-OHD) 1/15000 live birth CYP21 gene mutation 2/3 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 (17hydroxilase defect, 17 HSD, 5reductase defect, Star mutation) 1. fetal origin: 21-OH def./11OH 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

Treatment

TS

KS

17  -OH

CGD

CAIS

21 OH

PGD

PAIS

Rickets

Definition Decrease in the enchondral calcification of the growth plate. Growth plate deformities Decreased growth rate Skeletal deformities In adults: osteomalacia

Clinical signs Decreased growth rate Big fontanelle, craniotabes Swelling around growth plate: Rachitic bracelet

Bowleg (genu varum) windswept (genu varum + genu valgum)

Rachitic rosary Harrison’s sulcus

Radiographic findings Loss of demarcation Growth plate widens Irregular outlines Metaphysis cuped, flared

Classification Calciopenic Vitamin D-deficient Vitamin D 1- hydrohylase deficiency Hereditary 1,25 (OH)2 D resistant Phospopenic X-linked hypophosphatemic AD hypophosphatemic Hereditary hypophosphatemic rickets with hypercalciuria Renal tubular disorder – Fanconi sy.

Vitamin D- deficient rickets Inadequate vitamin D intake or formation in the skin (UV B dependent) 3-18 moths of age Breatsfeeding high risk 200-400 IU/ day

Stages of vitamin D-deficient rickets 25(OH)D    Calcium Low N PTH Starts to rise   Phosphorus N low ALP

Treatment Prevention 400-600 IU/ day Vitamin D 5-15000 IU/ day – 6-8 weeks (2-600.000. IU inramuscular) Ca supplementation: 600-1000 mg/ day Prevention 400-600 IU/ day

Vitamin D 1- hyroxylase deficiency Vitamin D dependent rickets type I renal 1 - hydroxylase is inactive During the first 2 years of life Treatment 0,25-2,0 ug/day calcitriol + calcium

Hereditary 1,25 (OH)2- resistant rickets Vitamin D dependent rickets typeII vitamin D receptor mutation- ressitance to vitamin D Treatment very high dose of calcitriol

X-linked hypophosphatemic rickets PHEx (phosphate-regulating gene with homologie to endopeptidases) X kr. Renal phosphate wasting hypophospataemia inapproprate 1,25 (OH)2 D Treatment Elemental phosphorus + calcitriol

AD hypophosphatemic rickets Rare disorder FGF23 (fibroblast growth factor family) Presentation: childhood, adulthood

Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) Similar to XLH BUT: appropriate 1,25 (OH)2 Vit. D hypercalciuria – kidney stones Treatment Phosphorus supplementation

Renal tubular disosrders- Fanconi syndrome Defects in the reabsorption of ion (Mg, P, Ca, Na, K, HCO3-), glucose, amino acids Causes: cystinosis, tyrosinaemia, galactosemia, Lowe syndrome Treatment phosphorus, calcitriol

Biochemical finding in different forms of rickets Serum Urine Ca P PTH ALP 25(OH)D 1,25(OH) TRP AAS Vit.D def N N/L H/N H L L/N/H - 1 def Vit.D res. HH Hypophos. ~+ hypercalciuria Fanconi +