Enzymatic pathways for Cortisol and Aldosterone:

  Desmolase   17-alpha-Hydroxylase   C-17-Lyase  
Cholesterol ---------------------> Pregnenolone -----------------------> 17-oh-Pregnenolone -------------------> Dehydroepiandrosterone
    |   |   |
| 3-beta-oh-steroid
| 3-beta-oh-steroid
    Progesterone   17-oh-Progesterone   Androstenedione
  21-Hydoxylase | 21-Hydroxylase | Peripheral tissues |
    Deoxycorticosterone   11-Deoxycortisol   Testosterone
  11-beta-Hydroxylase | 11-beta-Hydoxylase |    
    Corticosterone   Cortisol    
  18-Hydroxylase |        
  18-Oxidase |        

I. Pathophysiology

  1. Deficiency in production of cortisol and/or mineralocorticoids
  2. Due to deficiencies in either:
    1. 21-alpha-hydroxylase (90% of pts with CAH)--this enzyme has some role in mineralocorticoid production
    2. 11-beta-hydroxylase (10% of pts with CAH)--not involved in mineralocorticoid production

II. Epidemiology

  1. Prevalence of "classic," severe form is aprox. 1:14,000
  2. Prevalence of milder forms is probably from 1:100 to 1:1,000

III. Clinical features

  1. Dependent on which enzyme is affected and also severity of the impairment of the enzyme activity
  1. Features due to inadequate production of glucocorticoids
    1. Insufficient production of glucocorticoids in times of physiologic stress (trauma, infection, etc.)
    2. Accumulation of glucocorticoid precursors, many of which are converted to androgenic steroids, causing:
      1. Shortened stature (due to premature closure of epiphyses, despite accelerated growth rate in childhood)
      2. Early puberty
      3. Acne
      4. Virilization of external genitalia (e.g. clitoromegaly, hypotrophy of labia, or ambiguous genitalia) and infertility in females, sometimes in utero
      5. Hirsutism and amenorrhea in females
  1. Features due to inadequate production of mineralocorticoids (Seen in 21-alpha-hydroxylase deficiency, the "salt-wasting" form of CAH)
    1. Hyponatremia
    2. Hyperkalemia
    3. Hypotension with syncope or presyncope
  1. Features due to accumulation of deoxycortisol (a cortisol precursor which accumulates in 11-beta-hydroxylase deficiency, which has glucocorticoid and mineralocorticoid properties)
    1. Hypertension

IV. Diagnosis

  1. ACTH stimulation test to screen for deficiencies in glucocorticoid production capacity (check 17-oh-progesterone and deoxycortisol levels before and 1h after ACTH 250ug IV)
  2. Elevated serum levels of 17-hydroxyprogesterone suggest 21-alpha-hydroxylase deficiency
  3. E;evated serum levels of deoxycorticosterone and 11-deoxycortisol suggest 11-beta-hydroxylase deficiency
  4. Prenatal diagnosis can be achieved via chorionic villus sampling or amniocentesis using DNA analysis or measuring 17-hydroxy steroids in amniotic fluid

V. Treatment

  1. Glucocorticoids at lowest dose that achieves adrenal suppression
    1. Hydrocortisone (us. 6-25mg/m2/d divided BID-TID) is preferred because its physiologic action is closest to that of endogenonus Cortisol; also lower potential for growth suppression in children than other glucocorticoids.
    2. Remember to give "stress doses" of steroids (3-10x maintenance dose) during acute illness, perioperatively, etc.
  2. Mineralocorticoids (e.g. Fludrocortisone 0.05-0.2mg/d) as adjunctive therapy to glucocorticoids may be helpful in achieving better adrenal suppression w/less risk of Cushing's
  3. Antiandrogens, e.g. Flutamide (e.g. 10mg/kg/d divided TID) often used, again to reduce necessary dose of glucocorticoids
  4. Aromatase inhibitors, e.g. Testolactone (prevent conversion of androgens to estrogens) may help kids with mild CAH reach their height potential
  5. Prenatal treatment with dexamethasone (0.02 mg/kg/d divided BID-TID) may reduce risk of virilization of external genitalia in female fetuses.

(Source: AFP 59:1190, 1999)