17 alpha-hydroxylase deficiency pathophysiology: Difference between revisions

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{{17 alpha-hydroxylase deficiency}}
{{17 alpha-hydroxylase deficiency}}
{{CMG}}; {{AE}} {{MJ}}
{{CMG}}; {{AE}} {{MJ}}
==Overview==
==Overview==
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 and 17,20-lyase. 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.
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==
==Pathogenesis==
* 17 alpha-hydroxylase deficiency is a form of [[congenital adrenal hyperplasia]]; that results from deficiency of the [[enzyme]] [[17α-hydroxylase]].
* [[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:
* Through the pathway of [[steroid biosynthesis]], [[CYP17A1|17α-hydroxylase]] metabolizes [[pregnenolone]], [[progesterone]], [[17-hydroxypregnenolone]] and [[17-hydroxyprogesterone]]. In 17 alpha-hydroxylase deficiency steroid synthesis will be limited to [[progesterone]], [[11-deoxycorticosterone]] ([[Deoxycorticosterone|DOC]]), and [[corticosterone]].
** 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>


* The most important features of 17 alpha-hydroxylase deficiency include [[hypertension]], [[hypokalemia]] and [[sexual infantilism]].
[[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>]]
** [[Hypertension]] and [[hypokalemia]] result from accumulation of [[cortisol]] precursors, that they have [[mineralocorticoid]] characteristics.
 
** [[Sexual infantilism]] results from inability of [[adrenal cortex]] to synthesize [[androgens]] and [[estrogens]].
==Genetics==
* 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]].  
* 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==
* [[Ambiguous genitalia]]
* [[Hypertension]]


* 17 hydroxylase enzyme functions as both a 17α-hydroxylase and a 17,20-lyase. The dual activities mediate three key transformations in [[cortisol]] and [[sex steroid]] synthesis:
==Gross Pathology==
** 17α-hydroxylase mediates the pathway: [[pregnenolone]] → [[17-hydroxypregnenolone]], also [[progesterone]] → [[17-hydroxyprogesterone]].
[[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>
** 17,20-lyase mediates pathway [[17-hydroxypregnenolone]] → [[DHEA|Dehydroepiandrosterone]], also [[17-hydroxyprogesterone]] → [[androstenedione]]
*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>]]


These two enzyme deficiencies are different forms of defects of the same gene.  
==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>]]


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
==References==
{{Reflist|2}}

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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