Congenital adrenal hyperplasia classification
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Congenital adrenal hyperplasia main page |
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [2]
Overview
Types of CAH
Cortisol is an adrenal steroid hormone necessary for life; production begins in the second month of fetal life. Inefficient cortisol production results in rising levels of ACTH, which in turn induces overgrowth (hyperplasia) and overactivity of the steroid-producing cells of the adrenal cortex. The defects causing adrenal hyperplasia are congenital (i.e., present at birth).
Cortisol deficiency in CAH is usually partial, and not the most serious problem for an affected person. Synthesis of cortisol shares steps with synthesis of mineralocorticoids such as aldosterone, androgens such as testosterone, and estrogens such as estradiol. The resulting excessive or deficient production of these three classes of hormones produce the most important problems for people with CAH. Specific enzyme inefficiencies are associated with characteristic patterns of over- or underproduction of mineralocorticoids or sex steroids.
In all its forms, congenital adrenal hyperplasia due to 21-hydroxylase deficiency accounts for about 95% of diagnosed cases of CAH. Unless another specific enzyme is mentioned, "CAH" in nearly all contexts refers to 21-hydroxylase deficiency.
- Severe 21-hydroxylase deficiency causes salt-wasting CAH, with life-threatening vomiting and dehydration occurring within the first weeks of life. Severe 21-hydroxylase deficiency is also the most common cause of ambiguous genitalia due to prenatal virilization of genetically female (XX) infants.
- Moderate 21-hydroxylase deficiency is referred to as simple virilizing CAH; and typically is recognized by causing virilization of prepubertal children.
- Still milder forms of 21-hydroxylase deficiency are referred to as non-classical CAH and can cause androgen effects and infertility in adolescent and adult women.
CAH due to deficiencies of enzymes other than 21-hydroxylase present many of the same management challenges as 21-hydroxylase deficiency, but some involve mineralocorticoid excess or sex steroid deficiency.
- Lipoid congenital adrenal hyperplasia
- Congenital adrenal hyperplasia due to 17α-hydroxylase deficiency
- Congenital adrenal hyperplasia due to 3β-hydroxysteroid dehydrogenase deficiency
- Congenital adrenal hyperplasia due to 11β-hydroxylase deficiency
Further variability is introduced by the degree of enzyme inefficiency produced by the specific alleles each patient has. Some alleles result in more severe degrees of enzyme inefficiency. In general, severe degrees of inefficiency produce changes in the fetus and problems in prenatal or perinatal life. Milder degrees of inefficiency are usually associated with excessive or deficient sex hormone effects in childhood or adolescence, while the mildest form of CAH interferes with ovulation and fertility in adults.
Finally, specific problems may also differ with the genetic sex of the affected person. For example, the most common type of CAH, due to deficient 21-hydroxylase activity, can produce ambiguous genitalia in XX fetuses but not XY.
Treatment of all forms of CAH may include any of:
- supplying enough glucocorticoid to reduce hyperplasia and overproduction of androgens or mineralocorticoids
- providing replacement mineralocorticoid and extra salt if the person is deficient
- providing replacement testosterone or estrogen at puberty if the person is deficient
- additional treatments to optimize growth by delaying puberty or delaying bone maturation
- genital reconstructive surgery to correct problems produced by abnormal genital structure
All of these management issues are discussed in more detail in congenital adrenal hyperplasia due to 21-hydroxylase deficiency.
Biochemistry
| Common medical term | OMIM no. | Enzyme(s) | Gene location | Substrate(s) | Product(s) |
| 21-hydroxylase CAH | Online Mendelian Inheritance in Man (OMIM) 201910 | P450c21 | 6p21.3 | 17OH-progesterone→ progesterone→ |
11-deoxycortisol DOC |
| lipoid CAH (20,22-desmolase) |
Online Mendelian Inheritance in Man (OMIM) 201710 | StAR P450scc |
8p11.2 15q23-q24 |
transport of cholesterol cholesterol→ |
into mitochondria pregnenolone |
| 17α-hydroxylase CAH | Online Mendelian Inheritance in Man (OMIM) 202110 | P450c17 | 10q24.3 | pregnenolone→ progesterone→ 17OH-pregnenolone→ |
17OH-pregnenolone 17OH-progesterone DHEA |
| 3β-HSD CAH | Online Mendelian Inheritance in Man (OMIM) 201810 | 3βHSD II | 1p13 | pregnenolone→ 17OH-pregnenolone→ DHEA→ |
progesterone 17OH-progesterone androstenedione |
| 11β-hydroxylase CAH | Online Mendelian Inheritance in Man (OMIM) 202010 | P450c11β | 8q21-22 | 11-deoxycortisol→ DOC→ |
cortisol corticosterone |
Abbreviations:
- OMIM no. is Online Mendelian Inheritance in Man index number
- StAR is steroidogenic acute regulatory protein
- HSD is hydroxysteroid dehydrogenase.
- P450scc is cytochrome P450 side chain cleavage enzyme.
- 17OH-progesterone and 17OHP are 17-hydroxyprogesterone.
- 17OH-pregnenolone is 17-hydroxypregnenolone
- DHEA is dehydroepiandrosterone.
- DOC is deoxycorticosterone.
Since the 1960s most endocrinologists have referred to the forms of CAH by the traditional names in the left column, which generally correspond to the deficient enzyme activity. As exact structures and genes for the enzymes were identified in the 1980s, most of the enzymes were found to be cytochrome P450 oxidases and were renamed to reflect this. In some cases, more than one enzyme was found to participate in a reaction, and in other cases a single enzyme mediated in more than one reaction. There was also variation in different tissues and mammalian species.