Congenital Adrenal Hyperplasia

Question 1

congenital adrenal hyperplasia can be caused by loss of any one of what 4 enzymes for cortisol synthesis?

Answer 1

1. 21-alpha hydroxylase (most common)
2. 11-beta hydroxylase
3. 17-alpha hydroxylase
4. 3-beta hydroxysteroid dehydrogenase

Question 2

what is the common thread/pathology of all forms of congenital adrenal hyperplasia?

Answer 2

all result in low cortisol due to enzyme deficiency in one of the enzymes needed to synthesize cortisol

this stimulates ACTH release (which functions to increase cortisol synthesis) and adrenal hyperplasia while causing increased production of other hormones that are also made from cholesterol - mineralocorticoids and androgens

Question 3

what are the signs indicating congenital adrenal hyperplasia in babies?

Answer 3

remember these occur in babies, who can’t speak! so instead, low cortisol is detected as hypoglycemia and nausea/vomiting

Question 4

how does 21-alpha hydroxylase deficiency present?

Answer 4

most common form of congenital adrenal hyperplasia, cannot make cortisol or aldosterone so cholesterol is funneled into androgen synthesis

presents with symptoms of low cortisol and low mineralocorticoids and excess androgen

girls —> ambiguous genitalia
boys —> precocious puberty

Question 5

how does 11-beta hydroxylase deficiency affect steroid hormone synthesis?

Answer 5

recall cholesterol can be funneled into either aldosterone, cortisol, or androgen synthesis

11-beta hydroxylase is needed for cortisol synthesis and conversion of 11-deoxycorticosterone (mineralocorticoid intermediate) to aldosterone

11-deoxycorticosterone is weak but functional mineralocorticoid, so there is only deficiency of cortisol

Question 6

how does 11-beta hydroxylase deficiency present?

Answer 6

11-beta hydroxylase is needed for cortisol synthesis and conversion of 11-deoxycorticosterone (weak mineralocorticoid intermediate) to aldosterone

presents with symptoms of:
- low cortisol
- excess androgens: female ambiguous genitalia, male precocious puberty
- excess mineralocorticoids: HTN, hypokalemia

Question 7

what is the difference in presentation of 21-alpha hydroxylase vs 11-beta hydroxylase?

Answer 7

both enzymes are required for both cortisol and aldosterone synthesis; however, 11-beta hydroxylase is required after synthesis of 11-deoxycorticosterone (weak mineralocorticoid intermediate)

therefore, while both present with cortisol deficiency and androgen excess, 11-beta hydroxylase deficiency also presents with increased mineralocorticoid activity (HTN and hypokalemia)

Question 8

how does 17-alpha hydroxylase deficiency affect steroid hormone synthesis?

Answer 8

required for synthesis of both cortisol and androgens, so excess cholesterol is funneled into aldosterone synthesis

Question 9

what is the function of cytochrome P450c17 (CYP17A1) and where is it found?

Answer 9

found in adrenal glands and gonads, catalyzes 2 reactions: 17-hydroxylase (cortisol and androgen synthesis) and 17,20-lyase (androgen synthesis)

Question 10

how does 17-alpha hydroxylase deficiency present?

Answer 10

required for synthesis of both cortisol and androgens, excess cholesterol is funneled into aldosterone synthesis

presents with symptoms of:
- low cortisol
- excess mineralocorticoids: HTN, hypokalemia
- low androgens (recall this enzyme is part of larger CYP17A1 which is found in both adrenal gland and gonads): ambiguous external genitalia + undescended testes in males, primary amenorrhea at puberty in females

Question 11

which congenital adrenal hyperplasia is often diagnosed at puberty and why does this make sense?

Answer 11

17-alpha hydroxylase deficiency: required for synthesis of both cortisol and androgens, excess cholesterol is funneled into aldosterone synthesis

presents with androgen deficiency, which becomes apparent at puberty:
- males (XY) have female or ambitious external genitalia, but absent uterus/fallopian tubes and undescended testes
- females (XX) are normal at birth but have primary amenorrhea at puberty (theca cells cannot make estradiol from androgens)

Question 12

how does 3-beta hydroxysteroid dehydrogenase deficiency affect steroid hormone synthesis?

Answer 12

3-beta hydroxysteroid dehydrogenase deficiency is required for cholesterol synthesis into aldosterone, cortisol, AND androgens

very rare, presents with deficiency in all three hormones

Question 13

which congenital adrenal hyperplasia presents with deficiency of aldosterone, cortisol, AND androgens

Answer 13

3-beta hydroxysteroid dehydrogenase - required for cholesterol synthesis into aldosterone, cortisol, AND androgens

Question 14

which steroid hormone intermediate is measured in congenital adrenal hyperplasia newborn screening, and why does this make sense?

Answer 14

17-hydroxyprogesterone - elevated in 21-alpha hydroxylase deficiency, which is the most common form of CAH

Question 15

explain why glucocorticoids can be used to treat congenital adrenal hyperplasia

Answer 15

all forms present with cortisol deficiency, which can be replaced by glucocorticoids

this will also lower ACTH levels, thereby stopping overproduction of other hormones made from cholesterol (androgens or aldosterone)

Question 16

what type of RTA presents with 21-hydroxylase deficiency?

Answer 16

21-hydroxylase deficiency —> block in cortisol and aldosterone production

—> “salt wasting”: hyponatremia + hyperkalemia —> Type IV rental tubule acidosis

Question 17

Newborn is presenting with dehydration, hypoglycemia, Type IV RTA, and low BP, putting them at risk for shock. Further, ambiguous genitalia is noted. What enzyme are they deficient in?

Answer 17

21-hydroxylase deficiency —> block in cortisol and aldosterone production

XX infant will present with ambiguous genitalia due to androgen overproduction

[Type IV RTA —> hyponatremia, hyperkalemia]

Question 18

how does non-classic 21-hydroxylase deficiency present?

Answer 18

21-hydroxylase deficiency —> block in cortisol and aldosterone production

classic form presents with salt wasting + hypoglycemia/low BP + androgen excess

non-classic does NOT present with salt wasting and external genitalia are normal… presents with hirsutism + oligomenorrhea/infertility (may resemble PCOS!)

Question 19

which of the following forms of congenital adrenal hyperplasia presents with HTN?
a. 21-hydroxylase deficiency
b. 11-hydroxylase deficiency
c. 3-beta HSD deficiency

Answer 19

11-hydroxylase deficiency —> block in cortisol synthesis + excess androgen synthesis, but deoxycorticosterone (DOC) intermediate can act as a mineralocorticoid —> hypertension

note this will cause RAAS activity (renin, AT2) to go DOWN via negative feedback!

Question 20

what is the source of placental aromatase deficiency (fetal or maternal) and how does it present?

Answer 20

maternal/placental aromatase deficiency: androgens cannot be converted to estrogens, BOTH female newborn AND mother will demonstrate virilization

Question 21

An X,Y infant presents with female external genitalia and HTN. What type of congenital adrenal hyperplasia is most likely?

Answer 21

17-alpha-1-hydroxylase/ 17,20-lyase deficiency: blocks cortisol and androgen production

no adrenal or gonadal androgens —> low DHEA, androstenedione, testosterone, and DHT

blocked cortisol production —> increased ACTH —> increased corticosterone which prevents adrenal crisis (mineralocorticoid)

increased deoxycorticosterone (DOC, mineralocorticoid) —> HTN with low RAAS activity

Question 22

which 2 forms of congenital adrenal hyperplasia present with HTN?

Answer 22

1. 11-hydroxylase deficiency —> block in cortisol synthesis + excess androgen synthesis
2. 17-alpha-1-hydroxylase/ 17,20-lyase deficiency: blocks cortisol and androgen production

in both cases, deoxycorticosterone (DOC) intermediate can act as a mineralocorticoid —> HTN + low RAAS activity

Question 23

intact synthesis of testosterone, cortisol, and aldosterone but ABSENT DHT = deficiency in what enzyme?

Answer 23

5-alpha-reductase deficiency in the testes

testes develop (AMH produced) but fail to descend, under-virilization or female external genitalia, masculinization of non-genital tissues at puberty (+/- growth of phallus)