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| {{Congenital adrenal hyperplasia due to 11β-hydroxylase deficiency}} | | {{Congenital adrenal hyperplasia due to 11β-hydroxylase deficiency}} |
| {{CMG}}; {{AE}} {{Ammu}} | | {{CMG}}; {{AE}} {{Ammu}} |
| | ==Overview== |
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| ==Overview== | | ==Historical Perspective== |
| '''11β-Hydroxylase deficient congenital adrenal hyperplasia''' ('''11β-OH CAH''') is an uncommon form of [[congenital adrenal hyperplasia]] resulting from a defect in the [[gene]] for the [[enzyme]] which mediates the final step of [[cortisol]] synthesis in the [[adrenal gland|adrenal]]. 11β-OH CAH results in [[hypertension]] due to excessive [[mineralocorticoid]] effects. It also causes excessive [[androgen]] production both before and after birth and can [[virilization|virilize]] a genetically female fetus or a child of either sex.
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| | ==Classification== |
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| ==Pathophysiology== | | ==Pathophysiology== |
| ''Congenital adrenal hyperplasia'' (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. All of the forms of CAH involve excessive or defective production of [[sex steroid]]s and can pervert or impair development of [[primary sex characteristic|primary]] or [[secondary sex characteristic]]s in affected infants, children, and adults. Many also involve excessive or defective production of [[mineralocorticoid]]s, which can cause [[hypertension]] or salt wasting.
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| 11β-Hydroxylase mediates the final step of the [[glucocorticoid]] pathway, producing [[cortisol]] from 11-deoxycortisol. It also catalyzes the conversion of 11-deoxycorticosterone (DOC) to [[corticosterone]] in the [[mineralocorticoid]] pathway.
| | ==Causes== |
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| | ==Differential Diagnosis== |
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| | ==Epidemiology and Demographics== |
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| | ==Risk Factors== |
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| ===Genetics=== | | ==Screening== |
| The enzyme which mediates 11β-hydroxylase activity is now known as P450c11β since it is one of the [[cytochrome P450 oxidase]] enzymes located in the inner [[mitochondrion|mitochondrial]] membrane of cells of the adrenal cortex. It is coded by a gene at 8q21-22. Like the other forms of CAH, a number of different defective alleles for the gene have been identified, producing varying degrees of impaired 11β-hydroxylase activity. Also like the other forms of CAH, 11β-OH CAH is inherited as an [[Dominance relationship#Autosomal recessive gene|autosomal recessive disease]].
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| ==Differentiating 11β-Hydroxylase deficient congenital adrenal hyperplasia from other Diseases== | | ==Natural history, Complications and Prognosis== |
| 11β-OH CAH resembles [[congenital adrenal hyperplasia|21-hydroxylase deficient CAH]] in its [[androgen]]ic manifestations: partial [[virilization]] and [[ambiguous genitalia]] of genetically female infants, childhood virilization of both sexes, and rarer cases of virilization or [[infertility]] of adolescent and adult women. The [[mineralocorticoid]] effect differs: [[hypertension]] is usually the clinical clue that a patient has 11- rather than 21-hydroxylase CAH. Diagnosis of 11β-OH CAH is usually confirmed by demonstration of marked elevations of 11-deoxycortisol and 11-deoxycorticosterone (DOC), the substrates of 11β-hydroxylase. Management is similar to that of 21-hydroxylase deficient CAH except that mineralocorticoids need not be replaced.
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| ==Natural History, Complications, and Prognosis== | | ==History and Symptoms== |
| ===Complications===
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| ====Sex steroid effects of 11β-OH CAH====
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| Because 11β-hydroxylase activity is not necessary in the production of [[sex steroid]]s ([[androgen]]s and [[estrogen]]s), the hyperplastic adrenal cortex produces excessive amounts of [[DHEA]], [[androstenedione]], and especially [[testosterone]].
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| These [[androgen]]s produce effects that are similar to those of [[congenital adrenal hyperplasia|21-hydroxylase deficient CAH]]. In the severe forms, XX (genetically female) fetuses can be markedly virilized, with [[ambiguous genitalia]] that look more male than female, though internal female organs, including [[ovary|ovaries]] and [[uterus]] develop normally.
| | ==Physical Examination== |
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| XY fetuses (genetic males) typically show no signs of excess androgens.
| | ==Laboratory Findings== |
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| In milder mutations, androgen effects in both sexes appear in mid-childhood as early pubic hair, overgrowth, and accelerated bone age. Although "nonclassic" forms causing [[hirsutism]] and menstrual irregularities and appropriate steroid elevations have been reported, most have not had verifiable mutations and mild 11β-hydroxylase deficient CAH is currently considered a very rare cause of hirsutism and infertility.
| | ==CT== |
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| All of the issues related to virilization, neonatal assignment, advantages and disadvantages of genital surgery, childhood and adult virilization, gender identity and sexual orientation are similar to those of 21-hydroxylase CAH and elaborated in more detail in [[Congenital adrenal hyperplasia]].
| | ==MRI== |
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| ==Diagnosis== | | ==Echocardiography or Ultrasound== |
| ===Symptoms===
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| ====Mineralocorticoid aspects of 11β-OH CAH====
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| [[Mineralocorticoid]] manifestations of severe 11β-hydroxylase deficient CAH can be biphasic, changing from deficiency (salt-wasting) in early infancy to excess ([[hypertension]]) in childhood and adult life.
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| Salt-wasting in early infancy does not occur in most cases of 11β-OH CAH but can occur because of impaired production of [[aldosterone]] aggravated by inefficiency of salt conservation in early infancy. When it occurs it resembles the salt-wasting of severe [[congenital adrenal hyperplasia|21-hydroxylase deficient CAH]]: poor weight gain and vomiting in the first weeks of life progress and culminate in life-threatening [[dehydration]], [[hyponatremia]], [[hyperkalemia]], and [[metabolic acidosis]] in the first month.
| | ==Other Imaging Findings== |
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| Despite the inefficient production of aldosterone, the more characteristic mineralocorticoid effect of 11β-OH CAH is [[hypertension]]. Progressive adrenal hyperplasia due to persistent elevation of ACTH results in extreme overproduction of 11-deoxycorticosterone (DOC) by mid-childhood. DOC is a weak mineralocorticoid, but usually reaches high enough levels in this disease to cause effects of mineralocorticoid excess: salt retention, volume expansion, and [[hypertension]].
| | ==Other Diagnostic Studies== |
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| ==Treatment==
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| ===Pharmacotherapy===
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| As with other forms of CAH, the primary therapy of 11β-hydroxylase deficient CAH is life-long [[glucocorticoid]] replacement in sufficient doses to prevent [[adrenal insufficiency]] and suppress excess mineralocorticoid and androgen production.
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| Salt-wasting in infancy responds to intravenous saline, dextrose, and high dose [[hydrocortisone]], but prolonged [[fludrocortisone]] replacement is usually not necessary. The hypertension is ameliorated by glucocorticoid suppression of DOC.
| | ==Medical Therapy== |
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| Long term [[glucocorticoid]] replacement issues are similar to those of [[congenital adrenal hyperplasia|21-hydroxylase CAH]], and involve careful balance between doses sufficient to suppress androgens while avoiding suppression of growth. Because the enzyme defect does not affect [[sex steroid]] synthesis, gonadal function at puberty and long-term fertility should be normal if adrenal androgen production is controlled. See [[congenital adrenal hyperplasia]] for a more detailed discussion of androgen suppression and fertility potential in adolescent and adult women.
| | ==Surgery== |
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| ==Related Chapters== | | ==Secondary Prevention== |
| *[[Congenital adrenal hyperplasia]] for an overview of CAH, and a more detailed discussion of management issues related to the common forms of 21-hydroxylase deficiency. Nearly all of the sex steroid-related issues are the same for both 11β-hydroxylase and 21-hydroxylase deficient CAH.
| | ==Cost-effectiveness of the Therapy== |
| *[[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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| *[[Intersex]] and [[ambiguous genitalia]]
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| *[[Adrenal insufficiency]]
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| | ==Future or Investigational therapies== |
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| [[Category:Pediatrics]]
| | ==Reference== |
| [[Category:Endocrinology]]
| | {{Reflist}} |
| [[Category:Genetic disorders]] | | [[Category:Hereditary cancers]] |
| [[Category:Intersexuality]]
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