('''CAH''') refers to any of several
Autosomal Recessive diseases resulting from defects in steps of the
Synthesis of
Cortisol from
Cholesterol by the
Adrenal Gland s.
Most of these diseases involve excessive or defective production of
Sex Steroid s and can pervert or impair development of
Primary or
Secondary Sex Characteristic s 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:
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
Mineralocorticoid s such as
Aldosterone ,
Androgen s such as
Testosterone , and
Estrogen s 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 Steroid s.
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 '', 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 ''; and typically is recognized by causing virilization of prepubertal children.
- Still milder forms of 21-hydroxylase deficiency are referred to as '' 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.
Further variability is introduced by the degree of
Enzyme inefficiency produced by the specific
Allele s 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
Androgen s or
Mineralocorticoid s
# 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
Enzyme s with amplifiable activity, noticeable effects only occur in people with two defective
Allele s of these
Gene s. Hundreds of different allelic
Mutation s 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.
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 Oxidase s 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
Chromosome s and
Gonad s 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. 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 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
