Disorder of the sex development Rickets

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Disorder of the sex developmentRickets

• A. Luczay

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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
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DIFFERENTIATIONOF 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
PRIMARY FOLLICLES
CONDUCTING DUCT
SPERMATO- GONIUMS
MÜLLERIAN DUCT REGRESSION
FALLOPIAN TUBE
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GENITAL DIFFERENTIATION
INDIFFERENT STAGE

INDIFFERENT STAGE
GONAD MESONEPHROS MÜLLERIAN DUCT WOLFFIAN DUCT
UROGENITAL FOLD
LABIOSCROTAL SWELLING
MALE
FEMALE
GLANS
UROGENI- TAL FOLD
FUSIONED UROGENITAL FOLD
URETH-RAL SLIT
EPIDIDYMIS
OVARY
TESTIS
FALLO-PIAN TUBE
ANUS
VAS DEFERENS
GLANS PENIS
URETHRAL MEATUS
CLITORIS
SEMINAL VESICLE
UTERUS
VAGINAL ORIFICE
PROSTATE
RAPHE
VAGINA
FEMALE
MALE
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DISORDERS OF THE EXTERNAL GENITALIA
SINECKER
PRADER
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CLINICAL ASSESSMENTOF INFANTS WITH AMBIGUOUS
GENITALIA
GONADS
PALPABLE
NON-PALPABLE
INCREASED
NORMAL
NORMAL
KARYOTYPE
SERUM Te HIGH LOW
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Classification
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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

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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

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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

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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

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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

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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

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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

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Complet gonadal dysgenesisSwyer syndrome

• Bilateral streak gonads
• Apparently normal female external genitalia
• High risk of gonadoblastoma, germinoma
• Karyotype 46,XY

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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

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Parcial gonadal dysgenesis

• Ambigous genitalia (Leydig cell mass)
• Partial rest of Müllerian duct
• Karyotype 46,XY
• High risk of gonadoblastoma

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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

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Steroid Hormone Biosynthesis
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17-? hydroxilase defect

• Rare form of CAH
• Both testosterone and estrogen synthesis is
  decreased
• Hypertension, hypokalemia

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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

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Complete androgen insensitivity

• X q11-12 AR gene
• Female external genitalia, good breast
  development, hairless
• Low risk of gonadoblstoma (2-5)

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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

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Parcial androgen insensitiviy

• X q11-12
• The seerity of undervirilisation depend on the
  receptor sensitivity.
• High risk of gonadoblastoma

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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

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Steroid Hormone Biosynthesis
P450c21
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Cngenital adrenal hyperplasia(21-OHD)

• 1/15000 live birth
• CYP21 gene mutation
• 2/3 salt wasting form

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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

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Treatment
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TS
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KS
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17 ? -OH
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CGD
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CAIS
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21 OH
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PGD
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PAIS
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Rickets
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Definition

• Decrease in the enchondral calcification of the
  growth plate.

• Growth plate deformities
• Decreased growth rate
• Skeletal deformities

In adults osteomalacia
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Clinical signs

• Decreased growth rate
• Big fontanelle, craniotabes
• Swelling around growth plate

Rachitic bracelet
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Bowleg (genu varum) windswept (genu
varum genu valgum)
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Rachitic rosary Harrisons sulcus
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Radiographic findings
Loss of demarcation Growth plate widens Irregular
outlines Metaphysis cuped, flared
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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.

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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

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Stages of vitamin D-deficient rickets
Stage 1 Stage 2 Stage 3
25(OH)D ? ?? ???
Calcium ? Low N ?
PTH Starts to rise ? ??
Phosphorus N ? low
ALP ? ? ?
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Treatment

• 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

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Vitamin D 1-? hyroxylase deficiencyVitamin 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

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Hereditary 1,25 (OH)2- resistant ricketsVitamin
D dependent rickets typeII

• vitamin D receptor mutation- ressitance to
  vitamin D
• Treatment
• very high dose of calcitriol

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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

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AD hypophosphatemic rickets

• Rare disorder
• FGF23 (fibroblast growth factor family)
• Presentation childhood, adulthood

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Hereditary hypophosphatemic rickets with
hypercalciuria (HHRH)

• Similar to XLH
• BUT appropriate 1,25 (OH)2 Vit. D
• hypercalciuria kidney stones
• Treatment
• Phosphorus supplementation

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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

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Biochemical finding in different forms of rickets
Serum Serum Serum Serum Serum Urine 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 L -
1? def L N/L H H N L L -
Vit.D res. L L H H N HH L -
Hypophos. N L N H N N L -
hypercalciuria N L N H N H L -
Fanconi N L N H N H L