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| '''For patient information click [[{{PAGENAME}} (patient information)|here]]''' | | '''For patient information click [[{{PAGENAME}} (patient information)|here]]''' |
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| {{Infobox_Disease | | | {{Infobox_Disease | |
| Name = Congenital adrenal hyperplasia | | | Name = Congenital adrenal hyperplasia | |
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| OMIM_mult = {{OMIM2|201710}} {{OMIM2|202110}} {{OMIM2|201810}} {{OMIM2|202010}}| | | OMIM_mult = {{OMIM2|201710}} {{OMIM2|202110}} {{OMIM2|201810}} {{OMIM2|202010}}| |
| MedlinePlus = 000411 | | | MedlinePlus = 000411 | |
| eMedicineSubj = ped | | | eMedicineSubj = | |
| eMedicineTopic = 48 | | | eMedicineTopic = | |
| MeshID = D000312 | | | MeshID = D000312 | |
| }} | | }} |
| {{Search infobox}}
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| {{CMG}}
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| __NOTOC__
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| '''Associate Editor-In-Chief:''' {{CZ}}
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| ==Overview==
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| '''Congenital adrenal hyperplasia''' ('''CAH''') refers to any of several [[autosomal]] [[recessive]] conditions resulting from biochemical paths of the [[steroidogenesis]] of [[cortisol]] from [[cholesterol]] by the [[adrenal gland]]s.
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| Most of these conditions involve greater or lesser production of [[sex steroid]]s and can alter development of [[primary sex characteristic|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. Approximately 95% of cases of CAH are due to [[congenital adrenal hyperplasia due to 21-hydroxylase deficiency|21-hydroxylase deficiency]].
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| Examples of conditions caused by various forms of CAH:
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| * [[ambiguous genitalia]], in some females, such that it can be initially difficult to determine sex
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| * [[vomiting]] due to [[natriuresis|salt-wasting]] leading to [[dehydration]] and death
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| * early [[pubarche|pubic hair]] and rapid growth in childhood
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| * [[precocious puberty]] or failure of [[puberty]] to occur ([[sexual infantilism]]: absent or [[delayed puberty]])
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| * [[hirsutism|excessive facial hair]], [[virilization]], and/or [[menstrual cycle|menstrual irregularity]] in adolescence
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| * [[infertility]] due to [[anovulation]]
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| * [[hypertension]]
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| ==History==
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| 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|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.
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| 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?
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| 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.
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| 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.
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| [[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.
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| However, the last decade has seen a number of new developments, discussed more extensively in [[congenital adrenal hyperplasia due to 21-hydroxylase deficiency]]:
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| # debate over the value of [[genital reconstructive surgery]] and changing standards
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| # debate over [[sex assignment]] of severely virilized XX infants
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| # new treatments to improve height outcomes
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| # [[newborn screening]] programs to detect CAH at birth
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| # increasing attempts to treat CAH before birth
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| == Epidemiology and Demographics ==
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| * The disorder in the most classical form is thought to affect approximately 1 in 15-30,000 patients. Milder forms of the disease are estimated to occur in as many as 1 in 100-1000 patients. 90% of CAH is due to a complete or partial deficiency in 21-hyroxylase. 5-8% of CAH is due to deficiency in 11-hydroxylase. In rare instances, 17-alpha-hydroxylase and 3-beta-hydroxysteroid dehydrogenase deficiency can lead to CAH. Certain ethnic groups are thought to be at increased risk such as Yupik Eskimos and Jews of Moroccan ancestry.
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| * 21-Hydroxylase
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| *:* Defective conversion of 17-hydroxyprogesterone to 11-deoxycortisol leads to decreased cortisol synthesis and increased ACTH secretion. The resulting adrenal stimulation leads to increased production of androgens. Aldosterone secretion is also impaired in some patients. There are several clinical syndromes based on the degree of enzyme deficiency. These include the simple virilizing form, salt-wasting form and nonclassical form.
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| * 11-Hydroxylase
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| *:* Deficiency of this enzyme leads to excessive production of androgens and mineralocorticoids. There is excessive production of 11-deoxycorticosterone, which has mineralocorticoid effect, and adrenal androgens.
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| == Pathophysiology & Etiology==
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| * Simple Virilizing Form
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| *:* Female fetuses demonstrate evidence of androgen excess including genital ambiguity. Precocious puberty, accelerated growth followed by premature growth arrest due to epiphiseal fusion can be noted. Because virilization or androgen excess can be very mild, it can be overlooked until later in life.
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| * Salt-Wasting Form
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| *:* These patients may have virilizing features but 2/3 will also manifest mineralocorticoid deficiency with salt wasting, hyperkalemia, and hypotension, usually within the first 2 weeks of life.
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| * Nonclassical Form
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| *:* Patients may present with amenorrhea/oligomenorrhea with signs of androgen excess such as hirsutism. These women usually present around puberty and resemble patients with polycystic ovarian syndrome.
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| ==Types of CAH==
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| [[Image:DHEA1_svg.png|thumb|300px|Production of DHEA from Cholesterol. ([[Cortisol]] is a [[glucocorticoid]].)]]
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| [[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 [[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).
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| 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.
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| 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.
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| *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.
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| *Moderate 21-hydroxylase deficiency is referred to as '''''simple virilizing CAH'''''; and typically is recognized by causing virilization of prepubertal children.
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| *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.
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| 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.
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| *[[Lipoid congenital adrenal hyperplasia]]
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| *[[Congenital adrenal hyperplasia due to 17 alpha-hydroxylase deficiency|Congenital adrenal hyperplasia due to 17α-hydroxylase deficiency]]
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| *[[Congenital adrenal hyperplasia due to 3 beta-hydroxysteroid dehydrogenase deficiency|Congenital adrenal hyperplasia due to 3β-hydroxysteroid dehydrogenase deficiency]]
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| *[[Congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency|Congenital adrenal hyperplasia due to 11β-hydroxylase deficiency]]
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| 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.
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| 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.
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| Treatment of all forms of CAH may include any of:
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| # supplying enough [[glucocorticoid]] to reduce hyperplasia and overproduction of [[androgen]]s or [[mineralocorticoid]]s
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| # providing replacement mineralocorticoid and extra salt if the person is deficient
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| # providing replacement [[testosterone]] or [[estrogen]] at puberty if the person is deficient
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| # additional treatments to optimize growth by delaying puberty or delaying [[bone maturation]]
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| # [[genital reconstructive surgery]] to correct problems produced by abnormal genital structure
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| All of these management issues are discussed in more detail in [[congenital adrenal hyperplasia due to 21-hydroxylase deficiency]].
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| ===Genetics===
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| All involved [[genes]] are autosomal. See the table under 'Biochemistry' subheading for [[chromosome|chromosomal]] locations.
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| 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.
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| 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.
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| ===Biochemistry===
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| {| style="border-collapse:collapse" border=1 cellpadding=5
| | {{Congenital adrenal hyperplasia}} |
| |- style="background-color:#ccc"
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| | '''Common medical term'''
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| | '''OMIM no.'''
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| | '''Enzyme(s)'''
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| | '''Gene location'''
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| | '''Substrate(s)'''
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| | '''Product(s)'''
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| | [[Congenital adrenal hyperplasia due to 21-hydroxylase deficiency|21-hydroxylase CAH]]
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| | {{OMIM|201910}}
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| | P450c21
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| | 6p21.3
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| | 17OH-progesterone→<br/>[[progesterone]]→
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| | 11-deoxycortisol<br/>[[11-deoxycorticosterone|DOC]]
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| |-
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| | [[Lipoid congenital adrenal hyperplasia|lipoid CAH]]<br/>(20,22-desmolase)
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| | {{OMIM|201710}}
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| | StAR<br/>P450scc
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| | 8p11.2<br/>15q23-q24
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| | transport of [[cholesterol]]<br/>[[cholesterol]]→
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| | into mitochondria<br/>[[pregnenolone]]
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| |-
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| | [[Congenital adrenal hyperplasia due to 17 alpha-hydroxylase deficiency|17α-hydroxylase CAH]]
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| | {{OMIM|202110}}
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| | P450c17
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| | 10q24.3
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| | [[pregnenolone]]→<br/>[[progesterone]]→<br/>17OH-pregnenolone→
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| | 17OH-pregnenolone<br/>17OH-progesterone<br/>[[DHEA]]
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| |-
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| | [[Congenital adrenal hyperplasia due to 3 beta-hydroxysteroid dehydrogenase deficiency|3β-HSD CAH]]
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| | {{OMIM|201810}}
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| | 3βHSD II
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| | 1p13
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| | [[pregnenolone]]→<br/>17OH-pregnenolone→<br/>[[DHEA]]→
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| | [[progesterone]]<br/>17OH-progesterone<br/>[[androstenedione]]
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| |-
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| | [[Congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency|11β-hydroxylase CAH]]
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| | {{OMIM|202010}}
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| | P450c11β
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| | 8q21-22
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| | 11-deoxycortisol→<br/>DOC→
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| | [[cortisol]]<br/>[[corticosterone]]
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| |}
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| Abbreviations:
| | {{CMG}}; '''Associate Editor-In-Chief:''' {{CZ}} |
| * OMIM no. is [[Online Mendelian Inheritance in Man]] index number
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| * StAR is [[steroidogenic acute regulatory protein]]
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| * HSD is hydroxysteroid dehydrogenase.
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| * P450scc is [[cytochrome]] P450 [[side chain]] cleavage enzyme.
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| * 17OH-progesterone and 17OHP are [[17-hydroxyprogesterone]].
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| * 17OH-pregnenolone is [[17-hydroxypregnenolone]]
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| * DHEA is [[dehydroepiandrosterone]].
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| * DOC is [[deoxycorticosterone]].
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| 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.
| | ==[[Congenital adrenal hyperplasia overview|Overview]]== |
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| == Diagnosis == | | ==Classification== |
| | [[Congenital adrenal hyperplasia classification#Types of CAH|Types of CAH]] | [[Congenital adrenal hyperplasia classification#Genetics|Genetics]] | [[Congenital adrenal hyperplasia classification#Biochemistry|Biochemistry]] |
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| Prenatal diagnosis can be made in both of these disorders by chorionic villous sampling, but this can only be done at 8-10 weeks. In order to prevent the deleterious effect of excess androgens on genital (and brain!) development, therapy must be started earlier. This is most often considered if there is an affected sibling. Treatment is dexamethasone, which is not degraded by the placenta, but is associated with significant maternal weight gain, hypertension, and edema.
| | ==[[Congenital adrenal hyperplasia historical perspective|Historical perspective]]== |
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| === History and Symptoms === | | ==[[Congenital adrenal hyperplasia pathophysiology|Pathophysiology]]== |
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| * 11-Hydroxylase
| | ==[[Congenital adrenal hyperplasia epidemiology and demographics|Epidemiology & demographics]]== |
| *:* The clinical manifestations are of . The virilization of neonates may be mild or as severe as 21-hydroxylase deficiencies. The remainder of patients present with precocious puberty and acne in men, or with hirsutism and menstrual irregularities in women. Hypertension and hypokalemia are present in 2/3 and help distinguish from 21-hydroxylase deficiencies.
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| === Physical Examination === | | ==[[Congenital adrenal hyperplasia risk factors|Risk factors]]== |
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| [[Hypertension]] may be present | | ==[[Congenital adrenal hyperplasia screening|Screening]]== |
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| ==== Appearance of the Patient ==== | | ==[[Congenital adrenal hyperplasia causes|Causes]]== |
| [[Hirsuitism]] may be present | |
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| ==== GU ==== | | ==[[Congenital adrenal hyperplasia differential diagnosis|Differentiating congenital adrenal hyperplasia from other diseases]]== |
| Ambiguous genitalia in females and penile enlargement in males
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| === Laboratory Findings === | | ==[[Congenital adrenal hyperplasia natural history|Natural History, Complications & Prognosis]]== |
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| ==== Electrolyte and Biomarker Studies ==== | | ==Diagnosis== |
| In 11-hydroxylase deficiencis, hypokalemia is present in 2/3 and help distinguish from 21-hydroxylase deficiencies.
| | [[Congenital adrenal hyperplasia history and symptoms|History & Symptoms]] | [[Congenital adrenal hyperplasia physical examination|Physical examination]] | [[Congenital adrenal hyperplasia laboratory tests|Lab Tests]] | [[Congenital adrenal hyperplasia electrocardiogram|Electrocardiogram]] | [[Congenital adrenal hyperplasia chest x ray|Chest X Ray]] | [[Congenital adrenal hyperplasia CT|CT]] | [[Congenital adrenal hyperplasia MRI|MRI]] | [[Congenital adrenal hyperplasia echocardiography or ultrasound|Echocardiography or Ultrasound]] | [[Congenital adrenal hyperplasia other imaging findings|Other Imaging Findings]] | [[Congenital adrenal hyperplasia other diagnostic studies|Other Diagnostic Studies]] |
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| == Treatment== | | ==Treatment== |
| | '''Medical therapy:''' [[Congenital adrenal hyperplasia medical therapy#21-Hydroxylase|21-Hydroxylase]] | [[Congenital adrenal hyperplasia medical therapy#11-Hydroxylase|11-Hydroxylase]] |
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| === Acute Pharmacotherapies ===
| | '''Surgical therapy:''' [[Congenital adrenal hyperplasia surgery|Surgery]] |
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| * 21-Hydroxylase
| | '''Prevention:''' [[Congenital adrenal hyperplasia primary prevention|Primary prevention]] | [[Congenital adrenal hyperplasia secondary prevention|Secondary prevention]] |
| *:* Treatment is aimed at decreasing the drive to produce ACTH (AdrenoCorticoTropic Hormone), thereby decreasing androgen secretion. Glucocorticoids are given usually as hydrocortisone 25 mg QD in divided doses. The dose of steroids must be carefully titrated so that androgen production is minimized, but growth inhibition and Cushing’s syndrome from glucocorticoid excess is avoided. Assessing bone age and growth rate, signs of androgen excess and menstrual cycling gauge response to therapy. Adjunctive therapy with flutamide, an anti-androgen and testolactone, and anti-aromatase, have been shown to minimize the effects of excess androgens, reduce the dose of glucocorticoids and normalize growth rates.
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| *:* Mineralocorticoids, with or without evidence of evidence of salt loss, should be given in the form of fludrocortisone. It decreases excessive renin and Angiotensin II (AII) production. AII stimulates early steps in the steroidogenic pathway and leads to more androgen production. Both renin and AII are elevated in the salt-wasting and virilizing forms of CAH. The usual adult dose is 0.1 mg/day.
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| * 11-Hydroxylase
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| *:* Treatment is similar to 21-hydroxylase deficiency with glucocorticoid replacement. Clinical assessment of virilization, growth velocity, hair growth, menstrual function and blood pressure are necessary. Despite adequate glucocorticoid replacement, medication may be required to control blood pressure. Spironolactone is a good choice as well as calcium blockers.
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| ==References== | | ==Related chapters== |
| {{Reflist}}
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| ==See also==
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| *[[Ambiguous genitalia]] | | *[[Ambiguous genitalia]] |
| *[[Female pseudohermaphroditism]] | | *[[Female pseudohermaphroditism]] |
| *[[Adrenal insufficiency]] | | *[[Adrenal insufficiency]] |
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| ==External links== | | ==Resources== |
| * [http://www.caresfoundation.org CARES Foundation: Congenital Adrenal Research, Education, and Support] | | * [http://www.caresfoundation.org CARES Foundation: Congenital Adrenal Research, Education, and Support] |
| * [http://congenitaladrenalhyperplasia.org CongenitalAdrenalHyperplasia.org] | | * [http://congenitaladrenalhyperplasia.org CongenitalAdrenalHyperplasia.org] |
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| * [http://www.endotext.org/pediatrics/pediatrics8a/pediatricsframe8a.htm A more advanced discussion of 21-hydroxylase deficiency by an eminent researcher of the disease.] | | * [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://magicfoundation.org/www/docs/100/congenital_adrenal_hyperplasia.html MAGIC Foundation: Family Support, Annual Convention with Families and Medical Experts] |
| {{SIB}}
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| {{Endocrine pathology}} | | {{Endocrine pathology}} |
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| | [[Category:Disease]] |
| [[Category:Pediatrics]] | | [[Category:Pediatrics]] |
| [[Category:Endocrinology]] | | [[Category:Endocrinology]] |
| [[Category:Genetic disorders]] | | [[Category:Genetic disorders]] |
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| [[Category:Intersexuality]] | | [[Category:Intersexuality]] |
| [[Category:Mature chapter]] | | [[Category:Mature chapter]] |
