21-hydroxylase deficiency pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Ahmad Al Maradni, M.D. [2]
Overview
Development of congenital adrenal hyperplasia due to 21-hydroxylase deficiency is the result of defective P450c21 enzyme.
Pathophysiology
The defective enzyme P450c21, commonly referred to as 21-hydroxylase (21-OH), is embedded in the smooth endoplasmic reticulum of the cells of the adrenal cortex. It catalyzes hydroxylation of 17-hydroxyprogesterone to 11-deoxycortisol in the glucocorticoid pathway from pregnenolone to cortisol. It also catalyzes hydroxylation of progesterone to 11-deoxycorticosterone (DOC) in the mineralocorticoid pathway from pregnenolone to aldosterone.[1]
Deficient activity of this enzyme reduces the efficiency of cortisol synthesis, with consequent elevation of ACTH levels and hyperplasia of the adrenal cortex. ACTH stimulates uptake of cholesterol and synthesis of pregnenolone. Steroid precursors up to and including progesterone, 17-hydroxypregnenolone, and especially 17-hydroxyprogesterone (17OHP) accumulate in the adrenal cortex and in circulating blood. Blood levels of 17OHP can reach 10-1000 times the normal concentration.
Since 21-hydroxylase activity is not involved in synthesis of androgens, a substantial fraction of the large amounts of 17-hydroxypregnenolone is diverted to synthesis of DHEA, androstenedione, and testosterone beginning in the third month of fetal life in both sexes.
Synthesis of aldosterone is also dependent on 21-hydroxylase activity. Although fetal production is impaired, it causes no prenatal effects, as the placental connection allows maternal blood to "dialyze" the fetus and maintain both electrolyte balance and blood volume.
Genetics[1]
File:Autorecessive.svg The CYP21 gene for the P450c21 enzyme (also known as 21-hydroxylase) is at 6p21.3, amid genes HLA B and HLA DR coding for the major human histocompatibility loci (HLA). CYP21 is paired with a nonfunctional pseudogene CYP21A. Scores of abnormal alleles of CYP21 have been documented, most arising from recombinations of homologous regions of CYP21 and CYP21A. Differences in residual enzyme activity of the various alleles account for the various degrees of severity of the disease. Inheritance of all forms of 21-hydroxylase CAH is autosomal recessive.
Persons affected by any forms of the disease have two abnormal alleles, and both parents are usually carriers (heterozygotes). When parents both carry an abnormal allele, each child has a 25% chance of having the disease, a 50% chance of being an asymptomatic carrier like parents, and a 25% chance of having two normal genes.
It is now possible to test for heterozygosity by measuring 17-hydroxyprogesterone elevation after ACTH stimulation, or more recently by direct gene sequencing.
Late onset (nonclassical) congenital adrenal hyperplasia
Other alleles result in even milder degrees of hyperandrogenism that may not even cause problems in males and may not be recognized until adolescence or later in females. Mild androgen effects in young women may include hirsutism, acne, or anovulation (which in turn can cause infertility).
Virilization of female infants[1]
Virilization of genetically female (XX) infants usually produces obvious genital ambiguity. Inside the pelvis, the ovaries are normal and since they have not been exposed to testicular antimullerian hormone, the uterus, fallopian tubes, upper vagina, and other mullerian structures are normally formed as well. However, the high levels of testosterone in the blood can enlarge the phallus, partially or completely close the vaginal opening, enclose the urethral groove so that it opens at the base of the phallus, on the shaft or even at the tip like a boy. Testosterone can cause the labial skin to become as thin and rugated as a scrotum, but cannot produce palpable gonads (i.e., testes) in the folds.
Childhood onset (simple virilizing) congenital adrenal hyperplasia
Mutations that result in some residual 21-hydroxylase activity cause milder disease, traditionally termed simple virilizing congenital adrenal hyperplasia (SVCAH). In these children the mineralocorticoid deficiency is insignificant and salt-wasting does not occur. The androgen excess is mild enough that virilization is not apparent or goes unrecognized at birth and in early childhood. However, androgen levels are above normal and slowly rise during childhood, producing noticeable effects between 2 and 9 years of age.
Salt-wasting crises in infancy
The excessive amounts of adrenal testosterone produce little effect on the genitalia of male infants with severe congenital adrenal hyperplasia. If a male infant with congenital adrenal hyperplasia is not detected by newborn screening, he will appear healthy and normal and be quickly discharged home to his family. However, the lack of aldosterone results in a high rate of sodium loss in the urine. Urinary sodium concentrations may exceed 50 mEq/L. With this rate of salt loss, the infant cannot maintain blood volume, and hyponatremic dehydration begins to develop by the end of the first week of life. Potassium and acid excretion are also impaired when mineralocorticoid activity is deficient, and hyperkalemia and metabolic acidosis gradually develop. Ability to maintain circulation is further limited by the effect of cortisol deficiency. The early symptoms are spitting and poor weight gain, but most infants with severe congenital adrenal hyperplasia develop vomiting, severe dehydration, and circulatory collapse (shock) by the second or third week of life.