embryology and CAH

Question 1

key to sexual dimorphism

Answer 1

SRY (sex determining region of Y) which is located on the short arm of the Y chromosome. Presence of Y chromosome independent of number of X chromosomes imparts male development by initiating testicular differentiation

Question 2

describe development of undifferentiated gonads

Answer 2

At 4-5 weeks: appear as paired genital ridges which form in the posterior abdominal wall medial to mesonephros. They form from proliferation of the epithelium and condensation of underlying mesenchyme

Question 3

Trx factors in genital ridge

Answer 3

1. Wilms tumor related gene (WT-1) - mutations associated with gonadal dysgenesis and Wilms tumor/ nephropathy. 2. NR5A1 aka steroidogenic factor (SF-1)- deletions can cause gonadal dysgenesis, adrenal failure and persistent mullerian structures

Question 4

Germ cell development

Answer 4

Initially develop in yolk sac then migrate to genital ridge at 6th week. If this does not occur, gonads don’t develop (streak gonads)

Question 5

development of primitive sex cords

Answer 5

During arrival of of primordial germ cells, the epithelium of the genital ridge proliferates, and epithelial cells penetrate the underlying mesenchyme, forming the primitive sex cords. Indifferent gonad has an inner medulla and outer cortex

Question 6

Describe gonad differentiation into testes

Answer 6

At 6 weeks- SRY expression. Primitive sex cords form testis or medullary cords. Mesonephric cells migrate into testis. Differentiation of sertoli cells (from surface epithelium) and leydig cells. Tunica albuginea separates testis cords from surface epithelium. Sertoli cells are in the testis cords and leydig cells lie between testis cords (bgin production of testosterone by 8th week)

Question 7

Trxn factors important for testicular differentiation

Answer 7

1. SOX-9: target of SRY. With SF-1 elevates anti-mullerian hormone conc.

Question 8

Camptomelic dysplasia

Answer 8

deletion/mutation of SOX-9. Results in severe skeletal dysplasia and gonadal dysgenesis in 75% of pts.

Question 9

Describe gonad differentiation into ovaries plus genes involved

Answer 9

Requires 2 X chromosomes and absent Y, plus migration of germ cells. Cortex develops into ovaries and medullary cords degenerate. Genes involved are DAX1, WNT-4, RSPO1 and FOXL2

Question 10

List the internal duct structures in male

Answer 10

Wolffian ducts aka mesonephric ducts develop into epididymis, vas deferens and seminal vesicles

Question 11

Male internal duct differentiation

Answer 11

8 weeks- Testosterone produced by Leydig cells stimulates growth of wolffian structures. Antimullerian hormone produced by Sertoli cells- induces mullerian duct regression

Question 12

List the internal duct structures in female

Answer 12

Paramesonephric aka mullerian ducts develop into fallopian tuves, midline uterus, upper portion of vagina

Question 13

Female internal duct differentiation

Answer 13

8 weeks- absence of local testosterone and AMH causes Wolffian duct regression and retention of mullerian duct

Question 14

Rokitansky syndrome

Answer 14

absent or underdeveloped müllerian structures in a 46,XX female

Question 15

List the indifferent external genitalia and the structures they develop into

Answer 15

genital tubercle: glans penis or clitoris. urethral folds: penile urethra or labia minora. Labial-scrotal (genital) swellings: scrotum or labia majora

Question 16

What hormones determine development of male external genitalia

Answer 16

testosterone and DHT- test is converted to DHT by 5 alpha-reductase. DHT has higher affinity for receptor than test. Penile growth and formation of penile urethra is particularly dependent on DHT.

Question 17

Testosterone production is stimulated by…

Answer 17

In 1st trimester, placental HCG stimulates leydig cells to make testosterone. After 1st trimester, hypothalamic-pituitary-testicular axis required for continued testosterone production

Question 18

When is male external genitalia formation complete

Answer 18

By 13 weeks- can not be corrected by subsequent androgen exposure

Question 19

Female androgen exposure in utero results in…

Answer 19

Prior to 13 weeks: urogenital sinus and insertion of urethra into vagina. After 13 weeks can cause clitoromegaly but cannot result in posterior labial fusion or penile urethra

Question 20

define cryptorchidism

Answer 20

Failure of the testes to reach the scrotal sac. Testes reach the inguinal region by 12 weeks and scrotum by 33 weeks

Question 21

Prader classification of external genitalia

Answer 21

stage 0 is female. Stage 5 is male. And everything in between

Question 22

Causes of 46, XX disorder of sex development

Answer 22

Congenital adrenal hyperplasia (most common), SRY translocation, ovotesticular DSD and gestational hyperandrogenism

Question 23

Causes of 46, XY disorder of sex development

Answer 23

Pure/partial gonadal dysgenesis (SRY mutation, underexpressed SOX9), SF1 or WT1 mutations, duplication of DAX1 or Wnt-4, underexpression of DMRT1 and DMRT2), mixed gonadal dysgenesis (45X/ 46 XY), testicular regression, or Leydig cell dysfunction, defects in steroid metabolism, defects in androgen action

Question 24

List possible defects in steroidogenesis that can cause 46 XY disorder of sex development

Answer 24

7-dehydrocholesterol reductase deficiency (SLOs), STAR deficiency, 3-β-hydroxysteroid dehydrogenase deficiency, 17α-hydroxylase and 17,20 lyase deficiency, 17b-Hydroxysteroid dehydrogenase deficiency

Question 25

List possible defects in testosterone metabolism that can cause 46 XY disorder of sex development

Answer 25

5 alpha reductase deficiency- AR disorder. Results in Low DHT which affects development of penis, penile urethra and scrotum

Question 26

5 alpha reductase deficiency Sx

Answer 26

Males are undervirilized. Testes usually in inguinal canal or labial-scrotal folds. Wollfian ducts differentiated. At puberty, spontaneous virilization occurs. High rate of male gender identity

Question 27

Complete androgen insensitivity syndrome cause and Sx- gonads, external genitalia, puberty, identity

Answer 27

Mutation in androgen receptor gene. 46 XY, Testes develop intraabdominally or in inguinal canal and androgen is produced by body can not respond to it. Normal female external genitalia with short vagina and absence of Mullerian and Wollfian structures. At puberty, breast develop due to test conversion to estrogen. LIttle/no pubic or axillary hair. female gender identity

Question 28

layers of adrenal gland and what they produce

Answer 28

Zona Glomerulosa – Mineralocorticoids. Zona Fasciculata – Glucocorticoids. Zona Reticularis - Androgens

Question 29

What causes congenital adrenal hyperplasia

Answer 29

21-hydroxylase deficiency (most common- AR), 11B-hydroxylase deficiency, STAR deficiency, 3B-hydroxysteroid dehydrogenase deficiency, and 17alpha hydroxylase/ 17,20 lyase deficiency

Question 30

How does 21-hydroxylase deficiency cause CAH

Answer 30

21-hydroxylase is involved in making aldosterone and cortisol. Since these are not made, the precursors build up and are shuttled to the testosterone pathway producing an excess of testosterone from the adrenal glands

Question 31

21-hydroxylase deficiency Sx in males and females

Answer 31

males: no genital abnormalities. Females: virilization of external genitalia. Both: hyperpigmentation, hyponatremia/hyperkalemia due to aldosterone deficiency. Mild forms may present later with early pubic hair, axillary hair, penile/clitoral enlargement

Question 32

21-hydroxylase deficiency diagnosis

Answer 32

Suspected in virilized XX infant, or XY infant with hyponatremia and hyperkalemia. Confirmed by 17-OH progesterone elevation.

Question 33

21-hydroxylase deficiency treatment

Answer 33

Surgery in females. Hydrocortisone (replace cortisol), florinef (replace mineralocorticoid deficiency). For acute adrenal insufficency- IM or IV solu-cortef

Question 34

11B-hydroxylase deficiency

Answer 34

11B-hydroxylase is a step in making cortisol and aldosterone. Deficiency results in a build up of 11-deoxycorticoserone and 11-deoxycortisol. Virilization, but no salt wasting b/c 11-deoxycorticosterone has mineralocorticoid activity. HTN is frequent finding (due to salt retention)

Question 35

StAR protein deficiency

Answer 35

Congenital lipoid hyperplasia. StAR is involved in trasnfer of cholesterol from outer to inner mitochondrial membrane . This results in a deficiency of aldosterone, cortisl and testosterone. Females have normal genitalia, males have female genitalia. Salt wasting. Fatal if not detected early

Question 36

StAR deficiency imaging

Answer 36

Cholesterol filled adrenal gland is enlarged

Question 37

3B- hydroxysteroid dehydrogenase deficiency

Answer 37

virilization in girls, undervirilization in boys, salt wasting

Question 38

17alpha hydroxylase/ 17,20 lyase deficiency

Answer 38

excess aldosterone and deficient cortisol and testosterone. HTn (secondary to increased 11-deoxycorticosterone), hypokalemia. Females born with normal genitalia and present at puberty with failure to develop secondary sex characteristics. Males born undervirilized

Question 39

5) Categorize adrenal enzymatic blocks as: 1) salt-wasting/salt retaining, and 2) virilizing/undervirilizing

Answer 39

salt wasting: 21 hydroxylase deficiency, StAR deficiency, 3B hydroxysteroid dehydrogenase deficiency, Salt retaining: 11B-hydroxylase deficiency, 17alpha hydroxylase/ 17,20 lyase. Virilizing: 21-hydroxylase def, 11B-hydroxylase def, 3B-hydroxysteroid dehydrogenase (girls only) Undervirilzing: StAr def, 3B-hydroxysteroid dehydrogenase (boys only), 17a- hydroxylase/ 17,20 lyase def (boys only)