Congenital adrenal hyperplasia
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2008-05-24T00:37:14Z
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{{dablink|CAH redirects here. For other meanings of CAH see [[CAH (disambiguation)]]}}
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{{unreferenced|date=February 2008}}
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{{Infobox_Disease |
Name = Congenital adrenal hyperplasia |
Image = Cortisol2.svg |
Caption = [[Cortisol]] |
DiseasesDB = 1854 |
DiseasesDB_mult = {{DiseasesDB2|1832}} {{DiseasesDB2|4}} {{DiseasesDB2|1841}} {{DiseasesDB2|2565}} |
ICD10 = {{ICD10|E|25|0|e|20}} |
ICD9 = {{ICD9|255.2}} |
ICDO = |
OMIM = 201910 |
OMIM_mult = {{OMIM2|201710}} {{OMIM2|202110}} {{OMIM2|201810}} {{OMIM2|202010}}|
MedlinePlus = 000411 |
eMedicineSubj = ped |
eMedicineTopic = 48 |
MeshID = D000312 |
}}
'''Congenital adrenal hyperplasia''' ('''CAH''') refers to any of several [[autosomal]] [[recessive]] [[disease]]s resulting from [[mutation]]s of [[gene]]s for [[enzyme]]s mediating the biochemical steps of production of [[cortisol]] from [[cholesterol]] by the [[adrenal gland]]s ([[steroidogenesis]]).
Most of these conditions involve excessive or deficient production of [[sex steroid]]s and can alter development of [[primary sex characteristic|primary]] or [[secondary sex characteristic]]s in some affected infants, children, or 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. Approximately 95% of cases of CAH are due to [[congenital adrenal hyperplasia due to 21-hydroxylase deficiency|21-hydroxylase deficiency]].
Examples of conditions caused by various forms of CAH:
* [[ambiguous genitalia]], in some females, such that it can be initially difficult to determine sex
* [[vomiting]] due to [[natriuresis|salt-wasting]] leading to [[dehydration]] and death
* early [[pubarche|pubic hair]] and rapid growth in childhood
* [[precocious puberty]] or failure of [[puberty]] to occur ([[sexual infantilism]]: absent or [[delayed puberty]])
* [[hirsutism|excessive facial hair]], [[virilization]], and/or [[menstrual cycle|menstrual irregularity]] in adolescence
* [[infertility]] due to [[anovulation]]
* [[hypertension]]
==Overview of the multiple types of CAH==
[[Image:DHEA1.svg|thumb|300px|Production of DHEA from Cholesterol. ([[Cortisol]] is a [[glucocorticoid]].)]]
Cortisol is an adrenal [[steroid hormone]] that is required for normal endocrine function. Production begins in the second month of fetal life. Poor cortisol production is a hallmark of most forms of CAH. Inefficient cortisol production results in rising levels of [[adrenocorticotropic hormone|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 '''''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 17 alpha-hydroxylase deficiency|Congenital adrenal hyperplasia due to 17α-hydroxylase deficiency]]
*[[Congenital adrenal hyperplasia due to 3 beta-hydroxysteroid dehydrogenase deficiency|Congenital adrenal hyperplasia due to 3β-hydroxysteroid dehydrogenase deficiency]]
*[[Congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency|Congenital adrenal hyperplasia due to 11β-hydroxylase 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 steroid|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 [[Gender|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]].
===Genetics===
All involved [[genes]] are autosomal. See the table under 'Biochemistry' subheading for [[chromosome|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., [[Genetic carrier|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.
===Biochemistry===
<!-- Image with unknown copyright status removed: [[Image:pathway.gif|thumb|250px|Enzymatic pathway for biosynthesis of cortisol and aldosterone, beginning with cholesterol. Italics denote enzymes.]] -->
<!-- Image with unknown copyright status removed: [[Image:cahpathway.gif|thumb|250px|Accumulation of progesterone and 17-hydroxyprogesterone as a result of a 21-hydroxylase deficiency. Italics denote enzymes.]] -->
{| style="border-collapse:collapse" border=1 cellpadding=5
|- style="background-color:#ccc"
| '''Common medical term'''
| '''OMIM no.'''
| '''Enzyme(s)'''
| '''Gene location'''
| '''Substrate(s)'''
| '''Product(s)'''
|-
| [[Congenital adrenal hyperplasia due to 21-hydroxylase deficiency|21-hydroxylase CAH]]
| {{OMIM|201910}}
| P450c21
| 6p21.3
| 17OH-progesterone→<br/>[[progesterone]]→
| 11-deoxycortisol<br/>[[11-deoxycorticosterone|DOC]]
|-
| [[Lipoid congenital adrenal hyperplasia|lipoid CAH]]<br/>(20,22-desmolase)
| {{OMIM|201710}}
| StAR<br/>P450scc
| 8p11.2<br/>15q23-q24
| transport of [[cholesterol]]<br/>[[cholesterol]]→
| into mitochondria<br/>[[pregnenolone]]
|-
| [[Congenital adrenal hyperplasia due to 17 alpha-hydroxylase deficiency|17α-hydroxylase CAH]]
| {{OMIM|202110}}
| P450c17
| 10q24.3
| [[pregnenolone]]→<br/>[[progesterone]]→<br/>17OH-pregnenolone→
| 17OH-pregnenolone<br/>17OH-progesterone<br/>[[DHEA]]
|-
| [[Congenital adrenal hyperplasia due to 3 beta-hydroxysteroid dehydrogenase deficiency|3β-HSD CAH]]
| {{OMIM|201810}}
| 3βHSD II
| 1p13
| [[pregnenolone]]→<br/>17OH-pregnenolone→<br/>[[DHEA]]→
| [[progesterone]]<br/>17OH-progesterone<br/>[[androstenedione]]
|-
| [[Congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency|11β-hydroxylase CAH]]
| {{OMIM|202010}}
| P450c11β
| 8q21-22
| 11-deoxycortisol→<br/>DOC→
| [[cortisol]]<br/>[[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 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.
==History==
An Italian anatomist, [[Luigi De Crecchio]] provided the earliest known description of a case of probable CAH. <blockquote>I propose in this narrative that it is sometimes extremely difficult and even impossible to determine sex during life. In one of the [[anatomy|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 [[glans penis|corona]] was 3 cm long and 8 cm in circumference. There was an ample [[foreskin|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]].</blockquote> De Crecchio then described the internal organs, which included a normal [[vagina]], [[uterus]], [[fallopian tube|tubes]], and [[ovary|ovaries]]. <blockquote>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.</blockquote> 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 "[[syphilis|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]], [[gender role|role]], and [[sexual orientation|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. '''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 [[karyotype|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
==See also==
*[[Ambiguous genitalia]]
*[[Female pseudohermaphroditism]]
*[[Adrenal insufficiency]]
==External links==
* [http://www.caresfoundation.org CARES Foundation: Congenital Adrenal Research, Education, and Support]
* [http://congenitaladrenalhyperplasia.org CongenitalAdrenalHyperplasia.org]
* [http://www.dshs.state.tx.us/newborn/hand_cah.shtm Congenital Adrenal Hyperplasia: A Handbook for Parents]
* [http://www.dshs.state.tx.us/newborn/cahbroch.shtm The ABC's of Congenital Adrenal Hyperplasia]
* [http://www.rarediseases.org/search/rdbdetail_abstract.html?disname=Adrenal%20Hyperplasia%2C%20Congenital%20%28General%29|National Organization for Rare Disorders (NORD): Adrenal Hyperplasia, Congenital]
* [http://www.hopkinsmedicine.org/pediatricendocrinology/cah/index.html Guide to Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency for parents or patients from Johns Hopkins]
* [http://www.endotext.org/pediatrics/pediatrics8a/pediatricsframe8a.htm A more advanced discussion of 21-hydroxylase deficiency by an eminent researcher of the disease.]
* [http://magicfoundation.org/www/docs/100/congenital_adrenal_hyperplasia.html MAGIC Foundation: Family Support, Annual Convention with Families and Medical Experts]
* [http://www.livingwithcah.com LivingWithCAH.com: CAH Support Group]
{{Endocrine pathology}}
[[Category:Pediatrics]]
[[Category:Endocrinology]]
[[Category:Genetic disorders]]
[[Category:Autosomal recessive disorders]]
[[Category:Intersexuality]]
[[de:Adrenogenitales Syndrom]]
[[es:Hiperplasia suprarrenal congénita]]
[[it:Iperplasia surrenale congenita]]
[[nl:Adrenogenitaal syndroom]]
[[pl:Wrodzony przerost nadnerczy]]