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| {{Infobox_Disease |
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| | {{Congenital adrenal hyperplasia due to 17 alpha-hydroxylase deficiency}} |
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| | {{CMG}}; {{AE}} {{Ammu}} |
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| DiseasesDB = 1841 |
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| OMIM = 202110 |
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| MeshID = D000312 |
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| {{Congenital adrenal hyperplasia}} | |
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| ==Overview==
| | {{SK}} 17 alpha-hydroxylase deficiency; 17 alpha-hydroxylase deficiency; Adrenal hyperplasia, hypertensive form; Deficiency of steroid 17 alpha-monooxygenase; Steroid 17 alpha hydroxylase deficiency |
| '''Congenital adrenal hyperplasia due to 17α-hydroxylase deficiency''' is an uncommon form of [[congenital adrenal hyperplasia]] resulting from a defect in the [[gene]] for the [[enzyme]] [[CYP17A1]], which mediates several key transformations in the synthesis of both [[cortisol]] and [[sex steroid]]s. Because CYP17A1 mediates several reactions and different defective [[allele]]s can result in different combinations of impaired activity, people affected by this type of CAH can display a wide variety of problems and effects. Some versions of this disease cause [[ambiguous genitalia]] in genetic males, failure of the ovaries to function at puberty in genetic females, and/or [[hypertension]] due to excessive [[mineralocorticoid]] production.
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| ==Pathophysiology== | | '''For patient information, click [[{{PAGENAME}} (patient information)|here]].''' |
| | ==[[Congenital adrenal hyperplasia due to 17 alpha-hydroxylase deficiency overview|Overview]]== |
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| [[Image:DHEA1.svg|thumb|left|300px|17α-hydroxylase converts [[pregnenolone]] and [[progesterone]] to their 17-hydroxy forms. It corresponds to the first two downward arrows in this reaction scheme.]] | | ==[[Congenital adrenal hyperplasia due to 17 alpha-hydroxylase deficiency historical perspective|Historical Perspective]]== |
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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, respectively.
| | ==[[Congenital adrenal hyperplasia due to 17 alpha-hydroxylase deficiency classification|Classification]]== |
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| The enzyme itself is attached to the smooth [[endoplasmic reticulum]] of the steroid-producing cells of the [[adrenal gland|adrenal cortex]] and [[gonad]]s.
| | ==[[Congenital adrenal hyperplasia due to 17 alpha-hydroxylase deficiency pathophysiology|Pathophysiology]]== |
| 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]]
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| *and [[progesterone]] → [[17-hydroxyprogesterone]].
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| *As 17,20-lyase it mediates 17-hydroxypregnenolone → [[DHEA]].
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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. Different alleles of the CYP17A1 gene result in enzyme molecules with a range of impaired or reduced function that produces a range of clinical problems.
| | ==[[Congenital adrenal hyperplasia due to 17 alpha-hydroxylase deficiency causes|Causes]]== |
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| The dual enzyme activities were for many decades assumed to represent two entirely different genes and enzymes. Thus, medical textbooks and nosologies until quite recently described two different diseases: ''17α-hydroxylase deficient CAH'', and a distinct and even rarer defect of sex steroid synthesis termed ''17,20-lyase deficiency'' (which is not a form of CAH). In the last decade it has become clearer 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.
| | ==[[Congenital adrenal hyperplasia due to 17 alpha-hydroxylase deficiency differential diagnosis|Differentiating Congenital adrenal hyperplasia due to 17 alpha-hydroxylase deficiency From Other Diseases]]== |
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| ===Genetics=== | | ==[[Congenital adrenal hyperplasia due to 17 alpha-hydroxylase deficiency epidemiology and demographics|Epidemiology and Demographics]]== |
| ====17α-hydroxylase deficient CAH====
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| The gene for the cytochrome [[CYP17A1]] enzyme resides on chromosome 10q24.3. Mutations of this gene result in altered activities of the enzyme and the various forms of [[congenital adrenal hyperplasia]] and sex steroid deficiency due to its impairment. As are most enzyme deficiencies, these disorders are inherited in an [[autosomal recessive]] manner with a reported incidence of about 1 in 50,000 births. The [[OMIM]] number for diseases arising from mutations of this gene is [http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=202110 202110].
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| ====17,20-lyase deficiency==== | | ==[[Congenital adrenal hyperplasia due to 17 alpha-hydroxylase deficiency risk factors|Risk Factors]]== |
| 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 as described above. In these people the defect had the effect of an isolated impairment of [[sex steroid]] synthesis, with no significant effects on [[mineralocorticoid]] or [[glucocorticoid]] production, and no adrenal hyperplasia, mineralocorticoid overproduction, or hypertension.
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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., breasts 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.
| | ==[[Congenital adrenal hyperplasia due to 17 alpha-hydroxylase deficiency screening|Screening]]== |
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| ==Natural History, Complications, and Prognosis== | | ==[[Congenital adrenal hyperplasia due to 17 alpha-hydroxylase deficiency natural history, complications and prognosis|Natural History, Complications and Prognosis]]== |
| ===Complications===
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| ====Glucocorticoid Effects of 17α-hydroxylase deficient CAH====
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| Although production of cortisol is inefficient enough to raise ACTH, the 50-100-fold elevations of [[corticosterone]] have enough weak [[glucocorticoid]] activity to prevent glucocorticoid deficiency and adrenal crisis.
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| ====Effects of Impaired Sex Steroid Synthesis==== | |
| 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 appear. 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 CAH, 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.
| | ==Diagnosis== |
| | | [[Congenital adrenal hyperplasia due to 17 alpha-hydroxylase deficiency history and symptoms|History and Symptoms]] | [[Congenital adrenal hyperplasia due to 17 alpha-hydroxylase deficiency physical examination|Physical Examination]] | [[Congenital adrenal hyperplasia due to 17 alpha-hydroxylase deficiency laboratory findings|Laboratory Findings]] | [[Congenital adrenal hyperplasia due to 17 alpha-hydroxylase deficiency CT|CT]] | [[Congenital adrenal hyperplasia due to 17 alpha-hydroxylase deficiency MRI|MRI]] | [[Congenital adrenal hyperplasia due to 17 alpha-hydroxylase deficiencyultrasound|Ultrasound]] | [[Congenital adrenal hyperplasia due to 17 alpha-hydroxylase deficiency other imaging findings|Other Imaging Findings]] | [[Congenital adrenal hyperplasia due to 17 alpha-hydroxylase deficiency other diagnostic studies|Other Diagnostic Studies]] |
| 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 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 testoserone deficiency.
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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 DOC, [[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 distinguishig 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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| ==Treatment== | | ==Treatment== |
| The most difficult management decisions are posed by the more ambiguous genetic (XY) males. Most who are severely undervirilized, looking more female than male, are raised as females with surgical removal of the nonfunctional testes. If raised as males, a brief course of testosterone can be given in infancy to induce growth of the penis. Surgery may be able to repair the hypospadias. The testes should be salvaged by [[orchiopexy]] if possible. Testosterone must be replaced in order for puberty to occur and continued throughout adult life.
| | [[Congenital adrenal hyperplasia due to 17 alpha-hydroxylase deficiency medical therapy|Medical Therapy]] | [[Congenital adrenal hyperplasia due to 17 alpha-hydroxylase deficiency surgery|Surgery]] | [[Congenital adrenal hyperplasia due to 17 alpha-hydroxylase deficiency prevention|Prevention]] | [[Congenital adrenal hyperplasia due to 17 alpha-hydroxylase deficiency cost-effectiveness of therapy|Cost-Effectiveness of Therapy]] | [[Congenital adrenal hyperplasia due to 17 alpha-hydroxylase deficiency future or investigational therapies|Future or Investigational Therapies]] |
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| ===Pharmacotherapy===
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| ====Management of 17α-hydroxylase and 17,20-lyase deficiencies====
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| Hypertension and mineralocorticoid excess is treated with [[glucocorticoid]] replacement, as in other forms of [[congenital adrenal hyperplasia|CAH]].
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| Most genetic females with both forms of the deficiency will need replacement estrogen to induce puberty. Most will also need periodic progestin to regularize menses. Fertility is usually reduced because egg maturation and ovulation is poorly supported by the reduced intra-ovarian steroid production.
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| ==Related Chapters==
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| *[[Congenital adrenal hyperplasia]] for an overview of CAH, more detailed discussion of management issues related to all forms of CAH, and links to support groups.
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| *[[Lipoid congenital adrenal hyperplasia]]
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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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| *[[Intersex]] and [[ambiguous genitalia]]
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| *[[Adrenal insufficiency]]
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| [[Category:Endocrinology]] | | [[Category:Oncology]] |
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| {{WH}}
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