Congenital adrenal hyperplasia historical perspective


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History
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:
 * 1) debate over the value of genital reconstructive surgery and changing standards
 * 2) debate over sex assignment of severely virilized XX infants
 * 3) new treatments to improve height outcomes
 * 4) newborn screening programs to detect CAH at birth
 * 5) increasing attempts to treat CAH before birth