Disorder of the sex development Rickets A. Luczay

Disorder of the sex Disorder of the sex developmentdevelopment

RicketsRickets

Disorder of the sex Disorder of the sex developmentdevelopment

RicketsRickets

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


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





(Swyer syndroma)














45X/46,XY Mixed gonadal dysgenesis (ovoteticular DSD)




duct syndrome





(Swyer syndroma)


















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





(Swyer syndroma)


















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





(Swyer syndroma)


















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





(Swyer syndroma)


















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





(Swyer syndroma)


















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





(Swyer syndroma)


















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%)





(Swyer syndroma)


















duct syndrome

Parcial androgen insensitiviyParcial androgen insensitiviy

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





(Swyer syndroma)


















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





(Swyer syndroma)








Androgen overproduction



2. fetoplacental origin aromatase defect







duct syndrome

TreatmentTreatment

TSTS

KSKS

17 17 -OH -OH

CGDCGD

CAISCAIS

21 OH21 OH

PGDPGD

PAISPAIS

RicketsRickets

DefinitionDefinition

Decrease in the enchondral Decrease in the enchondral calcification of the growth plate.calcification of the growth plate.

-Growth plate deformities

-Decreased growth rate

-Skeletal deformitiesIn adults: osteomalacia

Clinical signsClinical signs

Decreased growth rateDecreased growth rate Big fontanelle, craniotabesBig fontanelle, craniotabes Swelling around growth plate:Swelling around growth plate:

Rachitic bracelet

Bowleg (genu varum) windswept

(genu varum + genu valgum)

Rachitic rosary Harrison’s sulcus

Radiographic findingsRadiographic findings

Loss of demarcation

Growth plate widens

Irregular outlines

Metaphysis cuped, flared

ClassificationClassification

CalciopenicCalciopenic Vitamin D-deficientVitamin D-deficient Vitamin D 1Vitamin D 1- -

hydrohylase deficiencyhydrohylase deficiency Hereditary Hereditary

1,25 (OH)1,25 (OH)22 D resistant D resistant

PhospopenicPhospopenic X-linked X-linked

hypophosphatemichypophosphatemic AD AD

hypophosphatemichypophosphatemic Hereditary Hereditary

hypophosphatemic hypophosphatemic rickets with rickets with hypercalciuriahypercalciuria

Renal tubular Renal tubular disorder – Fanconi sy.disorder – Fanconi sy.

Vitamin D- deficient ricketsVitamin D- deficient rickets

Inadequate vitamin D intake or Inadequate vitamin D intake or formation in the skin (UV B formation in the skin (UV B dependent)dependent)

3-18 moths of age3-18 moths of age Breatsfeeding high riskBreatsfeeding high risk 200-400 IU/ day200-400 IU/ day

Stages of vitamin D-deficient Stages of vitamin D-deficient ricketsrickets

Stage 1Stage 1 Stage 2Stage 2 Stage 3Stage 3

25(OH)D25(OH)D

CalciumCalcium Low NLow N

PTHPTH Starts to Starts to riserise

PhosphorusPhosphorus NN lowlow

ALPALP

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

PreventionPrevention 400-600 IU/ day400-600 IU/ day

Vitamin D 1-Vitamin D 1- hyroxylase hyroxylase deficiencydeficiency

Vitamin D dependent rickets type IVitamin D dependent rickets type I renal 1 -renal 1 - hydroxylase is inactive hydroxylase is inactive During the first 2 years of lifeDuring the first 2 years of life

TreatmentTreatment 0,25-2,0 ug/day calcitriol + calcium0,25-2,0 ug/day calcitriol + calcium

Hereditary 1,25 (OH)Hereditary 1,25 (OH)22- resistant - resistant ricketsrickets

Vitamin D dependent rickets typeIIVitamin D dependent rickets typeII

vitamin D receptor mutation-vitamin D receptor mutation- ressitance to vitamin Dressitance to vitamin D

TreatmentTreatment very high dose of calcitriolvery high dose of calcitriol

X-linked hypophosphatemic X-linked hypophosphatemic ricketsrickets

PHEx (phosphate-regulating gene with PHEx (phosphate-regulating gene with homologie to endopeptidases) X kr.homologie to endopeptidases) X kr.

Renal phosphate wastingRenal phosphate wastinghypophospataemiahypophospataemia

inapproprate 1,25 (OH)inapproprate 1,25 (OH)2 2 DD

TreatmentTreatmentElemental phosphorus + calcitriolElemental phosphorus + calcitriol

AD hypophosphatemic AD hypophosphatemic ricketsrickets

Rare disorderRare disorder FGF23 (fibroblast growth factor FGF23 (fibroblast growth factor

family)family) Presentation: childhood, adulthoodPresentation: childhood, adulthood

Hereditary hypophosphatemic Hereditary hypophosphatemic rickets with hypercalciuria rickets with hypercalciuria

(HHRH)(HHRH)

Similar to XLHSimilar to XLH

BUT: appropriate 1,25 (OH)BUT: appropriate 1,25 (OH)2 2 Vit. DVit. D

hypercalciuria – kidney stoneshypercalciuria – kidney stones

TreatmentTreatment Phosphorus supplementationPhosphorus supplementation

Renal tubular disosrders- Renal tubular disosrders- Fanconi syndromeFanconi syndrome

Defects in the reabsorption of ion Defects in the reabsorption of ion

(Mg, P, Ca, Na, K, HCO(Mg, P, Ca, Na, K, HCO33--), ),

glucose, amino acidsglucose, amino acids

Causes: cystinosis, tyrosinaemia, Causes: cystinosis, tyrosinaemia, galactosemia, Lowe galactosemia, Lowe

syndromesyndrome

TreatmentTreatment phosphorus, calcitriolphosphorus, calcitriol

Biochemical finding in different Biochemical finding in different forms of ricketsforms 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 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 +

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Disorder of the sex development Rickets A. Luczay