gender d evelopment disoreders and congenital a drenal h yperplasia
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Gender Gender DDevelopment evelopment Disoreders and Disoreders and
Congenital Adrenal Congenital Adrenal Hyperplasia Hyperplasia
Dr Olcay EvliyaoğluDr Olcay Evliyaoğlu
Mesoderm
WT1LIM-1
SF1Bipotantial gonad
SRYSOX 9DMRT1 ve 2
DAX 1WNT 4
Testes
Ovary
Sertoli H.
Leydig H.
AMH
Testosterone
Estradiol
Genes involved in gonadal Genes involved in gonadal differentiationdifferentiation
Genes involved in gonadal Genes involved in gonadal differentiationdifferentiation
46, XY Gonadal
Dysgenesis
46, XY Gonadal
Dysgenesis
SOX9SOX9
SRYSRY
Del(2q)
Del (9p)
Del (10g)Dup (X)p21
(DAX 1)
WT1WT1
SF 1SF 1
Campomelic dysplasia
Adrenal insufficiency
Dennys-Drash sendromuFrasier sendromuWAGR sendromu
DMRT 1 - 2
Gonadal dysgenesisGonadal dysgenesis
Disorders of steroid Disorders of steroid biosynthesisbiosynthesis
Adrenal Adrenal ccorteortexx
EmbryoloEmbryologygy
MeMessoderm........adrenal oderm........adrenal ccorteortexx
EEcctoderm.........adrenal medullatoderm.........adrenal medulla
Fetal adrenal Fetal adrenal ccorteortex at x at 5-6 5-6 weeksweeks– DefinitDefinite e zon zone (outer layer)e (outer layer) (glu (gluccooccortiorticcoid oid and and
mineralomineraloccortiorticcoid)oid)– FetalFetal zon zone (inner layer)e (inner layer) (andr (androgogenienicc
prepreccurursorssors))
At birth adrenal gland is the 0,5 % of the At birth adrenal gland is the 0,5 % of the birth weight birth weight
GlomeruloGlomerulossa 15a 15%%
FasiFasicculata 75ulata 75%%
RetiReticcularis 10ularis 10%%
Fetal zonFetal zone disappears at about 1 years of e disappears at about 1 years of ageage
Glomerularis Glomerularis and and fasifasicculata ulata development development continues untill continues untill 3 y3 yearsears
RetiReticcularis ularis development continues untill development continues untill 15 15 yyearsears
Congentital adrenal hyperplasiaCongentital adrenal hyperplasiaEnzyme deficiencyEnzyme deficiency Girls Girls Boys Boys Lab Lab
Lipoid formLipoid form SeSexual xual infantiliinfantilissmm
salt wastingsalt wasting
Insufficient Insufficient virilivirilisation sation
Salt wasting Salt wasting
All steroid hormones are All steroid hormones are lowlow
Low response to ACTH Low response to ACTH stimstim
ACTH ACTH andand PRA PRA high high
3beta HSD3beta HSD Virilisation Virilisation
Salt wastingSalt wasting
Insufficient Insufficient virilivirilisation sation
Salt wasting Salt wasting
Delta steroids are Delta steroids are increasedincreased
ACTH ACTH andand PRA PRA highhigh
2121 hydoxylase def hydoxylase def classical type classical type
Virilisation Virilisation
Salt wastingSalt wasting
MaMaccrogenıtalrogenıtaliaia
Salt wasting Salt wasting
17OH progesteron17OH progesteronee increasedincreased
Androgens increased Androgens increased
ACTH ACTH andand PRA PRA increasedincreased
2121 hydoxylase def late hydoxylase def late onset type onset type
Premature Premature adrenadrenarchearche, , hirsutismushirsutismus, , menstrual menstrual irregularity irregularity ,a,accne,ınfertine,ınfertilitylity
PrematurPrematuree adrena adrenarcherche Increased Increased 7OHprogesteron7OHprogesterone e response to response to ACTHACTH
11 beta hydorxylase 11 beta hydorxylase deficiencydeficiency
Virilisation , hypertensionVirilisation , hypertension Macrogenitalia,Macrogenitalia, 11deoksi 11deoksi ccortıortıccosteronosteronee increaseincrease
11deoksı11deoksıccortıortıssol ol increaseincrease
PRA suppresedPRA suppresed
17’hydroxylase deficiency17’hydroxylase deficiency Sexual infantilisim Sexual infantilisim hypertension hypertension
Insufficient Insufficient virilivirilisation sation
hypertensionhypertension
Androstenedione/ Androstenedione/ testesterone increasedtestesterone increased
ACTH high, PRA lowACTH high, PRA low
Lipoid congenital adrenal hyperplasia
stAR proteinstAR protein absent absent
No steroid hormone synthesisNo steroid hormone synthesis
High High ACTH ACTH and and LHLH
Increased Increased LDL reLDL recc
ChCholesterololesterol increase and is storedincrease and is stored
MitoMitochchondrial ondrial and cellular damageand cellular damage
21-21- hydroxylase deficiency hydroxylase deficiency– Expressed in zExpressed in zona fasiona fasicculataulata– 21-21- hydroxylase gene hydroxylase gene(CYP21) (CYP21) localized on localized on
6p21.3 6p21.3 chrom chrom – 1/5000- 1/15000 1/5000- 1/15000 live birthlive birth
21- hydroxylase deficiency
Clinical forms Clinical forms
I- I- Classical Classical A- A- salt loosing salt loosing B- B- simple virilising simple virilising
II- Non II- Non classical classical
21- hydroxylase deficiency
- - 95% of C95% of CAH AH casescases
21- hydroxylase deficiency- 46,XX - 46,XX gender development disordergender development disorder mild cmild cliteromegalliteromegalyy →→phallus phallus penıs + complete penıs + complete labioscrotal fusion (I – V Prader staging)labioscrotal fusion (I – V Prader staging)- - ±± salt wasting salt wasting
21- hydroxylase deficiency
- 46,XY- 46,XY accelerated growth and virilization accelerated growth and virilization±± salt wasting salt wasting
21- hydroxylase deficiency
- 17 alfa - OHP significantly high- 17 alfa - OHP significantly high- Exaggerated 17OHP response to ACTH stimulation- Exaggerated 17OHP response to ACTH stimulation
21 hydroxylase deficiency resulting in salt wasting
- P450c21 activity is absent near complete- P450c21 activity is absent near complete- Girls are recognized at birth.- Girls are recognized at birth.- Boys - Boys
Can be overloolked Can be overloolked If not recognized death with salt wastingIf not recognized death with salt wastingSymptoms of salt wasting appear after the first 10-Symptoms of salt wasting appear after the first 10-
14 days of life14 days of life
11-beta hydroxylase deficiency11-beta hydroxylase deficiency– Expressed in zona fasiculataExpressed in zona fasiculata– Glucocortikoid deficiency + excess androgen Glucocortikoid deficiency + excess androgen
+ hypertension+ hypertension
11-beta hydroxylase deficiency11-beta hydroxylase deficiency
- Cortisol - Cortisol ↓↓- DOC ↑ 11 deoksicortisol ↑- DOC ↑ 11 deoksicortisol ↑
3-beta hydroxysteroid dehydrogenase 3-beta hydroxysteroid dehydrogenase deficiencydeficiency
– 46, XX fetus46, XX fetus high DHEAS high DHEAS– 46, XY fetus46, XY fetus low testosterone low testosterone
3-beta hydroxysteroid dehydrogenase deficiency
17 alpfa hydoxylase/ 17-20 liyase deficiency-P450c17 absence -P450c17 absence increase in corticosterone increase in corticosterone -Corticosterone has glucocortikoid activity.-Corticosterone has glucocortikoid activity.
-DOC -DOC ↑, sodium retantion , hypertension, hyperkalemia, plasma renin ↓ ↑, sodium retantion , hypertension, hyperkalemia, plasma renin ↓
Treatment Treatment
CAHCAH– Glucocorticoid treatment (hydrocortisone)10-Glucocorticoid treatment (hydrocortisone)10-
15 mg /m2/ day15 mg /m2/ day– Fludrocortisone 0,1mg/ dayFludrocortisone 0,1mg/ day
Acute adrenal insufficiency Acute adrenal insufficiency treatment treatment
Fluid and electrolyte treatment Fluid and electrolyte treatment 400cc/m2 serum saline IV in 1 hour or 400cc/m2 serum saline IV in 1 hour or 20cc/kg serum saline IV in 1 hour20cc/kg serum saline IV in 1 hour
– Fluid treatment according to dehydration degree Fluid treatment according to dehydration degree Glucocorticoid treatmentGlucocorticoid treatment– Hydrocortisone 100-75mg/m2/ day half of it as bolusHydrocortisone 100-75mg/m2/ day half of it as bolus– Remaining half is added to 24 hour fluidRemaining half is added to 24 hour fluid– 2. day 75mg/m2/ day oral2. day 75mg/m2/ day oral– 3. day 50mg/m2/ day3. day 50mg/m2/ day– 4. day 30 mg/m2/ day4. day 30 mg/m2/ day
Mineralocorticoid treatmentMineralocorticoid treatment– Fludrocortisone 0.1-0.15 mg/ day Fludrocortisone 0.1-0.15 mg/ day – Newborns need more doseNewborns need more dose
Salt 1-2 gr/ day Salt 1-2 gr/ day (1 gr salt 17mEq, dose can be (1 gr salt 17mEq, dose can be increased to 8mEq/kg)increased to 8mEq/kg)
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