congenital adrenal hyperplasia Flashcards
Adrenal steroidogenisis review
Cortisol secretion from the ZFR is controlled by ACTH (controlled by CRH)
Aldosterone secretion from the ZG is mainly controlled by the RAAS, affected by Na balancee and fluid volume status, serum potassium independently increases aldosterone and closes feedback loop since aldosterone stimulates potassium excretion
Secretion of androgen precursors or weak adrenal androgens normally matures at or slightly before the time of puberty (adrenarche), in virulizing forms of CAH, abnormally high ACTH stimulation causes increased androgen secretion
Adrenocortical Steroids
Glucocorticoids (cortisol)- secretion is controlled by ACTH (diurnal pattern, cortisol levels, stimulated by stress)
Mineralocorticoid (aldosterone)- Secretion controlled mainly by RAAS, Na balance and fluid volume status, Independent Stimulatory effect of serum potassium
Androgen precursors (DHEA and androstenedione)- increase at adrenarche, central control but exact mechanism unknown, in common (virilizing forms of CAH 21OH, 11BOH deficiency), chronically high ACTH stimulates excessive secretion, extra adrenal conversion to Testosteron and DHT is the major source of virulization
Extra- adrenal conversion to testosterone and DHT in virilizing (common) forms of CAH 21OH or 11 0H deficicecny
DHEA is shunted out of the adrenals as Androstenedione
Andrestenedione is converted to Testosterone (17HSD) and then DHt (via 5areductase
Males get the SRY gene–> SRY protein–> converts gonads to testes
Testes Make testosterone (converts Wolfian ducts to male reproductive tract) and DHT (Makes the male genitalia). Antimullerian hormone the mullerian ducts regress
In females there is no SRY gene–> no SRY protein, makes the gonads to ovaries, No testosterone ( the wolfian ducts regress), and no DHT (genitals are female), No antimullerian hormone (the mullerian ducts–> femal e reproductive tract)
congenital adrenal hyperplasia
Defect in the biosynthesis of cortisol (decrease in steroidogenic enzyme activity, typically due to mutations in genes encoding adrenal steroidogenic enzymes
Decrease in cortisol secretion causes increase in ACTH secretion (loss of negative feedback), hyperplasia enlargement of adrenal cortex trophic effects of ACTH
All forms are autosomal recessive traits
Phenotypes of congenital adrenal hyperplasia determinations
Magnitude of enzyme deficiency and which enzyme is affected
Which adrenal hormones are deficient or excessive
Increase in mineralocorticoid effect from precursors in the cortisol or aldosterone pathways -> sodium and fluid retention, mineralocorticoid (low renin) HTN, reflex decrease in renin and aldosterone secretion, potassium loss
Increase in adrenal androgen production and conversion to T and DHT androgen receptor agonists leads to virilization XX fetus
Decrease in adrenal mineralocorticoid synthesis results in salt wasting – sodium and fluid loss, increase in renin secretion, potassium retention
Adrenal steroidogenic defects/ congenital neonatal findings of CAH
2 most common forms are adrenal specific
Cause Virilization of the XX fetus (21 hydroxylase deficiency, 11B- hydroxylase deficiency)
Very uncommon forms (adrenals and gonads are affected)- XX female phenotype, XY female phenotype or undervirilized male phenotype. 17 hydroxylase/ 17,20 lyase deficiency, 3 B hydroxysteroid dehydrogenase 2 deficiency, side chain cleavage enzyme deficiency ( cyp p450 enzymes)
21 OH deficiency > 95% of CAH cases
Decrease in cortisol leads to increase in ACTH (loss of negative feedback), causes adrenal hyperplasia
Precursors spill into androgen pathway- virilizing
Failure to synthesize Doc and aldosterone decrease in mineralocorticoid production (salt wasting)
21OH deficiency causes 95% of the cases bc:
- genetic locus is within the HLA region of the MHC (high rate of immune diversity
- The 21 OH locus contains duplicated genes- an inactive pseudogene paired with lots of homologous
- during meiosis (during recomb- the pseudogene may pai with the acitve gene), recombination can result in unequal crossing over and loss of allels or transfer of point mutations
21 OH deficiency pediatric clinical presenttions
salt losing form: female newborns with marked virilization hopefully detected at birth, males and unrecognized females (vomiting, lethargy, dehydration in the first weeks of life)
Simple virilizing form (adequate mineralocorticoid production), females with varying degrees of amiguous genitalia, males or females with signs of androgen excess in early childhood, pubic hair, phallic growth linear growth acceleration
Latest onset form- older females, normal genitalia
21 OH deficiency lab and electrolytes
Elevated plasma levels- 17 OH progesterone, androstenedione, testosterone , DHEA, DHEAS, increased androgens cause of amibuous gentialia in XX fetus
Electrolyte imbalance with dehydration in salt losing form, due to inability to synthesize aldosterone and other adrenal mineralocorticoids, hyponatremia, hyperkalima, may have metabolic acidosis hypoglycemia, elevated plasma renin activity
CAH is most common cause of 46XXDSD (formerly female pseudohermaphroditism)
21 OH deficiency Newborn screening
17 OH progesterone concentration on filter paper blood spot, identifies Salt losing SL males early enough to prevent life threatening salt losing crisis. Pitfalls (false positive in premies, no differentiation of SL from non SL, rare false negatives, CYP21 genotyping may be used as confirmatory test
Treatment of 21 def CAH
glucocorticoid replacement, hydrocortisone decreases ACTH and thus lowers adrenal androgen precursor production, mineralocorticoid replacement and salt supplement in SL Form
Salt losing crisis (IV saline, solucortef), stress (extra hydrocortisome), surgery (genitalia in virulized females), psychological counseling
Prenatal treatment of 21 OH deficiecny
Avoid or reduce prenatal virilization in females by decreasing fetal ACTH (negative feedback)
Dexamethasone (not inactivated by placenta) is a potent glucocorticoid and decreases ACTH secretion
Stop only if fetus is 46XY or other tests rule out the diagnosis
11 B hydroxylase deficiency
2nd most common form of CAH
HTN virilizing CAH, low renin HTN
Clinical manifestations: XX ambiguous genitalia, postnatal virilization in both sexes (males present with early signs of puberty), HTN (after infancy), late onset forms XX
Excess spills over into androgen pathway–> virilization, OR spills in the cort pathway-> too much DOC, from the ZFR increases and binds to the mineralocorticoid receptors in the kidney leading to increase NA reabsorption, volume expansion, and HTN. This suppresses renin secretion from the kidney and leads to decreased aldosterone synthesis in the ZG
11 hydroxylase genetics
Duplicated locus 8 q22, CYP11B1 (11BOH in glucocorticoid path, stimulated by ACTH), CYP 11B2 (aldosterone synthesis, only in ZG-mineralocorticoid pathway, stimulated by RAAS)
CYP 11B1 mutated in 11OH deficiecny CAH (point mutation, small deletions, insertions, duplications, unequal crossover can cause chimeric nonfuctional 11 B OH gene
