The deficiency in one of the five enzymes required in the steroidogenic pathway for the biosynthesis of cortisol (hydrocortisone) results in a group of diseases known collectively as congenital adrenal hyperplasia (CAH).
The diseases are inherited as autosomal recessive disorders. As a result of impaired cortisol synthesis by the adrenal cortex, there is excessive secretion from the pituitary of adrenocorticotropic hormone (ACTH), or corticotrophin, which stimulates the adrenal cortex to synthesize and secrete more cortisol. ACTH stimulation causes diffuse hyperplasia of the adrenal gland, and usually the disease is recognized in infancy. Greater than 90% of cases of CAH are caused by reduced or absent activity of the 21-hydroxylase enzyme, known as CYP21, or Classic CAH. This form of CAH presents in early infancy, early childhood or adolescence, depending upon the magnitude of the deficient enzyme activity. In severe cases, very low CYP21 activity causes low aldosterone secretion, salt loss and hypovolemia. Combined with hypotension and hypoglycemia from cortisol deficiency, this results in neonatal death during the first month of life if not recognized and adequately treated. Because the androgen synthetic pathway does not require CYP21 activity, there is excess androgen secretion, and virilization in the female fetus causing varying degrees of sexual ambiguity at birth.
The immediate precursor in classic CAH and the substrate for CYP21 is 17- hydroxyprogesterone (17-OHP). The measurement of 17-OHP in the newborn blood spot can discriminate infants with salt-wasting or Simple Virilizing CAH from non-affected infants. The newborn screening test usually does not detect attenuated or late onset nonclassical CAH patients. When values exceed the normal range, 17-OHP analysis is repeated using organic extraction to remove interfering substances. The normal values for 17-OHP vary with birth weight and gestational age, and cutoffs should be adjusted accordingly.
Oral hydrocortisone in a physiologic replacement dose is the treatment of choice for CAH. The more potent glucocorticoids are contraindicated in the growing child and adolescent because of the difficulty in determining a physiologic versus pharmacologic dose. In children with salt-losing CAH, 9·-fluorohydrocortisone should maintain normal electrolyte balance without excessive natriuretic or glucocorticoid effects. Monitoring plasma 17-OHP and androgen levels, growth velocity, and an occasional bone age offer the basic tools for adequate, effective therapy.