A. Pathogenesis
[Figure] "Steroid Metabolism"

1. Overall incidence of severe classic form is ~1:15,000 births
2. Group of autosomal recessive disorders of cortisol biosynthesis
3. Defects are found in the cortical cells of the adrenal glands
4. Common CAH
   1. ~95% of cases caused by 21-hydroxylase deficiency (chromosome 6p21.3 gene)
   2. Carrier state 1:60 for 21-hydroxylase (CYP21A2, P450c21) mutations
5. Uncommon CAH
   1. ~5% of cases are caused by 11-hydroxylase deficiency
   2. Smaller number of cases of 17a-hydroxylase or other deficiencies [3]
   3. Mutation in P450 oxidoreductase also causes CAH [4]
6. Leads to decreased production of both cortisol and aldosterone
7. Two Forms of CAH
   1. Salt-losing (~67%) - presents as life-threatening adrenal crisis age 2-3 weeks
   2. Simple virilizing (non-salt losing, ~33%) - presents with early virilization within 5 years
   3. Both forms include ambiguous genitalia in girls

B. Endocrine Effects

1. Reduced Cortisol Secretion
   1. Absence of cortisol leads to lack of feedback inhibition in pituitary and hypothalamus
   2. This leads to increased adrenocorticotropic hormone (ACTH) release from pituitary
   3. Chronic elevated ACTH leads to bilateral adrenal hyperplasia
   4. Also leads to increased corticotropin releasing hormone (CRH) from hypothalamus
2. ~75% of CAH lack aldosterone production
   1. Reduced aldosterone leads to increased renin and then angiotensin II (AT2) production
   2. This causes hypertension (HTN)
   3. Reduced aldosterone leads to sodium loss and potassium retention (hyperkalemia)
3. Effects on Sex Steroids
   1. Enzyme deficiency leads to accumulation of progesterone and 17-OH-progesterone
   2. These precursors are converted to androstenedione and then to testosterone
   3. Elevated adrenal androgen levels lead to ambigous genitalia in women
   4. Elevated adrenal androgens in boys lead to penile growth with small tests
   5. Precocious puberty can occur
4. Effects on Adrenal Medula
   1. Normal glucocorticoid levels are required for normal adrenal medullary development
   2. 21-hydroxylase deficiency leads to adrenomedullary hypofunction (as well as dysplasia) [5]
   3. Thus, sympathetic (epinephrine/metanephrine) neuroendocrine systems are compromised

C. Symptoms of Untreated CAH

1. Severity of symptoms depend on effects of specific 21-hydroxylase mutations
2. Life-threatening adrenal insufficiency (salt-losing form)
3. Pseudo-precocious puberty
4. Virilization of female genitalia
5. Premature growth acceleration
6. Premature epiphyseal fusion
7. Adult short stature
8. Hirsutism

D. Laboratory Diagnosis of Common CAH

1. 17-Hydroprogestone (17HP) Levels (normal <3 nmol/L)
   1. Classic CAH: Highly elevated 17HP (>242 nmol/L) in random blood sample
   2. Nonclassic CAH: Corticotropin stimulation test leading to increased 17HP
   3. Many carriers will have slightly raised levels of 17HP (<30nmol/L)
2. Generally elevated testosterone
3. Normal or reduced cortisol and aldosterone
4. Normal dehydroepiandrosterone (DHEA)
5. Above normal renin levels
6. Normal FSH, LH, and prolactin

E. Treatment

1. Treatment Goals
   1. Normalize glucocorticoid and mineralocorticoid levels
   2. Suppress androgen production, at least partly
2. Glucocorticoid Replacement
   1. Hydrocortisone - for replacement of glucocorticoid activity (some mineralocorticoid)
   2. Hydrocortisone dose 10-20mg/m2 per day (three divided doses) under normal conditions
   3. Under stress conditions, hydrocortisone doses up to 100-200mg/m2 divided
   4. Stress dosing of glucocorticoids is critical as patients cannot mount a normal response
   5. Maternal dexamethasone can be given to pregnant women with a fetus with/at risk of CAH
3. Aldosterone Replacement
   1. Fludrocortisone - may be added for patients with severe salt-losing forms; 0.1-0.2mg/d
   2. High salt diet (1-2gm of sodium chloride daily) should be added with salt-losing forms
4. Blocking Virilization
   1. Androgen receptor blocker - flutamide (DHT receptor blocker)
   2. Aromatase inhibitor - testolactone
   3. Cyproterone has also been used for androgen suppression
   4. Ambiguous genitalia best managed surgically during age 2-6 months in girls

References

1. Merke DP and Bornstein SR. 2005. Lancet. 365:2125
2. Speiser PW and White PC. 2003. NEJM. 349(8):776
3. Adashi EY and Hennebold JD. 1999. NEJM. 340(9):709
4. Arlt W, Walker EA, Draper N, et al. 2004. Lancet. 363(9427):2128
5. Dennery PA, Seidman DS, Stevenson DK. 2001. NEJM. 344(8):581