21-hydroxylase deficiency pathophysiology: Difference between revisions
No edit summary |
No edit summary |
||
| Line 22: | Line 22: | ||
It is now possible to test for [[heterozygote|heterozygosity]] by measuring 17-hydroxyprogesterone elevation after [[ACTH]] stimulation, or more recently by direct gene sequencing. | It is now possible to test for [[heterozygote|heterozygosity]] by measuring 17-hydroxyprogesterone elevation after [[ACTH]] stimulation, or more recently by direct gene sequencing. | ||
==References== | ==References== | ||
{{Reflist|2}} | {{Reflist|2}} | ||
Revision as of 20:46, 3 September 2015
|
Congenital adrenal hyperplasia due to 21-hydroxylase deficiency Microchapters |
|
Differentiating Congenital adrenal hyperplasia due to 21-hydroxylase deficiency from other Diseases |
|---|
|
Diagnosis |
|
Treatment |
|
Case Studies |
|
21-hydroxylase deficiency pathophysiology On the Web |
|
American Roentgen Ray Society Images of 21-hydroxylase deficiency pathophysiology |
|
Directions to Hospitals Treating Congenital adrenal hyperplasia due to 21-hydroxylase deficiency |
|
Risk calculators and risk factors for 21-hydroxylase deficiency pathophysiology |
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 is the result of multiple enzymatic deficiencies.
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.
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
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.