Congenital adrenal hyperplasia (CAH) refers to any of several autosomal recessive diseases resulting from defects in steps of the synthesis of cortisol from cholesterol by the adrenal glands. Most of these diseases involve excessive or defective production of sex steroids and can pervert or impair development of primary or secondary sex characteristics in affected infants, children, and adults. Only a small minority of people with CAH can be said to have an intersex condition, but this attracted American public attention in the late 1990s and many accounts of varying accuracy have appeared in the popular media.
Examples of problems caused by various forms of CAH:
- ambiguous genitalia such that it is difficult to determine sex
- vomiting leading to dehydration and death in early infancy
- early pubic hair and rapid growth in childhood
- precocious puberty or failure of puberty to occur
- excessive facial hair, virilization, and/or menstrual irregularity in adolescence
- infertility due to anovulation
Overview of the multiple 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 other enzymes 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.
All involved genes are autosomal. See Table 1 for chromosomal locations.
Because they code for enzymes with amplifiable activity, noticeable effects only occur in people with two defective alleles of these genes. Hundreds of different allelic mutations of these genes have been reported. Nearly always, each parent of an affected person is an unaffected heterozygote (i.e., asymptomatic carrier of one defective gene and one normal gene and has no ill effects). Each child of that pair of parents has a 25% chance of being affected, “having CAH”. Prenatal diagnosis and heterozygote detection are now possible.
Although mutations leading to the various forms of CAH have been found all over the world, there are substantial differences in the carrier rates of specific abnormal alleles in different regions and ethnic groups.
|Common medical term||OMIM no.||Enzyme(s)||Gene location||Substrate(s)||Product(s)|
|21-hydroxylase CAH||P450c21||6p21.1||17OH-progesterone→progesterone→||11-deoxycortisol DOC|
|lipoid CAH (20,22-desmolase)||StAR P450scc||8p11.2 15q23-q24||transport of cholesterol
|into mitochondria pregnenolone|
|3β-HSD CAH||3βHSD II||1p13||pregnenolone→17OH-pregnenolone→DHEA→||progesterone
- 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.
An Italian anatomist, Luigi De Crecchio provided the earliest known description of a case of probable CAH.
I propose in this narrative that it is sometimes extremely difficult and even impossible to determine sex during life. In one of the anatomical theaters of the hospital…, there arrived toward the end of January a cadaver which in life was the body of a certain Joseph Marzo… The general physiognomy was decidedly male in all respects. There were no feminine curves to the body. There was a heavy beard. There was some delicacy of structure with muscles that were not very well developed… The distribution of pubic hair was typical of the male. Perhaps the lower extremities were somewhat delicate, resembling the female, and were covered with hair… The penis was curved posteriorly and measured 6 cm, or with stretching, 10 cm. The corona was 3 cm long and 8 cm in circumference. There was an ample prepuce. There was a first grade hypospadias… There were two folds of skin coming from the top of the penis and encircling it on either side. These were somewhat loose and resembled labia majora.
De Crecchio then described the internal organs, which included a normal vagina, uterus, tubes, and ovaries. It was of the greatest importance to determine the habits, tendencies, passions, and general character of this individual… I was determined to get as complete a story as possible, determined to get at the base of the facts and to avoid undue exaggeration which was rampant in the conversation of many of the people present at the time of the dissection. He interviewed many people and satisfied himself that Joseph Marzo “conducted himself within the sexual area exclusively as a male,” even to the point of contracting the “French disease” on two occasions. The cause of death was another in a series of episodes of vomiting and diarrhea.
This account, translated by Alfred Bongiovanni from De Crecchio (Sopra un caso di apparenzi virili in una donna. Morgagni 7:154-188, 1865), contains nearly all the important themes and issues. Were this man’s male gender identity, role, and orientation determined by his anatomy, by his testosterone, or by his sex of rearing? His presumed female chromosomes and gonads obviously did not make him female. Yet despite his careful documentation of Marzo’s unambiguous social role, De Crecchio rejects his male identity and describes him as “una donna,” revealing the 19th century assumption that a person’s “true sex” can be determined by inspection of internal organs. Then as now, such a case prompted “undue exaggeration” and much “conversation.” And then as now, we see the conflict between the desire of the scientist to learn and understand, and the sense of violation of poor Joseph Marzo’s privacy. Finally, were the episodes of vomiting and diarrhea the salt-wasting of CAH?
The association of excessive sex steroid effects with diseases of the adrenal cortex have been recognized for over a century. The term adrenogenital syndrome was applied to both sex-steroid producing tumors and severe forms of CAH for much of the 20th century, before some of the forms of CAH were understood. Congenital adrenal hyperplasia, which also dates to the first half of the century, has become the preferred term to reduce ambiguity and to emphasize the underlying pathophysiology of the disorders.
Much of our modern understanding and treatment of CAH comes from research conducted at Johns Hopkins Medical School in Baltimore in the middle of the 20th century. Lawson Wilkins, “founder” of pediatric endocrinology, worked out the apparently paradoxical pathophysiology: that hyperplasia and overproduction of adrenal androgens resulted from impaired capacity for making cortisol. He reported use of adrenal cortical extracts to treat children with CAH in 1950. Genital reconstructive surgery was also pioneered at Hopkins. After application of karyotyping to CAH and other intersex disorders in the 1950s, John Money, JL Hampson, and JG Hampson persuaded both the scientific community and the public that sex assignment should not be based on any single biological criterion, and gender identity was largely learned and has no simple relationship with chromosomes or hormones. See Intersex for a fuller history, including recent controversies over reconstructive surgery.
Hydrocortisone, fludrocortisone, and prednisone were available by the late 1950s. By 1980 all of the relevant steroids could be measured in blood by reference laboratories for patient care. By 1990 nearly all specific genes and enzymes had been identified.
However, the last decade has seen a number of new developments, discussed more extensively in congenital adrenal hyperplasia due to 21-hydroxylase deficiency:
- debate over the value of genital reconstructive surgery and changing standards
- debate over sex assignment of severely virilized XX infants
- new treatments to improve height outcomes
- newborn screening programs to detect CAH at birth
- increasing attempts to treat CAH before birth
- Intersex and Ambiguous genitalia
- Adrenal insufficiency