Gender Development Disoreders and Congenital Adrenal Hyperplasia Dr Olcay Evliyaoğlu

Genes involved in gonadal differentiation Sertoli H. AMH DMRT1 ve 2 Testes SOX 9 WT1 LIM-1 Leydig H. Testosterone SRY Mesoderm Bipotantial gonad SF1 DAX 1 WNT 4 Estradiol Ovary

46, XY Gonadal Dysgenesis SOX9 SRY SF 1 Del(2q) Del (9p) WT1 Del (10g) Campomelic dysplasia SOX9 SRY SF 1 46, XY Gonadal Dysgenesis Del(2q) Adrenal insufficiency Del (9p) WT1 DMRT 1 - 2 Del (10g) Dennys-Drash sendromu Frasier sendromu WAGR sendromu Dup (X)p21 (DAX 1)

Gonadal dysgenesis

Disorders of steroid biosynthesis

Adrenal cortex

Embryology Mesoderm........adrenal cortex Ectoderm.........adrenal medulla Fetal adrenal cortex at 5-6 weeks Definite zone (outer layer) (glucocorticoid and mineralocorticoid) Fetal zone (inner layer) (androgenic precursors)

At birth adrenal gland is the 0,5 % of the birth weight Glomerulosa 15% Fasiculata 75% Reticularis 10%

Fetal zone disappears at about 1 years of age Glomerularis and fasiculata development continues untill 3 years Reticularis development continues untill 15 years

Congentital adrenal hyperplasia Enzyme deficiency Girls Boys Lab Lipoid form Sexual infantilism salt wasting Insufficient virilisation Salt wasting All steroid hormones are low Low response to ACTH stim ACTH and PRA high 3beta HSD Virilisation Delta steroids are increased 21 hydoxylase def classical type Macrogenıtalia 17OH progesterone increased Androgens increased ACTH and PRA increased 21 hydoxylase def late onset type Premature adrenarche, hirsutismus, menstrual irregularity ,acne,ınfertility Premature adrenarche Increased 7OHprogesterone response to ACTH 11 beta hydorxylase deficiency Virilisation , hypertension Macrogenitalia, 11deoksi cortıcosterone increase 11deoksıcortısol increase PRA suppresed 17’hydroxylase deficiency Sexual infantilisim hypertension hypertension Androstenedione/ testesterone increased ACTH high, PRA low

Lipoid congenital adrenal hyperplasia stAR protein absent No steroid hormone synthesis High ACTH and LH Increased LDL rec Cholesterol increase and is stored Mitochondrial and cellular damage

21- hydroxylase deficiency Expressed in zona fasiculata 21- hydroxylase gene(CYP21) localized on 6p21.3 chrom 1/5000- 1/15000 live birth

21- hydroxylase deficiency Clinical forms I- Classical A- salt loosing B- simple virilising II- Non classical

21- hydroxylase deficiency - 95% of CAH cases

21- hydroxylase deficiency - 46,XX gender development disorder mild cliteromegaly →phallus  penıs + complete labioscrotal fusion (I – V Prader staging) - ± salt wasting

21- hydroxylase deficiency - 46,XY accelerated growth and virilization ± salt wasting

21- hydroxylase deficiency - 17 alfa - OHP significantly high - Exaggerated 17OHP response to ACTH stimulation

21 hydroxylase deficiency resulting in salt wasting - P450c21 activity is absent near complete - Girls are recognized at birth. - Boys Can be overloolked If not recognized death with salt wasting Symptoms of salt wasting appear after the first 10-14 days of life

11-beta hydroxylase deficiency Expressed in zona fasiculata Glucocortikoid deficiency + excess androgen + hypertension

11-beta hydroxylase deficiency - Cortisol ↓ - DOC ↑ 11 deoksicortisol ↑

3-beta hydroxysteroid dehydrogenase deficiency 46, XX fetus high DHEAS 46, XY fetus low testosterone

3-beta hydroxysteroid dehydrogenase deficiency

17 alpfa hydoxylase/ 17-20 liyase deficiency -P450c17 absence  increase in corticosterone -Corticosterone has glucocortikoid activity. -DOC ↑, sodium retantion , hypertension, hyperkalemia, plasma renin ↓

Treatment CAH Glucocorticoid treatment (hydrocortisone)10-15 mg /m2/ day Fludrocortisone 0,1mg/ day

Acute adrenal insufficiency treatment Fluid and electrolyte treatment 400cc/m2 serum saline IV in 1 hour or 20cc/kg serum saline IV in 1 hour Fluid treatment according to dehydration degree Glucocorticoid treatment Hydrocortisone 100-75mg/m2/ day half of it as bolus Remaining half is added to 24 hour fluid 2. day 75mg/m2/ day oral 3. day 50mg/m2/ day 4. day 30 mg/m2/ day

Mineralocorticoid treatment Fludrocortisone 0.1-0.15 mg/ day Newborns need more dose Salt 1-2 gr/ day (1 gr salt 17mEq, dose can be increased to 8mEq/kg)