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==Overview==
 
Humans have 46 [[chromosomes]]. [[Chromosomes]] contain all of your [[genes]] and [[DNA]], the building blocks of the body. Two of these [[chromosomes]], the [[sex chromosomes]], determine if you become a [[boy]] or a [[girl]]. Loss the [[paternally]] or [[maternally]] derived [[X chromosome]] would lead to the class [[45 XO karyotype]]. Sometimes, an individual may have two [[cells lines]] with different [[genetic]] makeups. The percentage of this [[mosaicism]] is said to determine the severity of the [[phenotype]] in the [[patient]]. [[Structural abnormalities]] such as the formation of a [[ring chromosome]] or an [[isochromosome]] and other mechanisms such as [[lyonization]] or [[imprinting]] also play a role in the [[pathophysiology]] of [[Turner Syndrome]].
 
==Pathophysiology==
 
*The normal [[karyotype]] of a [[female]] and [[male]] is 46 XX and 46 XY respectively.
*Loss of the [[Y chromosome]] would mean an absence of the sex determining region of Y and therefore, the absence of [[testis]] determining factor (responsible for the process that converts [[dihydrotestosterone]] to [[testosterone]] and thereby the development of male [[genitalia]]).
*[[Karyotype]] abnormalities may take place during the formation of [[reproductive cells]] (45 XO) or during [[cell division]] processes responsible for [[fetal]] development ([[mosaicism]]).
*[[Turner syndrome]] is not an inherited condition.
*Therefore the physical manifestations of [[Turner’s syndrome]] are due to [[aneuploidy]], absence of two normal [[sex chromosomes]] or [[haploinsufficiency]] (presence of 1 set of [[genes]] in the [[cell]] instead of 2 ) of [[genes]] present in the [[Y chromosome]].
*[[Distal]] to [[Xq24]], small deletions of the long arm of the [[X-chromosome]] are not included in the [[diagnosis]] of TS. <ref name="pmid15371580">{{cite journal| author=Sybert VP, McCauley E| title=Turner's syndrome. | journal=N Engl J Med | year= 2004 | volume= 351 | issue= 12 | pages= 1227-38 | pmid=15371580 | doi=10.1056/NEJMra030360 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15371580  }} </ref>
*Females with [[short stature]] and deletion of the [[distal]] region of the [[paternal]] X [[chromosome]] including the [[SHOX gene]] are generally not diagnosed with [[Turner syndrome]].
*Similarly, individuals with deletions of [[Xq24]], with [[primary]] or [[secondary]] [[amenorrhea]] and without [[short stature]] are diagnosed as [[premature ovarian failure]].
*Small deletions of the long arm of the [[X-chromosome]] [[distal]] to [[Xq24]] are not included in the diagnosis of [[Turner syndrome]].
*A study of 67 [[Turner syndrome]] in China found 50 percent of the [[patients]] with the classic [[45 X karyotype]] followed by the [[mosaic]] pattern, a [[chromosomal structural abnormality]] ([[isochromosome]] or [[ring chromosome]]) and a Y [[chromosomal structural abnormality]]. <ref name="pmid30560013">{{cite journal| author=Cui X, Cui Y, Shi L, Luan J, Zhou X, Han J| title=A basic understanding of Turner syndrome: Incidence, complications, diagnosis, and treatment. | journal=Intractable Rare Dis Res | year= 2018 | volume= 7 | issue= 4 | pages= 223-228 | pmid=30560013 | doi=10.5582/irdr.2017.01056 | pmc=6290843 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=30560013  }} </ref>
 
===Karyotypes===
 
'''Nondisjunction'''
*During [[meiosis]] in either parent, a [[nondisjunction]] event can occur that leaves the [[gamete]], either [[oocyte]] or [[spermatocyte]], with neither X nor Y [[chromosome]].
*When this [[gamete]] combines with a [[gamete]] from the other parent (with a normal X [[chromosome]]), the [[embryo]] lacks the normal two [[chromosomes]].
*This leaves the [[embryo]] with 45 [[chromosomes]] and a single X [[chromosome]], denoted 45,X (or, sometimes 45,XO, where the "O" is used as a placeholder). This is found in 50% of individuals with [[Turner syndrome]].
 
'''Chromosomal structure'''
*An X [[chromosome]] can form a [[ring chromosome]] for example by losing a portion of the smaller arm, enabling the end of the long arm to wrap around. This is detrimental for the X [[chromosome]] in two ways. **Either the lost portion itself makes the [[chromosome]] less functional.
**Or it causes [[nondisjunction]], as described above. Thus, the causes listed here are partly overlapping.
*When such a [[ring chromosome]] combines with another [[ring chromosome]] in [[fertilization]], the pair is denoted as 46, XrXp-, where rXp- means a [[ring chromosome]] missing the small (p) arm of the [[chromosome]].
*Another variant of [[abnormal chromosomal structure]] is [[chromosomes]] with two long arms of the X [[chromosomes]] attached, and are called [[isochromosomes]].
*Variants of [[chromosomal structure]] occur in 30% of individuals with [[Turner syndrome]].
 
'''Nonfunctional Y'''
*Very rarely, the [[embryo]] has a normal X [[chromosome]] and a portion of the Y [[chromosome]].
* In these cases, the Y [[chromosome]] does not have a functional SRY (and so develops as a female), the diagnosis is XY [[gonadal dysgenesis]].[1]
*It is possible that some [[Turner syndrome]] diagnosis is due to [[gonadal dysgenesis]], particularly when it is caused by a large deletion of the Y [[chromosome]].
 
'''Mosaicism'''
*Each of the causes mentioned above can occur as a [[mosaicism]], that is, some of the [[cells]] carry the [[mutation]] and some don'tThat is, two [[cell]] lines of different [[genetic]] make ups exist.
*This happens if the error takes place in one [[cell]] after the very first divisions of the early [[embryo]] after [[fertilization]].
*The exact mixture of the two different [[cell]] types depends on when the [[nondisjunction]] occurred. *However, if the [[nondisjunction]] occurs after enough divisions, the fraction of abnormal [[cells]] is probably not large enough to show any significant effects.
*For instance, such a 45,X/46,XY individual will develop as a male, without [[Turner syndrome]].
**It is hypothesized that lower the percentage of [[mosaicism]], the lesser is the [[phenotype]] expression.
*[[Mosaicism]] is found in about 20% of individuals with [[Turner syndrome]].
 
'''No single Y'''
*There is no equivalent [[syndrome]] which results in a Y [[chromosome]] with no X, as such a condition is fatal in [[utero]].
 
'''Lyonization'''
*In a normal 46 XX female, a process called [[lyonization]] inactivates one of the X [[chromosomes]] to equalize the number of expressible [[genes]] in males and females.
*Some [[genes]] escape this inactivation and contribute to the [[pathophysiology]] in [[Turner Syndrome]].
*[[Turner syndrome]] might be due to the partial or complete absence of these inactivated [[genes]] and the presence of functional [[homologues]] of the Y [[chromosome]]. <ref name="pmid17562588">{{cite journal| author=Kesler SR| title=Turner syndrome. | journal=Child Adolesc Psychiatr Clin N Am | year= 2007 | volume= 16 | issue= 3 | pages= 709-22 | pmid=17562588 | doi=10.1016/j.chc.2007.02.004 | pmc=2023872 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17562588  }} </ref>
 
'''Imprinting'''
*[[Imprinting]] is an alteration in the expression of a [[gene]], depending on whether it has been inherited from the mother or father.
*In the case of [[imprinting]], it is not known whether there is a specific correlation between retention of the maternal or paternal [[chromosome]] and expression of particular [[phenotype]].
 
*[[Short Stature]] is said to be due to the [[haploinsufficiency]] of the [[short stature homeobox]] ([[SHOX gene]]) which is located on the [[pseudoautosomal]] region of the X [[chromosome]].
**The [[SHOX gene]] is also responsible for [[skeletal]] abnormalities such as [[high arched palate]], abnormal [[auricular]] development, [[cubitus valgus]], [[genu valgum]], [[Madelung deformity]] and [[short metacarpals]].
 
*[[Visuospatial]] deficits ([[visuo-spatial]] function, [[visuomotor]] learning and [[spatial working memory]]) in [[Turner syndrome]] is hypothesized to be independent of [[hormone deficiencies]] and due to abnormalities in [[parieto-occipital]] mechanisms/[[morphology]] along with volumetric differences in the [[superior parietal lobule]] and the [[postcentral gyrus]]. <ref name="pmid17562588">{{cite journal| author=Kesler SR| title=Turner syndrome. | journal=Child Adolesc Psychiatr Clin N Am | year= 2007 | volume= 16 | issue= 3 | pages= 709-22 | pmid=17562588 | doi=10.1016/j.chc.2007.02.004 | pmc=2023872 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17562588 }} </ref>
*Executive skill deficiencies are said to be due to abnormalities in the [[prefrontal-striatal pathways]].
*Reduced [[white matter]] in the [[frontal parietal pathways]] and defects in [[neurodevelopment]] and connectivity in these regions are responsible for the inability of [[Turner syndrome]] patients to link [[visuo-spatial]] functioning with executive functioning when performing complex tasks.
**The patient is able to compensate for this deficiency whilst performing simple tasks by recruiting [[fronto-parietal]] resources. This recruitment is not possible during complicated tasks.
*One study suggested that volumetric differences in the [[amygdala]] were responsible for poor facial recognition and judgement. Poor connectivity between the [[amygdala]] and [[fusiform]] and aberrant development in the [[orbitofrontal cortex]] and [[superior temporal sulcus]] further contribute to this.
*[[Premature ovarian failure]] is secondary to [[ovarian dysgenesis]] and early [[follicular apoptosis]].  
*[[Fractures]] are due to [[estrogen]] deficiency and X [[chromosomal abnormalities]]. <ref name="pmid12612263">{{cite journal| author=Frías JL, Davenport ML, Committee on Genetics and Section on Endocrinology| title=Health supervision for children with Turner syndrome. | journal=Pediatrics | year= 2003 | volume= 111 | issue= 3 | pages= 692-702 | pmid=12612263 | doi=10.1542/peds.111.3.692 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12612263  }} </ref>
*Increased susceptibility to [[gonadoblastomas]] are seen in those individuals with Y [[chromosomal abnormality karyotypes]].
**It is proposed that a [[gonadoblastoma]] susceptibility locus is located on the [[pericentromeric]] region of the Y [[chromosome]].
*Presence of [[autoimmune diseases]] may be due to [[haploinsufficiency]] of X [[chromosome]] or due to [[proinflammatory cytokines]] such as IL-6, IL-8 and [[tumor necrosis factor alpha]]. <ref name="pmid22218436">{{cite journal| author=Collett-Solberg PF, Gallicchio CT, Coelho SC, Siqueira RA, Alves ST, Guimarães MM| title=Endocrine diseases, perspectives and care in Turner syndrome. | journal=Arq Bras Endocrinol Metabol | year= 2011 | volume= 55 | issue= 8 | pages= 550-8 | pmid=22218436 | doi=10.1590/s0004-27302011000800008 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22218436  }} </ref>
 
*While [[phenotype-kartyotype]] correlations are unreliable in predicting clinical features in [[Turner syndrome]], some studies have suggested the following: <ref name="pmid15371580">{{cite journal| author=Sybert VP, McCauley E| title=Turner's syndrome. | journal=N Engl J Med | year= 2004 | volume= 351 | issue= 12 | pages= 1227-38 | pmid=15371580 | doi=10.1056/NEJMra030360 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15371580 }} </ref>
*#Loss of short and long arm of X [[chromosome]] – decreased [[ovarian]] function, number and survival of [[oocytes]].
*#Loss of interstitial or terminal long arm of X [[chromosome]] – [[Short stature]], primary or secondary [[ovarian failure]]
*#Loss of short arm of paternally inherited X [[chromosome]]- Full [[phenotype]]
*#Loss of a region at [[Xp22.3]] – [[Neurocognitive]] problems
*# Loss of a region at [[Xp11.4]] – Critical for the development of [[lymphedema]]
*#Presence of an [[isochromosome Xq]] – Increased risk of [[hypothyroidism]] and [[inflammatory bowel disease]]
*#Presence of ring chromosome – Increased risk of mental retardation.
*#Lack of the [[XIST locus]] – [[Phenotype]] with more severe mental retardation.
 
==References==
==References==
{{Reflist|2}}
{{Reflist|2}}
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Latest revision as of 16:24, 31 August 2020

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Akash Daswaney, M.B.B.S[2]

Overview

Humans have 46 chromosomes. Chromosomes contain all of your genes and DNA, the building blocks of the body. Two of these chromosomes, the sex chromosomes, determine if you become a boy or a girl. Loss the paternally or maternally derived X chromosome would lead to the class 45 XO karyotype. Sometimes, an individual may have two cells lines with different genetic makeups. The percentage of this mosaicism is said to determine the severity of the phenotype in the patient. Structural abnormalities such as the formation of a ring chromosome or an isochromosome and other mechanisms such as lyonization or imprinting also play a role in the pathophysiology of Turner Syndrome.

Pathophysiology

Karyotypes

Nondisjunction

Chromosomal structure

Nonfunctional Y

Mosaicism

  • Each of the causes mentioned above can occur as a mosaicism, that is, some of the cells carry the mutation and some don't. That is, two cell lines of different genetic make ups exist.
  • This happens if the error takes place in one cell after the very first divisions of the early embryo after fertilization.
  • The exact mixture of the two different cell types depends on when the nondisjunction occurred. *However, if the nondisjunction occurs after enough divisions, the fraction of abnormal cells is probably not large enough to show any significant effects.
  • For instance, such a 45,X/46,XY individual will develop as a male, without Turner syndrome.
    • It is hypothesized that lower the percentage of mosaicism, the lesser is the phenotype expression.
  • Mosaicism is found in about 20% of individuals with Turner syndrome.

No single Y

Lyonization

Imprinting

  • Imprinting is an alteration in the expression of a gene, depending on whether it has been inherited from the mother or father.
  • In the case of imprinting, it is not known whether there is a specific correlation between retention of the maternal or paternal chromosome and expression of particular phenotype.

References

  1. 1.0 1.1 Sybert VP, McCauley E (2004). "Turner's syndrome". N Engl J Med. 351 (12): 1227–38. doi:10.1056/NEJMra030360. PMID 15371580.
  2. Cui X, Cui Y, Shi L, Luan J, Zhou X, Han J (2018). "A basic understanding of Turner syndrome: Incidence, complications, diagnosis, and treatment". Intractable Rare Dis Res. 7 (4): 223–228. doi:10.5582/irdr.2017.01056. PMC 6290843. PMID 30560013.
  3. 3.0 3.1 Kesler SR (2007). "Turner syndrome". Child Adolesc Psychiatr Clin N Am. 16 (3): 709–22. doi:10.1016/j.chc.2007.02.004. PMC 2023872. PMID 17562588.
  4. Frías JL, Davenport ML, Committee on Genetics and Section on Endocrinology (2003). "Health supervision for children with Turner syndrome". Pediatrics. 111 (3): 692–702. doi:10.1542/peds.111.3.692. PMID 12612263.
  5. Collett-Solberg PF, Gallicchio CT, Coelho SC, Siqueira RA, Alves ST, Guimarães MM (2011). "Endocrine diseases, perspectives and care in Turner syndrome". Arq Bras Endocrinol Metabol. 55 (8): 550–8. doi:10.1590/s0004-27302011000800008. PMID 22218436.


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