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| {{Lipoid congential adrenal hyperplasia}} | | {{Lipoid congential adrenal hyperplasia}} |
| {{CMG}} | | {{CMG}} |
| ==What is CAH?==
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| ''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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| The most common type of CAH is due to [[Congenital adrenal hyperplasia due to 21-hydroxylase deficiency|deficiency of 21-hydroxylase]]. Lipoid CAH is one of the less common types of CAH due to deficiencies of other proteins and enzymes involved in cortisol synthesis.
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| ==Lipoid congenital adrenal hyperplasia==
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| Lipoid congenital adrenal hyperplasia results from defects in the steps from cholesterol to pregnenolone. The adrenals are large and filled with [[lipid]] globules derived from [[cholesterol]]. Life-threatening [[mineralocorticoid]] and [[glucocorticoid]] deficiency becomes apparent in infancy or early childhood. [[Sex steroid]] production is greatly impaired. XY infants (genetic males) are severely undervirilized so that the external genitalia at birth are female (normal or slightly virilized). XX infants have normal female anatomy and if their mineralocorticoid and glucocorticoid deficiencies are treated will often undergo spontaneous puberty. Lipid storage damages the adrenals and eventually the [[gonad]]s as well, so that all persons with this condition have so far been [[infertility|infertile]].
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| ==Pathophysiology and genetics of lipoid CAH==
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| Understanding of the molecular basis for this disease has been advanced in the last decade by better understanding of adrenal steroidogenesis as well as genetic studies of affected patients. It used to be assumed that lipoid CAH resulted from a defect of the enzymes that converted cholesterol to pregnenolone. The conversion reactions are mediated by a single enzyme, formerly referred to as 20,22-desmolase, but now identified as [[P450scc]] ([[side chain]] cleavage enzyme). However, as of 2003, only a single case of lipoid CAH due to a mutation and defect of P450scc has been identified.
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| All other cases of lipoid adrenal hyperplasia that have been studied have been found to be due to mutations of the [[gene]] for a protein which transports cholesterol into the mitochondria. This [[steroidogenic acute regulatory protein]] (StAR) is coded by a gene on 8p11.2. Inheritance is autosomal recessive. The [[OMIM]] number is 20170 for the deficiency.
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| Deficiency results in impaired synthesis of all three categories of adrenal steroids (cortisol, mineralocorticoids, sex steroids) and high levels of [[adrenocorticotropic hormone]] (ACTH). A low level of steroid synthesis proceeds even without efficient transport, but is rarely enough to prevent the consequences of deficiency.
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| ACTH stimulates growth of the adrenal cells, and increases [[Low density lipoprotein|LDL]] receptors to amplify transport of cholesterol into the adrenal cells, where it accumulates because little is transferred into the mitochondria. The adrenals become markedly enlarged by the combination of ACTH-induced [[hyperplasia]] and accumulated lipid. Lipid accumulation is thought to damage the cells further (“second hit hypothesis”).
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| Because the StAR protein is also involved in cholesterol transport into testicular and ovarian cells for sex steroid synthesis, [[testis|testicular]] production of [[testosterone]] and [[ovary|ovarian]] production of [[estrogen]] are also impaired. Lipid accumulation damages the [[Leydig cell]]s of the testes more completely than the [[granulosa cell]]s of the ovaries.
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| Lipoid CAH is quite rare in European and North American populations. Most cases have occurred in Japan and Korea (where the incidence is 1 in 300,000 births) and Palestinian Arabs. Despite autosomal recessive inheritance, there has been an unexplained preponderance of genetic females in reported cases.
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| The pathophysiology of lipoid CAH differs from other forms of CAH in certain aspects. First, the affected enzyme (StAR) is a transport protein rather than a steroidogenic enzyme. Second, because the defect is so proximal, all steroid synthesis is compromised and there are no effects of excessive mineralocorticoids or androgens to be suppressed. Third, lipid accumulation damages the testes and ovaries so that even with appropriate adrenal hormone replacement, gonadal function and fertility cannot be preserved.
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| ==Clinical manifestations of lipoid CAH==
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| Problems caused to persons with lipoid CAH can be divided into:
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| # mineralocorticoid deficiency,
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| # glucocorticoid deficiency,
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| # sex steroid deficiency, and
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| # damage to gonads caused by lipid accumulation.
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| ===Mineralocorticoid deficiency===
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| Most infants born with lipoid CAH have had genitalia female enough that no disease was suspected at birth. Because the adrenal [[zona glomerulosa]] is undifferentiated and inactive before delivery, it is undamaged at birth and can make [[aldosterone]] for a while, so the eventual salt-wasting crisis develops more gradually and variably than with severe [[congenital adrenal hyperplasia due to 21-hydroxylase deficiency|21-hydroxylase-deficient CAH]].
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| Most came to medical attention between 2 weeks and 3 months of age, when after a period of poor weight gain and vomiting, they were found to be dehydrated, with severe [[hyponatremia]], [[hyperkalemia]], and [[metabolic acidosis]] (a "salt-wasting crisis"). [[Renin]] but not [[aldosterone]] is elevated. Many infants born with this condition died before a diagnosis was recognized and treatment begun. In a few cases, signs and symptoms of mineralocorticoid and glucocorticoid deficiency have only developed after months or even years.
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| ===Glucocorticoid deficiency===
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| Inefficiency of [[cortisol]] synthesis has several consequences. Elevated ACTH is accompanied by and contributes to marked [[hyperpigmentation]] even in the newborn period. An inadequate cortisol response to stress undoubtedly hastens the deterioration as dehydration develops, can cause [[hypoglycemia]], and contributes to the high mortality rate in infancy.
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| ==Management of lipoid CAH==
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| Management of salt-wasting crises and mineralocorticoid treatment are as for other forms of salt-wasting [[congenital adrenal hyperplasia]]: saline and [[fludrocortisone]].
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| Glucocorticoids can be provided at minimal replacement doses because there is no need for suppression of excessive adrenal androgens or mineralocorticoids. As with other forms of adrenal insufficiency, extra glucocorticoid is needed for stress coverage.
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| XX females with lipoid CAH may need estrogen replacement at or after puberty. To date, ovulation and pregnancy has not been reported even with early diagnosis and careful glucocorticoid replacement to suppress ACTH-induced lipid damage to the ovaries.
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| Nearly all XY children have been so undervirilized that they have been raised as girls. The testes have been uniformly nonfunctional and are removed to prevent long term neoplastic risk.
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| ==Related Chapters== | | ==Related Chapters== |