17 alpha-hydroxylase deficiency pathophysiology: Difference between revisions

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{{Congenital adrenal hyperplasia due to 17 alpha-hydroxylase deficiency}}
{{17 alpha-hydroxylase deficiency}}
{{CMG}}; {{AE}} {{Ammu}}
{{CMG}}; {{AE}} {{MJ}}
 
==Overview==
==Overview==
17 alpha-hydroxylase deficiency is an uncommon form of [[congenital adrenal hyperplasia]] resulting from a defect in the [[gene]] [[CYP17A1]], which encodes for the [[enzyme]] 17 alpha-hydroxylase and 17,20-lyase. 17 alpha-hydroxylase deficiency is transmitted in an [[autosomal recessive]] pattern. [[Mineralocorticoid excess]] and lack of [[androgens]] are two main features in this disease.
==Pathogenesis==
* [[CYP17A1]] gene defects can cause two type of enzyme deficiencies: 17α-hydroxylase enzyme deficiency and 17,20-lyase deficiency. The dual activities mediate key transformations in [[cortisol]] and [[sex steroid]] synthesis:
** 17α-hydroxylase mediates the pathway: [[pregnenolone]] → [[17-hydroxypregnenolone]], also [[progesterone]] → [[17-hydroxyprogesterone]].
** 17,20-lyase mediates pathway [[17-hydroxypregnenolone]] → [[DHEA|Dehydroepiandrosterone]], also [[17-hydroxyprogesterone]] → [[androstenedione]].
* [[Mineralocorticoid excess]] is the major clinical clue distinguishing the 17α-hydroxylase deficiency from the 17,20-lyase deficiency, which only affects the [[Sex (activity)|sex]] [[steroids]].
* In 17 alpha-hydroxylase deficiency, [[steroid biosynthesis]] will be limited to [[progesterone]], [[11-deoxycorticosterone]] ([[Deoxycorticosterone|DOC]]), and [[corticosterone]].
* [[11-deoxycorticosterone]] ([[Deoxycorticosterone|DOC)]] binds to the mineralocorticoid receptor and its excess amounts in 17 alpha-hydroxylase deficiency causes [[aldosterone]] effects such as volume expansion, [[hypertension]], and [[hypokalemia]]. Also, [[11-deoxycorticosterone]] ([[Deoxycorticosterone|DOC)]] effects will suppress [[renin]] and [[aldosterone]] production.
* The most important features of 17 alpha-hydroxylase deficiency include [[hypertension]], [[hypokalemia]] and [[sexual infantilism]].
** [[Hypertension]] and [[hypokalemia]] result from accumulation of [[cortisol]] precursors, that have [[mineralocorticoid]] characteristics.
** [[Sexual infantilism]] results from the inability of [[adrenal cortex]] to synthesize [[androgens]] and [[estrogens]].<ref name="pmid8070426">{{cite journal |vauthors=Kater CE, Biglieri EG |title=Disorders of steroid 17 alpha-hydroxylase deficiency |journal=Endocrinol. Metab. Clin. North Am. |volume=23 |issue=2 |pages=341–57 |year=1994 |pmid=8070426 |doi= |url=}}</ref><ref name="pmid999330">{{cite journal |vauthors=Heremans GF, Moolenaar AJ, van Gelderen HH |title=Female phenotype in a male child due to 17-alpha-hydroxylase deficiency |journal=Arch. Dis. Child. |volume=51 |issue=9 |pages=721–3 |year=1976 |pmid=999330 |pmc=1546244 |doi= |url=}}</ref><ref name="pmid9452426">{{cite journal |vauthors=Auchus RJ, Lee TC, Miller WL |title=Cytochrome b5 augments the 17,20-lyase activity of human P450c17 without direct electron transfer |journal=J. Biol. Chem. |volume=273 |issue=6 |pages=3158–65 |year=1998 |pmid=9452426 |doi= |url=}}</ref><ref name="pmid6332824">{{cite journal |vauthors=Griffing GT, Wilson TE, Holbrook MM, Dale SL, Jackson TK, Ullrich I, Melby JC |title=Plasma and urinary 19-nor-deoxycorticosterone in 17 alpha-hydroxylase deficiency syndrome |journal=J. Clin. Endocrinol. Metab. |volume=59 |issue=5 |pages=1011–5 |year=1984 |pmid=6332824 |doi=10.1210/jcem-59-5-1011 |url=}}</ref><ref name="pmid15866602">{{cite journal |vauthors=Simsek E, Ozdemir I, Lin L, Achermann JC |title=Isolated 17,20-lyase (desmolase) deficiency in a 46,XX female presenting with delayed puberty |journal=Fertil. Steril. |volume=83 |issue=5 |pages=1548–51 |year=2005 |pmid=15866602 |doi=10.1016/j.fertnstert.2004.11.063 |url=}}</ref>
[[image:17 hydroxylase.gif|center|frame|800px|Adrenal steroid synthesis pathways in adrenal cortex and related enzymes <ref name="urlFile:Adrenal Steroids Pathways.svg - Wikimedia Commons">{{cite web |url=https://commons.wikimedia.org/wiki/File:Adrenal_Steroids_Pathways.svg|title=File:Adrenal Steroids Pathways.svg - Wikimedia Commons |format= |work= |accessdate=}}</ref>]]


==Pathogenesis==
* Congenital adrenal hyperplasia due to 17 alpha-hydroxylase deficiency produces decreased synthesis of both [[cortisol]] and [[sex steroid]]s, with resulting increase in [[mineralocorticoid]] production. Thus, common symptoms include mild [[hypocortisolism]], [[ambiguous genitalia]] in genetic males or failure of the ovaries to function at puberty in genetic females, and [[hypertension]] (respectively). This form of CAH results from deficiency of the [[enzyme]] [[17α-hydroxylase]] (also called [[CYP17A1]]).
* Congenital adrenal hyperplasia due to 17 alpha-hydroxylase deficiency accounts for less than 5% of the cases of [[congenital adrenal hyperplasia]]. 17α-hydroxylase deficiency impairs the efficiency of [[cortisol]] synthesis, resulting in high levels of [[ACTH]] secretion and hyperplasia of the adrenal glands.
* 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:
*As 17α-hydroxylase it mediates [[pregnenolone]] → [[17-hydroxypregnenolone]]
*and [[progesterone]] → [[17-hydroxyprogesterone]].
*As 17,20-lyase it mediates 17-hydroxypregnenolone → [[DHEA]].
*An expected second 17,20-lyase reaction (17-hydroxyprogesterone → [[androstenedione]]) is mediated so inefficiently in humans as to be of no known significance.
* 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. The [[OMIM]] number for diseases arising from mutations of this gene is [http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=202110 202110].
* 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.
===Mineralocorticoid Effects===
* 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 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.
[[Image:Steroidogenesis.png|thumb|center|800px|Production of DHEA from Cholesterol. ([[Cortisol]] is a [[glucocorticoid]].)]]
===Glucocorticoid effects===
* 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.
===Sex steroid effects===
* 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.
* 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.
* 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.
==17,20-Lyase deficiency==
{{Main|Isolated 17,20-lyase deficiency}}
* 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]] (e.g., DHEA in the adrenal, but also gonadal testosterone and estrogens) synthesis, whereas [[mineralocorticoid]] (e.g., aldosterone) and [[glucocorticoid]] (e.g., cortisol) levels remain normal.
* 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.
* Normal cortisol level can be explained by the strong negative feedback mechanism of cortisol on hypothalamus-pituitary axis system. That is, in the beginning, 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.
* 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.
* 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.
==Genetics==
==Genetics==
* 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.
* 17 alpha-hydroxylase deficiency is an [[inherited]] disease with an [[autosomal recessive]] pattern, which means both copies of the [[gene]] in each [[cell]] have [[gene]] [[mutations]].  
[[Image:Autorecessive.png|thumb|center|600px|11β-OH CAH is autosomal recessive]]
* Commonly, the parents of an individual with an [[autosomal recessive]] condition each carry one copy of the mutated [[gene]], but they typically do not show signs and symptoms of the condition.<ref name="pmid28476231">{{cite journal |vauthors=Hannah-Shmouni F, Chen W, Merke DP |title=Genetics of Congenital Adrenal Hyperplasia |journal=Endocrinol. Metab. Clin. North Am. |volume=46 |issue=2 |pages=435–458 |year=2017 |pmid=28476231 |doi=10.1016/j.ecl.2017.01.008 |url=}}</ref>
 
==Associated Conditions==
==Associated Conditions==
* [[Ambiguous genitalia]]
* [[Hypertension]]


==Gross Pathology==
==Gross Pathology==
[[Gross pathology]] findings in patients with 17 alpha-hydroxylase deficiency are:<ref name="radio">Congenital adrenal hyperplasia. Dr Henry Knipe and Dr M Venkatesh . Radiopaedia.org 2015.http://radiopaedia.org/articles/congenital-adrenal-hyperplasia</ref><ref name="pmid25372578">{{cite journal |vauthors=Teixeira SR, Elias PC, Andrade MT, Melo AF, Elias Junior J |title=The role of imaging in congenital adrenal hyperplasia |journal=Arq Bras Endocrinol Metabol |volume=58 |issue=7 |pages=701–8 |year=2014 |pmid=25372578 |doi= |url=}}</ref>
*Enlarged [[adrenal glands]]
*Wrinkled surface [[adrenal glands]]
*Cerebriform pattern [[adrenal glands]] ([[pathognomonic]] sign)
*Normal [[ultrasound]] appearances may also be seen
*[[Testicular]] masses may be identified representing [[adrenal]] rest tissue
[[Image:Cah.jpg|center|thumb|400px|frame|Adrenal gland, Cortex - Hyperplasia in a male rat from a chronic study. There are two adjacent foci of hyperplasia (H) in the zona fasciculata.<ref name="urlAdrenal Gland - Hyperplasia - Nonneoplastic Lesion Atlas">{{cite web |url=https://ntp.niehs.nih.gov/nnl/endocrine/adrenal/hyperpl/index.htm |title=Adrenal Gland - Hyperplasia - Nonneoplastic Lesion Atlas |format= |work= |accessdate=}}</ref>]]


==Microscopic Pathology==
==Microscopic Pathology==
In 17 alpha-hydroxylase deficiency [[microscopic]] findings may include:
* Diffuse cortical [[hyperplasia]] with smaller [[cells]]
* The cell [[cytoplasm]] can be vacuolated, and often more [[basophilic]]
* Rare [[mitotic]] figures may be present
* The [[hyperplastic]] cells typically lack features of cellular [[atypia]]<ref name="urlAdrenal Gland - Hyperplasia - Nonneoplastic Lesion Atlas">{{cite web |url=https://ntp.niehs.nih.gov/nnl/endocrine/adrenal/hyperpl/index.htm |title=Adrenal Gland - Hyperplasia - Nonneoplastic Lesion Atlas |format= |work= |accessdate=}}</ref>
[[Image:Cah mic.jpg|thumb|center|400px|frame|Adrenal gland, Cortex - Hyperplasia in a female rat from a chronic study. There is a hyperplastic lesion (H) in which cortical cells are increased in number but are smaller in size than adjacent normal cortical cells (NC)<ref name="urlAdrenal Gland - Hyperplasia - Nonneoplastic Lesion Atlas">{{cite web |url=https://ntp.niehs.nih.gov/nnl/endocrine/adrenal/hyperpl/index.htm |title=Adrenal Gland - Hyperplasia - Nonneoplastic Lesion Atlas |format= |work= |accessdate=}}</ref>]]


==References==
==References==
{{Reflist|2}}
{{Reflist|2}}
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Latest revision as of 16:04, 20 October 2017

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mehrian Jafarizade, M.D [2]

Overview

17 alpha-hydroxylase deficiency is an uncommon form of congenital adrenal hyperplasia resulting from a defect in the gene CYP17A1, which encodes for the enzyme 17 alpha-hydroxylase and 17,20-lyase. 17 alpha-hydroxylase deficiency is transmitted in an autosomal recessive pattern. Mineralocorticoid excess and lack of androgens are two main features in this disease.

Pathogenesis

Adrenal steroid synthesis pathways in adrenal cortex and related enzymes [6]

Genetics

Associated Conditions

Gross Pathology

Gross pathology findings in patients with 17 alpha-hydroxylase deficiency are:[8][9]

Adrenal gland, Cortex - Hyperplasia in a male rat from a chronic study. There are two adjacent foci of hyperplasia (H) in the zona fasciculata.[10]

Microscopic Pathology

In 17 alpha-hydroxylase deficiency microscopic findings may include:

Adrenal gland, Cortex - Hyperplasia in a female rat from a chronic study. There is a hyperplastic lesion (H) in which cortical cells are increased in number but are smaller in size than adjacent normal cortical cells (NC)[10]

References

  1. ↑ Kater CE, Biglieri EG (1994). "Disorders of steroid 17 alpha-hydroxylase deficiency". Endocrinol. Metab. Clin. North Am. 23 (2): 341–57. PMID 8070426.
  2. ↑ Heremans GF, Moolenaar AJ, van Gelderen HH (1976). "Female phenotype in a male child due to 17-alpha-hydroxylase deficiency". Arch. Dis. Child. 51 (9): 721–3. PMC 1546244. PMID 999330.
  3. ↑ Auchus RJ, Lee TC, Miller WL (1998). "Cytochrome b5 augments the 17,20-lyase activity of human P450c17 without direct electron transfer". J. Biol. Chem. 273 (6): 3158–65. PMID 9452426.
  4. ↑ Griffing GT, Wilson TE, Holbrook MM, Dale SL, Jackson TK, Ullrich I, Melby JC (1984). "Plasma and urinary 19-nor-deoxycorticosterone in 17 alpha-hydroxylase deficiency syndrome". J. Clin. Endocrinol. Metab. 59 (5): 1011–5. doi:10.1210/jcem-59-5-1011. PMID 6332824.
  5. ↑ Simsek E, Ozdemir I, Lin L, Achermann JC (2005). "Isolated 17,20-lyase (desmolase) deficiency in a 46,XX female presenting with delayed puberty". Fertil. Steril. 83 (5): 1548–51. doi:10.1016/j.fertnstert.2004.11.063. PMID 15866602.
  6. ↑ "File:Adrenal Steroids Pathways.svg - Wikimedia Commons".
  7. ↑ Hannah-Shmouni F, Chen W, Merke DP (2017). "Genetics of Congenital Adrenal Hyperplasia". Endocrinol. Metab. Clin. North Am. 46 (2): 435–458. doi:10.1016/j.ecl.2017.01.008. PMID 28476231.
  8. ↑ Congenital adrenal hyperplasia. Dr Henry Knipe and Dr M Venkatesh . Radiopaedia.org 2015.http://radiopaedia.org/articles/congenital-adrenal-hyperplasia
  9. ↑ Teixeira SR, Elias PC, Andrade MT, Melo AF, Elias Junior J (2014). "The role of imaging in congenital adrenal hyperplasia". Arq Bras Endocrinol Metabol. 58 (7): 701–8. PMID 25372578.
  10. ↑ 10.0 10.1 10.2 "Adrenal Gland - Hyperplasia - Nonneoplastic Lesion Atlas".
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