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)