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__NOTOC__
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{{Congenital adrenal hyperplasia due to 21-hydroxylase deficiency}}
{{21-hydroxylase deficiency}}


{{CMG}} {{AE}} {{AAM}}
{{CMG}}; '''Associate Editor-In-Chief:''' {{MJ}}, {{AAM}}


==Overview==
==Overview==
Development of [[congenital adrenal hyperplasia]] due to 21-hydroxylase deficiency is the result of a defective [[P450]]c21 enzyme. Genes involved in the pathogenesis of congenital adrenal hyperplasia due to 21-hydroxylase deficiency include the ''CYP21'' gene.
The progression to 21-hydroxylase deficiency usually involves the defective conversion of [[17-hydroxyprogesterone]] to [[11-deoxycorticosterone|11-deoxycortisol]] which results in decreased [[cortisol]] synthesis and therefore increased [[corticotropin]] ([[ACTH|ACTH)]] secretion. The resulting [[adrenal]] stimulation leads to increased production of [[androgens]] due to shunting of the pathway to [[androgen]] synthesis. More than 95% of cases of [[congenital adrenal hyperplasia]] ([[Congenital adrenal hyperplasia|CAH]]) are caused by 21-hydroxylase deficiency. The clinical manifestations of [[congenital adrenal hyperplasia]] is closely related to the type and severity of disease. The severity of disease relates to the type of [[mutation]] which causes [[enzyme]] inactivity or hypo-activity. There is a lack of [[enzyme]] in classic form of 21-hydroxylase deficiency; while in the non-classic form, [[enzymatic]] activity is reduced but sufficient to maintain normal [[glucocorticoid]] and [[mineralocorticoid]] production. The [[gene]] responsible for 21-hydroxylase deficiency is [[CYP21A1|CYP21A]]. This [[gene]] is located within the [[Human leukocyte antigen|human leucocyte antigen]] class III region of [[chromosome 6]]. Meiotic [[recombination]] occurs in this genomic region as a result of the high degree of [[sequence homology]] between [[CYP21A2]] and its [[pseudogene]] [[CYP21A1]]. Approximately 70% of [[CYP21A2]] [[genetic mutation]] is due to [[gene conversion]] and [[Microdeletion|micro-deletions]] in [[CYP21A1]] [[gene]].


==Pathophysiology==
== Pathophysiology ==
The defective enzyme [[P450]]c21, commonly referred to as 21-hydroxylase (21-OH), is embedded in the smooth [[endoplasmic reticulum]] of the cells of the [[adrenal gland|adrenal cortex]]. It catalyzes [[hydroxylation]] of [[17-hydroxyprogesterone]] to 11-deoxycortisol in the [[glucocorticoid]] pathway from [[pregnenolone]] to [[cortisol]]. It also catalyzes the hydroxylation of [[progesterone]] to 11-deoxycorticosterone (DOC) in the [[mineralocorticoid]] pathway from pregnenolone to [[aldosterone]].
===Pathogenesis===
Deficient activity of this enzyme reduces the efficiency of cortisol synthesis, with consequent elevation of [[adrenocorticotropic hormone]] ([[ACTH]]) levels and hyperplasia of the adrenal cortex. ACTH stimulates uptake of [[cholesterol]] and synthesis of pregnenolone. Steroid precursors up to and including progesterone, 17-hydroxypregnenolone, and especially 17-hydroxyprogesterone (17OHP) accumulate in the adrenal cortex and in circulating blood. Blood levels of 17OHP can reach 10-1000 times the normal concentration.
* [[21-hydroxylase]] enzyme is involved in the synthesis of [[aldosterone]] in [[zona glomerulosa]] and [[cortisol]] in [[zona fasciculata]]. Lack of 21-hydroxylase enzyme leads to decrease in [[cortisol]] and [[aldosterone]] levels and the rest of synthesis pathways produce extra [[androgens]] and lead to [[hirsutism]].
* More than 95% of all cases of [[congenital adrenal hyperplasia]] ([[CAH]]) are caused by 21-hydroxylase deficiency; the clinical manifestations of 21-hydroxylase deficiency is closely related to the type and severity of disease.
* The severity of disease relates to the type of [[mutation]], which causes [[enzyme]] inactivity or hypo activity.
* There is a lack of [[enzyme]] in classic type of [[21-hydroxylase]] deficiency; while in the non-classic form, enzymatic activity is reduced but sufficient to maintain normal [[glucocorticoid]] and [[mineralocorticoid]] production.
 
===Glucocorticoid pathway===
* In patients with 21-hydroxylase deficiency in [[zona fasciculata]], there is a defective conversion of [[17-hydroxyprogesterone]] to 11-[[deoxycortisol]] which results in decreased [[cortisol]] synthesis and therefore increased [[Corticotropin|corticotropin (ACTH)]] secretion.
===Mineralocorticoids pathway===
* In patients with 21-hydroxylase deficiency in [[zona glomerulosa]], there is a defective conversion of [[progesterone]] to 11-deoxycortisterone which results in decreased [[aldosterone]] synthesis.
* The lack of [[aldosterone]] causes large amounts of [[sodium]] loss in the [[urine]]. Urinary [[sodium]] concentrations are more than 50 mEq/L. As a result of high amount of [[sodium]] loss, [[blood volume]] and [[blood pressure]] can not be maintained in normal ranges.
* Due to [[mineralocorticoid]] deficiency, [[potassium]] and [[acid]] excretion are also impaired resulting in [[hyperkalemia]] and [[metabolic acidosis]].
* There is significant water loss and symptoms of [[dehydration]] due to salt wasting within the first two week of life. In severe form of [[CAH]], [[vomiting]], severe [[dehydration]], circulatory collapse and [[shock]]<nowiki/>develops in the second or third week of life.


Since 21-hydroxylase activity is not involved in synthesis of [[androgen]]s, a substantial fraction of the large amounts of 17-hydroxypregnenolone is diverted to synthesis of dehydroepiandrostenedione ([[DHEA]]), [[androstenedione]], and [[testosterone]] beginning in the third month of fetal life in both sexes.
===Androgen pathway===
* In the [[androgen]] synthesis pathway, 21-hydroxylase enzyme does not have a direct role; therefore with extra amount of other products from blocked [[cortisol]] and [[aldosterone]] synthesis, [[androgen]] pathway have extra [[Precursors|precursor]] [[metabolites]] resulting in [[androgen]] excess in the form of [[dehydroepiandrosterone]] and [[androstenedione]] accumulation.
* On the other hand, lack of [[cortisol]] removes the negative feedback on the [[pituitary gland]], resulting in an increase in [[ACTH]] level and consequently more increase in [[androgen]] synthesis pathway. High [[androgen]] level in [[21-hydroxylase]] deficient women during [[pregnancy]] causes [[ambiguous genitalia]] in female fetus; also in milder forms induces [[hirsutism]] and [[virilization]] in women. [[Adrenal]] [[androgens]] produce little effect on the [[genitalia]] of male [[infants]] with severe [[CAH]]. Excess [[androgen]] can cause [[precocious puberty]] in male child.


Synthesis of [[aldosterone]] is also dependent on 21-hydroxylase activity. Although fetal production is impaired, it causes no prenatal effects, as the [[placenta]]l connection allows maternal blood to "dialyze" the fetus and maintain both [[electrolyte]] balance and blood volume.
Below is the [[hormonal]] pathway of [[adrenal]] [[steroids]] and related [[enzymes]], also the mechanism of 21 hydroxylase deficiency symptoms.<ref name="pmid10857554">{{cite journal |vauthors=White PC, Speiser PW |title=Congenital adrenal hyperplasia due to 21-hydroxylase deficiency |journal=Endocr. Rev. |volume=21 |issue=3 |pages=245–91 |year=2000 |pmid=10857554 |doi=10.1210/edrv.21.3.0398 |url=}}</ref><ref name="pmid20823466">{{cite journal |vauthors=Speiser PW, Azziz R, Baskin LS, Ghizzoni L, Hensle TW, Merke DP, Meyer-Bahlburg HF, Miller WL, Montori VM, Oberfield SE, Ritzen M, White PC |title=Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline |journal=J. Clin. Endocrinol. Metab. |volume=95 |issue=9 |pages=4133–60 |year=2010 |pmid=20823466 |pmc=2936060 |doi=10.1210/jc.2009-2631 |url=}}</ref>


===Genetics===
The ''CYP21'' gene for the [[P450]]c21 enzyme (also known as 21-hydroxylase) is at 6p21.3, amid genes ''HLA B'' and ''HLA DR'' coding for the major human histocompatibility loci ([[HLA]]). ''CYP21'' is paired with a nonfunctional [[pseudogene]] ''CYP21A''. Scores of abnormal [[allele]]s of CYP21 have been documented, mostly arising from [[recombination]]s of homologous regions of ''CYP21'' and ''CYP21A''. Differences in residual enzyme activity of the various alleles account for the various degrees of severity of the disease. The inheritance of all forms of congenital adrenal hyperplasia due to 21-hydroxylase deficiency is [[autosomal recessive]].


Persons affected by any forms of the disease have two abnormal alleles, and both parents are usually carriers ([[heterozygote]]s). When parents both carry an abnormal allele, each child has a 25% chance of having the disease, a 50% chance of being an [[asymptomatic carrier]] like parents, and a 25% chance of having two normal genes.
[[image:21 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>]]


It is now possible to test for [[heterozygote|heterozygosity]] by measuring 17-hydroxyprogesterone elevation after [[ACTH]] stimulation, or more recently by direct gene sequencing.<ref name="pmid19228439">{{cite journal| author=Trakakis E, Loghis C, Kassanos D| title=Congenital adrenal hyperplasia because of 21-hydroxylase deficiency. A genetic disorder of interest to obstetricians and gynecologists. | journal=Obstet Gynecol Surv | year= 2009 | volume= 64 | issue= 3 | pages= 177-89 | pmid=19228439 | doi=10.1097/OGX.0b013e318193301b | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19228439  }} </ref>
== Genetics ==
* [[Congenital adrenal hyperplasia]] subtypes are all [[autosomal recessive]] and [[Monogenic disorder|monogenetic]]. The disease manifestation follows the [[allele]] that results in a more functional enzyme, and generally correlation between [[genotype]] and [[phenotype]] is good.<ref name="pmid20926536">{{cite journal |vauthors=Finkielstain GP, Chen W, Mehta SP, Fujimura FK, Hanna RM, Van Ryzin C, McDonnell NB, Merke DP |title=Comprehensive genetic analysis of 182 unrelated families with congenital adrenal hyperplasia due to 21-hydroxylase deficiency |journal=J. Clin. Endocrinol. Metab. |volume=96 |issue=1 |pages=E161–72 |year=2011 |pmid=20926536 |pmc=3038490 |doi=10.1210/jc.2010-0319 |url=}}</ref><ref name="pmid23359698">{{cite journal |vauthors=New MI, Abraham M, Gonzalez B, Dumic M, Razzaghy-Azar M, Chitayat D, Sun L, Zaidi M, Wilson RC, Yuen T |title=Genotype-phenotype correlation in 1,507 families with congenital adrenal hyperplasia owing to 21-hydroxylase deficiency |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=110 |issue=7 |pages=2611–6 |year=2013 |pmid=23359698 |pmc=3574953 |doi=10.1073/pnas.1300057110 |url=}}</ref>


__NOTOC__
=== CYP21A gene ===
{{Congenital adrenal hyperplasia}}
* The [[gene]] responsible for 21-hydroxylase deficiency is [[CYP21A1|CYP21A]]. This gene is located within the [[Human leukocyte antigen|human leucocyte antigen]] class III region of [[chromosome 6]].
[[CYP21A1|CYP21A]] gene has two types:


{{CMG}}; '''Associate Editor-In-Chief:''' {{CZ}}
===== CYP21A2 =====
* An active [[gene]] called [[CYP21A2]], which encodes 21-hydroxylase, a [[cytochrome P450]] type II [[enzyme]] containing 495 [[amino acids]].


==Overview==
===== CYP21A1 =====
* This [[gene]] is a non-functional [[pseudogene]] named [[CYP21A1]] or CYP21P. This [[pseudogene]] produces an [[enzyme]] with no activity because it lacks eight bases from [[codons]] 110-112, which results in a [[stop codon]].<ref name="pmid3487786">{{cite journal |vauthors=White PC, New MI, Dupont B |title=Structure of human steroid 21-hydroxylase genes |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=83 |issue=14 |pages=5111–5 |year=1986 |pmid=3487786 |pmc=323900 |doi= |url=}}</ref>


== Pathophysiology ==
===== Mutation mechanisms: =====
In patients with 21-hydroxylase deficiency, there is a defective conversion of 17-hydroxyprogesterone to 11-deoxycortisol which results in decreased cortisol synthesis and therefore increased corticotropin (ACTH) secretion and as a consequence of rising ACTH there is an increased production of androgens.<ref name="pmid10857554">{{cite journal |vauthors=White PC, Speiser PW |title=Congenital adrenal hyperplasia due to 21-hydroxylase deficiency |journal=Endocr. Rev. |volume=21 |issue=3 |pages=245–91 |year=2000 |pmid=10857554 |doi=10.1210/edrv.21.3.0398 |url=}}</ref>
* Meiotic [[recombination]] events occurs in this [[genomic]] region as a result of the high degree of [[sequence homology]] between [[CYP21A2]] and its [[pseudogene]] [[CYP21A1]].  
** Approximately 70% of disease associated with [[CYP21A2]] is due to [[gene conversion]] and [[Microdeletion|microdeletions]] in [[CYP21A1]] [[gene]].
** Approximately 25% to 30% are [[Chimerism|chimeric]] [[genes]] due to large [[Deletion (genetics)|deletions]].  
** Approximately 1% to 2% of cases are due to [[De novo mutation|de novo mutations]] because of high variability of the [[CYP21A2]] [[locus]].
** [[Chromosome 6]] [[uniparental disomy]] is rare cause of [[21-hydroxylase]] deficiency with an unknown [[prevalence]].  


[[image:Adrenal Steroids.png|600px]]
* [[Gene]] [[mutations]] that completely inactivates [[CYP21A2]] [[gene]] will result in the classic type and salt-wasting subtype.
* [[Gene]] [[mutations]] that maintain 1–2% of 21-hydroxylase activity will result in classic type and non-salt-wasting subtype. These patients have minimal [[aldosterone]] production that prevents a [[neonatal]] [[adrenal crisis]].<ref name="pmid2831244">{{cite journal |vauthors=Fiet J, Gueux B, Gourmelen M, Kuttenn F, Vexiau P, Couillin P, Pham-Huu-Trung MT, Villette JM, Raux-Demay MC, Galons H |title=Comparison of basal and adrenocorticotropin-stimulated plasma 21-deoxycortisol and 17-hydroxyprogesterone values as biological markers of late-onset adrenal hyperplasia |journal=J. Clin. Endocrinol. Metab. |volume=66 |issue=4 |pages=659–67 |year=1988 |pmid=2831244 |doi=10.1210/jcem-66-4-659 |url=}}</ref>


More than 95% of all cases of CAH are caused by 21-hydroxylase deficiency (21-OHD);
==Gross Pathology==
[[Gross]] [[pathology]] findings in patients with 21 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 of [[adrenal glands]]
*Cerebriform pattern in [[adrenal glands]] ([[pathognomonic]] sign)
*Normal [[ultrasound]] appearance


The clinical manifestation of congenital adrenal hyperplasia is closely related to the type and severity of impairment.
==Microscopic Pathology==
 
In [[21-hydroxylase]] deficiency [[microscopic]] findings may include:
== Genetics ==
* Diffuse [[Adrenal cortex|cortical]] [[hyperplasia]] with smaller [[Cell (biology)|cells]]
* Congenital adrenal hyperplasia subtypes are all autosomal recessive and monogenetic. The disease manifestation follows the allele that results in a more functional enzyme, and generally correlation between genotype and phenotype is good.<ref name="pmid20926536">{{cite journal |vauthors=Finkielstain GP, Chen W, Mehta SP, Fujimura FK, Hanna RM, Van Ryzin C, McDonnell NB, Merke DP |title=Comprehensive genetic analysis of 182 unrelated families with congenital adrenal hyperplasia due to 21-hydroxylase deficiency |journal=J. Clin. Endocrinol. Metab. |volume=96 |issue=1 |pages=E161–72 |year=2011 |pmid=20926536 |pmc=3038490 |doi=10.1210/jc.2010-0319 |url=}}</ref><ref name="pmid23359698">{{cite journal |vauthors=New MI, Abraham M, Gonzalez B, Dumic M, Razzaghy-Azar M, Chitayat D, Sun L, Zaidi M, Wilson RC, Yuen T |title=Genotype-phenotype correlation in 1,507 families with congenital adrenal hyperplasia owing to 21-hydroxylase deficiency |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=110 |issue=7 |pages=2611–6 |year=2013 |pmid=23359698 |pmc=3574953 |doi=10.1073/pnas.1300057110 |url=}}</ref><ref name="pmid20926536">{{cite journal |vauthors=Finkielstain GP, Chen W, Mehta SP, Fujimura FK, Hanna RM, Van Ryzin C, McDonnell NB, Merke DP |title=Comprehensive genetic analysis of 182 unrelated families with congenital adrenal hyperplasia due to 21-hydroxylase deficiency |journal=J. Clin. Endocrinol. Metab. |volume=96 |issue=1 |pages=E161–72 |year=2011 |pmid=20926536 |pmc=3038490 |doi=10.1210/jc.2010-0319 |url=}}</ref>
* The [[Cell (biology)|cell]] [[cytoplasm]] can be [[Vacuolization|vacuolated]], and often more [[basophilic]].
 
* Rare [[mitotic]] figures may be present
* Responsible gene for 21 OH deficiency is CYP21A. This gene is located within the [[Human leukocyte antigen|human leucocyte antigen]] class III region of chromosome 6. CYP21A gene has two types:
* The [[hyperplastic]] [[Cell (biology)|cells]] typically lack features of [[atypia|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>
*# An active gene called CYP21A2, which encodes 21-hydroxylase, a cytochrome P450 type II enzyme of 495 amino acids.
{|
*# The other gene is a non-functional pseudogene named CYP21A1 or CYP21P. This pseudogene produces an enzyme with no activity because it lacks eight bases from codons 110-112, which results in a stop codon<ref name="pmid3487786">{{cite journal |vauthors=White PC, New MI, Dupont B |title=Structure of human steroid 21-hydroxylase genes |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=83 |issue=14 |pages=5111–5 |year=1986 |pmid=3487786 |pmc=323900 |doi= |url=}}</ref>
|
 
[[Image:Cah mic.jpg|thumb|200px|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>]]
* Meiotic recombination events occurs in this genomic region as a result of the high degree of sequence homology between CYP21A2 and its pseudogene CYP21A1.
|
** Approximately 70% of CYP21A2 disease is due to gene conversion and micro-deletions in CYP21A1 gen.
[[Image:Cah.jpg|thumb|250px|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>]]
** Approximately 25% to 30% are chimeric genes due to large deletions.
|}
** Approximately 1% to 2% of cases are due to de novo mutations because of high variability of the CYP21A2 locus. 
** Chromosome 6 uniparental disomy is rare cause of 21-hydroxylase deficiency with an unknown prevalence.
Conventionally, classic 21OH deficiency is subclassified into salt wasting and simple virilising forms, which reflect the severity of aldosterone deficiency. Mutations that completely inactivate ''CYP21A2'' result in the salt-wasting phenotype, which, without neonatal screening, presents in the first 2 weeks of life with a life-threatening adrenal crisis ( table 2).<sup>23</sup> Patients with classic simple virilising congenital adrenal hyperplasia have mutations that retain 1–2% of 21OH activity and minimal aldosterone production prevents a neonatal crisis.<sup>40</sup> Excess fetal adrenal androgen exposure results in virilisation of external genitalia of 46,XX patients with classic 21OH deficiency (salt wasting and simple virilising; figure 3A). Without neonatal screening, male toddlers with the simple virilising form of the disorder are diagnosed with signs and symptoms of androgen excess. Postnatal excess androgen presence leads to premature growth of pubic hair and rapid skeletal growth in children. Patients with the non-classic form retain up to 50% of enzyme activity and mostly do not have adrenal insufficiency, but might have partial glucocorticoid deficiency, and female patients have normal genitalia.<sup>41</sup> Patients might present with mild androgen excess or have few or no symptoms. In fact, the term cryptic congenital adrenal hyperplasia was created to define patients with non-classic congenital adrenal hyperplasia who are identified by family genetic studies, but are otherwise asymptomatic.<sup>42</sup>


==References==
==References==
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Latest revision as of 15:39, 24 July 2020

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-In-Chief: Mehrian Jafarizade, M.D [2], Ahmad Al Maradni, M.D. [3]

Overview

The progression to 21-hydroxylase deficiency usually involves the defective conversion of 17-hydroxyprogesterone to 11-deoxycortisol which results in decreased cortisol synthesis and therefore increased corticotropin (ACTH) secretion. The resulting adrenal stimulation leads to increased production of androgens due to shunting of the pathway to androgen synthesis. More than 95% of cases of congenital adrenal hyperplasia (CAH) are caused by 21-hydroxylase deficiency. The clinical manifestations of congenital adrenal hyperplasia is closely related to the type and severity of disease. The severity of disease relates to the type of mutation which causes enzyme inactivity or hypo-activity. There is a lack of enzyme in classic form of 21-hydroxylase deficiency; while in the non-classic form, enzymatic activity is reduced but sufficient to maintain normal glucocorticoid and mineralocorticoid production. The gene responsible for 21-hydroxylase deficiency is CYP21A. This gene is located within the human leucocyte antigen class III region of chromosome 6. Meiotic recombination occurs in this genomic region as a result of the high degree of sequence homology between CYP21A2 and its pseudogene CYP21A1. Approximately 70% of CYP21A2 genetic mutation is due to gene conversion and micro-deletions in CYP21A1 gene.

Pathophysiology

Pathogenesis

Glucocorticoid pathway

Mineralocorticoids pathway

Androgen pathway

Below is the hormonal pathway of adrenal steroids and related enzymes, also the mechanism of 21 hydroxylase deficiency symptoms.[1][2]


Adrenal steroid synthesis pathways in adrenal cortex and related enzymes [3]

Genetics

CYP21A gene

CYP21A gene has two types:

CYP21A2
CYP21A1
Mutation mechanisms:

Gross Pathology

Gross pathology findings in patients with 21 hydroxylase deficiency are:[8][9]

Microscopic Pathology

In 21-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]
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]

References

  1. ↑ White PC, Speiser PW (2000). "Congenital adrenal hyperplasia due to 21-hydroxylase deficiency". Endocr. Rev. 21 (3): 245–91. doi:10.1210/edrv.21.3.0398. PMID 10857554.
  2. ↑ Speiser PW, Azziz R, Baskin LS, Ghizzoni L, Hensle TW, Merke DP, Meyer-Bahlburg HF, Miller WL, Montori VM, Oberfield SE, Ritzen M, White PC (2010). "Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline". J. Clin. Endocrinol. Metab. 95 (9): 4133–60. doi:10.1210/jc.2009-2631. PMC 2936060. PMID 20823466.
  3. ↑ "File:Adrenal Steroids Pathways.svg - Wikimedia Commons".
  4. ↑ Finkielstain GP, Chen W, Mehta SP, Fujimura FK, Hanna RM, Van Ryzin C, McDonnell NB, Merke DP (2011). "Comprehensive genetic analysis of 182 unrelated families with congenital adrenal hyperplasia due to 21-hydroxylase deficiency". J. Clin. Endocrinol. Metab. 96 (1): E161–72. doi:10.1210/jc.2010-0319. PMC 3038490. PMID 20926536.
  5. ↑ New MI, Abraham M, Gonzalez B, Dumic M, Razzaghy-Azar M, Chitayat D, Sun L, Zaidi M, Wilson RC, Yuen T (2013). "Genotype-phenotype correlation in 1,507 families with congenital adrenal hyperplasia owing to 21-hydroxylase deficiency". Proc. Natl. Acad. Sci. U.S.A. 110 (7): 2611–6. doi:10.1073/pnas.1300057110. PMC 3574953. PMID 23359698.
  6. ↑ White PC, New MI, Dupont B (1986). "Structure of human steroid 21-hydroxylase genes". Proc. Natl. Acad. Sci. U.S.A. 83 (14): 5111–5. PMC 323900. PMID 3487786.
  7. ↑ Fiet J, Gueux B, Gourmelen M, Kuttenn F, Vexiau P, Couillin P, Pham-Huu-Trung MT, Villette JM, Raux-Demay MC, Galons H (1988). "Comparison of basal and adrenocorticotropin-stimulated plasma 21-deoxycortisol and 17-hydroxyprogesterone values as biological markers of late-onset adrenal hyperplasia". J. Clin. Endocrinol. Metab. 66 (4): 659–67. doi:10.1210/jcem-66-4-659. PMID 2831244.
  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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