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Congenital adrenal hyperplasia
Congenital adrenal hyperplasia (CAH) refers to any of several autosomalrecessivediseases resulting from defects in steps of the synthesisof cortisolfrom cholesterolby the adrenal glands. Most of these diseases involve excessive or defective production of sex steroidsand can pervert or impair development of primaryor secondary sex characteristicsin affected infants, children, and adults. Only a small minority of people with CAH can be said to have an intersexcondition, 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:
Overview of the multiple types of CAHCortisolis an adrenal steroid hormonenecessary 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 mineralocorticoidssuch as aldosterone, androgenssuch as testosterone, and estrogenssuch 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 deficiencyaccounts for about 95% of diagnosed cases of CAH. Unless another specific enzyme is mentioned, "CAH" in nearly all contexts refers to 21-hydroxylase deficiency.
CAH due to deficiencies of other enzymes than 21-hydroxylasepresent many of the same management challenges as 21-hydroxylase deficiency, but some involve mineralocorticoidexcess or sex steroiddeficiency.
Further variability is introduced by the degree of enzymeinefficiency produced by the specific alleleseach 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 hormoneeffects in childhood or adolescence, while the mildest form of CAH interferes with ovulation and fertilityin adults. Finally, specific problems may also differ with the genetic sexof the affected person. For example, the most common type of CAH, due to deficient 21-hydroxylase activity, can produce ambiguous genitaliain XX fetuses but not XY. Treatment of all forms of CAH may include any of:
All of these management issues are discussed in more detail in congenital adrenal hyperplasia due to 21-hydroxylase deficiency. GeneticsAll involved genesare autosomal. See Table 1 for chromosomallocations. Because they code for enzymeswith amplifiable activity, noticeable effects only occur in people with two defective allelesof these genes. Hundreds of different allelic mutationsof these genes have been reported. Nearly always, each parent of an affected person is an unaffected heterozygote(i.e., asymptomatic carrierof 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 diagnosisand heterozygote detectionare 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. Biochemistry
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 oxidasesand 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. HistoryAn Italian anatomist, Luigi De Crecchioprovided 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 anatomicaltheaters 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 hairwas typical of the male. Perhaps the lower extremities were somewhat delicate, resembling the female, and were covered with hair... The peniswas curved posteriorly and measured 6 cm, or with stretching, 10 cm. The coronawas 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 orientationdetermined by his anatomy, by his testosterone, or by his sex of rearing? His presumed female chromosomesand gonadsobviously 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 Schoolin Baltimorein 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 karyotypingto CAH and other intersexdisorders 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 Intersexfor a fuller history, including recent controversies over reconstructive surgery. Hydrocortisone, fludrocortisone, and prednisonewere 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:
See also
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