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| 17α-hydroxylase deficiency is an uncommon form of [[congenital adrenal hyperplasia]] resulting from a defect in the [[gene]] ''[[CYP17A1]]'', which encodes for the [[enzyme]] 17α-hydroxylase. Congenital adrenal hyperplasia due to 17 alpha-hydroxylase deficiency is transmitted in an autosomal recessive pattern. On gross pathology, thickening of the [[adrenal gland]] and cerebriform appearance are characteristic findings of congenital adrenal hyperplasia due to 17 alpha-hydroxylase deficiency. On microscopic histopathological analysis, diffuse cortical hyperplasia and lipid-depleted cortical cells are characteristic findings of congenital adrenal hyperplasia due to 17 alpha-hydroxylase deficiency. | | 17α-hydroxylase deficiency is an uncommon form of [[congenital adrenal hyperplasia]] resulting from a defect in the [[gene]] ''[[CYP17A1]]'', which encodes for the [[enzyme]] 17α-hydroxylase. Congenital adrenal hyperplasia due to 17 alpha-hydroxylase deficiency is transmitted in an autosomal recessive pattern. On gross pathology, thickening of the [[adrenal gland]] and cerebriform appearance are characteristic findings of congenital adrenal hyperplasia due to 17 alpha-hydroxylase deficiency. On microscopic histopathological analysis, diffuse cortical hyperplasia and lipid-depleted cortical cells are characteristic findings of congenital adrenal hyperplasia due to 17 alpha-hydroxylase deficiency. |
| ==Pathogenesis== | | ==Pathogenesis== |
| * 17 alpha-hydroxylase deficiency results in a decreased synthesis of both [[cortisol]] and [[sex steroid]]s, in addition to an increase in [[mineralocorticoid]] production.
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| * This form of congenital adrenal hyperplasia results from deficiency of the [[enzyme]] [[17α-hydroxylase]] (also called [[CYP17A1]]).<ref name="w">Congenital adrenal hyperplasia due to 17 alpha-hydroxylase deficiency. Wikipedia (2016. https://en.wikipedia.org/wiki/Congenital_adrenal_hyperplasia_due_to_17_alpha-hydroxylase_deficiency Accessed on February 4, 2016</ref>
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| * 17α-hydroxylase deficiency impairs the efficiency of [[cortisol]] synthesis, resulting in high levels of [[adrenocorticotropic hormone]] secretion and hyperplasia of the adrenal glands.
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| * Clinical effects of this condition include overproduction of [[mineralocorticoid]]s and deficiency of prenatal and [[puberty|pubertal]] [[sex steroid]]s. CYP17A1 functions in [[steroidogenesis]], where it converts [[pregnenolone]] and [[progesterone]] to their 17-hydroxy forms. The enzyme itself is attached to the smooth [[endoplasmic reticulum]] of the steroid-producing cells of the [[adrenal gland|adrenal cortex]] and [[gonad]]s. CYP17A1 functions as both a 17α-hydroxylase and a 17,20-lyase. The dual activities mediate three key transformations in [[cortisol]] and [[sex steroid]] synthesis:
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| * As 17α-hydroxylase it mediates [[pregnenolone]] → [[17-hydroxypregnenolone]] and [[progesterone]] → [[17-hydroxyprogesterone]].
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| * As 17,20-lyase it mediates 17-hydroxypregnenolone → [[DHEA|Dehydroepiandrosterone]].
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| * An expected second 17,20-lyase reaction (17-hydroxyprogesterone → [[androstenedione]]) is mediated so inefficiently in humans as to be of no known significance.
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| * The hydroxylase reactions are part of the synthetic pathway to cortisol as well as sex steroids, but the lyase reaction is only necessary for sex steroid synthesis.
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| * The dual enzyme activities were for many decades assumed to represent two entirely different genes and enzymes: 7α-hydroxylase deficient congenital adrenal hyperplasia, and a distinct and even rarer defect of sex steroid synthesis termed 17,20-lyase deficiency. In the last decade, it has become clear that the two diseases are different forms of defects of the same gene. However, the clinical features of the two types of impairment are distinct enough that they are described separately in the following sections.
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| ===Mineralocorticoid Effects===
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| * The adrenal cortex is hyperplastic and overstimulated, with no impairment of the mineralocorticoid pathway. Consequently, levels of deoxycorticosterone, [[corticosterone]], and 18-deoxycorticosterone are elevated. Although these precursors of [[aldosterone]] are weaker mineralocorticoids, the extreme elevations usually provide enough volume expansion, blood pressure elevation, and potassium depletion to suppress [[renin]] and aldosterone production. Some persons with 17α-hydroxylase deficiency develop [[hypertension]] in infancy, and nearly 90% do so by late childhood. The low-renin [[hypertension]] is often accompanied by [[hypokalemia]] due to urinary potassium wasting and [[metabolic alkalosis]]. These features of mineralocorticoid excess are the major clinical clue distinguishing the more complete 17α-hydroxylase deficiency from the 17,20-lyase deficiency, which only affects the sex steroids. Treatment with glucocorticoid suppresses ACTH, returns mineralocorticoid production toward normal, and lowers blood pressure.
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| [[Image:Steroidogenesis.png|thumb|center|800px|Production of DHEA from Cholesterol. ([[Cortisol]] is a [[glucocorticoid]].)]]
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| ===Glucocorticoid Effects===
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| * Although production of cortisol is inefficient enough to normalize ACTH, the 50-100-fold elevations of [[corticosterone]] have enough weak [[glucocorticoid]] activity to prevent glucocorticoid deficiency and adrenal crisis.
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| ===Sex Steroid Effects===
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| * Genetic XX females affected by 17α-hydroxylase deficiency are born with normal female internal and external anatomy. At the expected time of [[puberty]], neither the adrenals nor the ovaries can produce sex steroids, so neither breast development nor pubic hair appears. Investigation of delayed puberty yields elevated [[gonadotropin]]s and normal karyotype while imaging confirms the presence of ovaries and an infantile uterus. Discovery of hypertension and hypokalemic [[alkalosis]] usually suggests the presence of one of the proximal forms of congenital adrenal hyperplasia, and the characteristic mineralocorticoid elevations confirm the specific diagnosis.
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| * A few milder forms of this deficiency in genetic females have allowed relatively normal breast development and irregular menstruation. Evidence suggests that only 5% of normal enzyme activity may be enough to allow at least the physical changes of female puberty, if not [[ovulation]] and fertility. In these girls, the elevated blood pressure was the primary clinical problem.
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| * 17α-Hydroxylase deficiency in genetic males (XY) results in moderate to severe reduction of fetal [[testosterone]] production by both adrenals and testes. [[virilization|Undervirilization]] is variable and sometimes complete. The appearance of the external [[genitalia]] ranges from normal female to ambiguous to mildly underdeveloped male. The most commonly described phenotype is a small [[phallus]], [[perineum|perineal]] [[hypospadias]], small blind pseudovaginal pouch, and intra-abdominal or [[inguinal canal|inguinal]] testes. [[Wolffian duct]] derivatives are hypoplastic or normal, depending on the degree of testosterone deficiency. Some of those with partial virilization develop [[gynecomastia]] at puberty even though masculinization is reduced. The presence of hypertension in the majority distinguishes them from other forms of partial androgen deficiency or [[androgen insensitivity syndrome|insensitivity]]. Fertility is impaired in those with more than minimal testosterone deficiency.
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| ==17,20-Lyase Deficiency==
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| * A very small number of people have reportedly had an abnormal allele that resulted primarily in a reduction of 17,20-lyase activity, rather than both the hydroxylase and lyase activities. In these people the defect had the effect of an isolated impairment of [[sex steroid]] synthesis, whereas [[mineralocorticoid]] (e.g., aldosterone) and [[glucocorticoid]] levels remain normal.
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| * Normal [[aldosterone]] level can be attributed to the fact that aldosterone is independent of hypothalamus-pituitary axis feedback system, being mainly controlled by the level of serum potassium. Because of the normal [[aldosterone]] level, [[hypertension]] is not expected.
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| * Normal [[cortisol]] level can be explained by the strong negative feedback mechanism of [[cortisol]] on hypothalamus-pituitary axis system. That is, in the beginning, the 17,20-lyase deficiency will block synthesis of sex steroid hormones, forcing the pathways to produce more [[cortisol]]. However, the initial excess of cortisol is rapidly corrected by negative feedback mechanism—high cortisol decreases secretion of [[adrenocorticotropic hormone]] (ACTH) from zona fasciculata of [[adrenal gland]]. Thus, there is no mineralocorticoid overproduction. Also, there is no adrenal hyperplasia.
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| * It has also been observed in patients that the [[adrenocorticotropic hormone]] (ACTH) level remains in the normal range. The reason for this is still unclear.
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| * The sex steroid deficiency produces effects similar to 17α-hydroxylase deficiency. Severely affected genetic females (XX) are born with normal internal and external genitalia and there are no clues to abnormality until adolescence when both the androgenic and estrogenic signs (e.g., [[breast]] and pubic hair) of puberty fail to occur. Gonadotropins are high and the [[uterus]] infantile in size. The ovaries may contain enlarged follicular cysts, and ovulation may not occur even after replacement of [[estrogen]].
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| ==Genetics==
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| * Congenital adrenal hyperplasia due to 17α-hydroxylase deficiency is inherited in an [[autosomal recessive]] manner. The most common abnormal [[allele]]s of this condition impair both the 17α-hydroxylase activity and the 17,20-lyase activity of CYP17A1.
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| [[Image:Autorecessive.png|thumb|center|600px|11β-OH CAH is autosomal recessive]]
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| ==Associated Conditions==
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| * [[Metabolic alkalosis]]
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| * [[Hypokalemia]]
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| * [[Abdominal hernia]]
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| ==Gross Pathology==
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| * On gross pathology the following changes are noted:
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| :* Thickening of adrenal gland<ref>Adrenocortical hyperplasia. American urological association (2016). https://www.auanet.org/education/modules/pathology/adrenal-gland/hyperplasia.cfm Accessed on January 28, 2016</ref>
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| :* Cerebriform appearance
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| ==Microscopic Pathology==
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| * On microscopic pathology the following changes are noted:
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| :* Diffuse cortical hyperplasia
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| :* Zona reticularis is markedly hyperplastic
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| :* Lipid-depleted cortical cells
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| ==References==
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| {{Reflist|2}}
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| [[Category:Disease]]
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| [[Category:Pediatrics]]
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| [[Category:Endocrinology]]
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| [[Category:Genetic disorders]]
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| [[Category:Intersexuality]]
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