GTS5:Turner syndrome: Difference between revisions - Compendium of Cancer Genome Aberrations

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~~__TOC__~~

(''General Instructions – The focus of these pages is the clinically significant genetic alterations in each disease type. This is based on up-to-date knowledge from multiple resources such as PubMed and the WHO classification books. The CCGA is meant to be a supplemental resource to the WHO classification books; the CCGA captures in a continually updated wiki-stye manner the current genetics/genomics knowledge of each disease, which evolves more rapidly than books can be revised and published. If the same disease is described in multiple WHO classification books, the genetics-related information for that disease will be consolidated into a single main page that has this template (other pages would only contain a link to this main page). Use [https://www.genenames.org/ HUGO-approved gene names and symbols] (italicized when appropriate), [https://varnomen.hgvs.org/ HGVS-based nomenclature for variants], as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples); to add (or move) a row or column in a table, click nearby within the table and select the > symbol that appears. Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see'' ''[[Author_Instructions]]'' ''and [[Frequently Asked Questions (FAQs)|FAQs]] as well as contact your [[Leadership|Associate Editor]] or [mailto:CCGA@cancergenomics.org Technical Support].)''

(''General Instructions – The focus of these pages is the clinically significant genetic alterations in each disease type~~, which~~ is based on ~~current~~ knowledge ~~within~~ the WHO classification books and ~~using resources such as PubMed for the latest information~~. If the same disease is described in multiple WHO classification books, the genetics-related information for that disease will be consolidated into a single main page that has this template (other pages would only contain a link to this main page). Use [https://www.genenames.org/ HUGO-approved gene names and symbols] (italicized when appropriate), [https://varnomen.hgvs.org/ HGVS-based nomenclature for variants], as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples); to add (or move) a row or column in a table, click nearby within the table and select the > symbol that appears ~~to be given options~~. Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see'' ''[[Author_Instructions]]'' ''and [[Frequently Asked Questions (FAQs)|FAQs]] as well as contact your [[Leadership|Associate Editor]] or [mailto:CCGA@cancergenomics.org Technical Support])''

==Primary Author(s)*==

Put your text here (''EXAMPLE:'' Jane Smith, PhD)

==WHO Classification of Disease==

(''Instructions: This table’s content will be ~~autogenerated~~.'')

(''Instructions: This table’s content from the WHO book will be autocompleted.'')

{| class="wikitable"

!Structure

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==Definition / Description of Disease==

==Related Terminology==

Put your text here (''Instructions: Include a brief general clinical description, diagnostic criteria, and differential diagnosis if applicable. Include disease context relative to other WHO classification categories, i.e. describe any ~~organ-specific~~ information ~~pertinent~~ to the genetic aspects of the disease ~~across~~ all ~~applicable~~ WHO classification books~~.'') ~~

(''Instructions: This table will have the related terminology from the WHO book autocompleted.)''

~~==Synonyms / Terminology==~~

{| class="wikitable"

~~Put your text here (''Instructions: Include currently used terms and major historical ones, adding “(historical)” after~~ the ~~latter~~.'')

|+

==Epidemiology / Prevalence==

|Acceptable

|

|-

|Not Recommended

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|}

==Definition/Description of Disease==

Put your text here (''Instructions: Include a brief general clinical description, diagnostic criteria, and differential diagnosis if applicable. Include disease context relative to other WHO classification categories, i.e. describe any information relevant to the genetic aspects of the disease from all WHO classification books in which the syndrome is described.'')

==Epidemiology/Prevalence==

Put your text here

==Genetic Abnormalities: Germline==

Put your text here and fill in the table (''~~Instruction~~: ~~Can include references in the table. Do not delete table. If multiple causes of~~ the ~~syndrome, include relative prevalence of genetic contributions to that~~ syndrome. In the notes, include additional details about most common mutations including founder mutations, mechanisms of molecular pathogenesis, alteration-specific prognosis and any other important ~~genetic~~-related information ~~with key~~ references.'')

Put your text here and fill in the table (''Instructions: Describe germline alteration(s) that cause the syndrome. In the notes, include additional details about most common mutations including founder mutations, mechanisms of molecular pathogenesis, alteration-specific prognosis and any other important genetics-related information. If multiple causes of the syndrome, include relative prevalence of genetic contributions to that syndrome. Please include references throughout the table. Do not delete the table.'')

{| class="wikitable sortable"

|-

~~|'''~~Gene~~'''~~

!Gene!!Genetic Variant or Variant Type!!Molecular Pathogenesis!!Inheritance, Penetrance, Expressivity

~~|'''~~Genetic Variant or Variant Type~~'''~~

!Notes

~~|'''~~Molecular Pathogenesis~~'''~~

~~|'''~~Inheritance, Penetrance, Expressivity~~'''~~

~~|'''~~Notes~~'''~~

|-

|EXAMPLE: BRCA1||EXAMPLE: Many||EXAMPLE: Multiple variant types leading to loss of function||

|EXAMPLE: ''BRCA1''||EXAMPLE: Many||EXAMPLE: Multiple variant types leading to loss of function||EXAMPLE: Autosomal recessive,

~30% penetrant for carriers

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|-

|EXAMPLE: Gene X

|EXAMPLE: List the specific mutation

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|-

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==Genetic Abnormalities: Somatic==

Put your text here and fill in the table (''~~Instruction~~: Describe significant second hit mutations, or somatic variants that present as a germline syndrome~~. Can include references in the table. Do not delete table~~. In the notes, include details about most common mutations, mechanisms of molecular pathogenesis, alteration-specific prognosis and any other important genetic-related information ~~with key~~ references.'')

Put your text here and fill in the table (''Instructions: Describe significant second hit mutations, or somatic variants that present as a germline syndrome. In the notes, include details about most common mutations, mechanisms of molecular pathogenesis, alteration-specific prognosis and any other important genetic-related information. Please include references throughout the table. Do not delete the table.'')

{| class="wikitable sortable"

|-

!Gene!!Genetic Variant or Variant Type!!Molecular Pathogenesis!!Inheritance, Penetrance, Expressivity

!Notes

|-

|EXAMPLE: ''BRCA1''||EXAMPLE: Biallelic inactivation variants||EXAMPLE: Second hit mutation can occur as copy neutral LOH, inactivating mutation, deletion, promoter hypermethylation, or a structural abnormality disrupting the gene.||

|

|-

|EXAMPLE: ''BRCA1''

|EXAMPLE: Reversion mutation

|EXAMPLE: After exposure to certain therapies (e.g. PARP inhibitors), a second mutation may restore gene function as a resistance mechanism.

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|-

|

|}

==Genes and Main Pathways Involved==

Put your text here and fill in the table (''Instructions: Please include references throughout the table. Do not delete the table.)''

{| class="wikitable sortable"

|-

!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome

|-

|EXAMPLE: ''BRAF'' and ''MAP2K1''; Activating mutations

|EXAMPLE: MAPK signaling

|EXAMPLE: Increased cell growth and proliferation

|-

|EXAMPLE: ''CDKN2A''; Inactivating mutations

|EXAMPLE: Cell cycle regulation

|EXAMPLE: Unregulated cell division

|-

|EXAMPLE: ''KMT2C'' and ''ARID1A''; Inactivating mutations

|EXAMPLE: Histone modification, chromatin remodeling

|EXAMPLE: Abnormal gene expression program

|-

|

|}

==Genetic Diagnostic Testing Methods==

Put your text here (''Instructions: Include recommended testing type(s) to identify the clinically significant genetic alterations.'')

==Additional Information==

Put your text here

==Links==

Put a link here or anywhere appropriate in this page (''Instructions: Highlight the text to which you want to add a link in this section or elsewhere, select the "Link" icon at the top of the wiki page, and search the name of the internal page to which you want to link this text, or enter an external internet address by including the "<nowiki>http://www</nowiki>." portion.'')

==References==

(use the "Cite" icon at the top of the page) (''Instructions: Add each reference into the text above by clicking where you want to insert the reference, selecting the “Cite” icon at the top of the wiki page, and using the “Automatic” tab option to search by PMID to select the reference to insert. If a PMID is not available, such as for a book, please use the “Cite” icon, select “Manual” and then “Basic Form”, and include the entire reference. To insert the same reference again later in the page, select the “Cite” icon and “Re-use” to find the reference; DO NOT insert the same reference twice using the “Automatic” tab as it will be treated as two separate references. The reference list in this section will be automatically generated and sorted''''.'')

==Notes==

<nowiki>*</nowiki>Primary authors will typically be those that initially create and complete the content of a page. If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the [[Leadership|''Associate Editor'']] or other CCGA representative. When pages have a major update, the new author will be acknowledged at the beginning of the page, and those who contributed previously will be acknowledged below as a prior author.

Prior Author(s):

[[Category:GTS5]][[Category:DISEASE]]

THIS IS WEHRE THE OLD TEMPLATE BEGINS

(''General Instructions – The focus of these pages is the clinically significant genetic alterations in each disease type, which is based on current knowledge within the WHO classification books and using resources such as PubMed for the latest information. If the same disease is described in multiple WHO classification books, the genetics-related information for that disease will be consolidated into a single main page that has this template (other pages would only contain a link to this main page). Use [https://www.genenames.org/ HUGO-approved gene names and symbols] (italicized when appropriate), [https://varnomen.hgvs.org/ HGVS-based nomenclature for variants], as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples); to add (or move) a row or column in a table, click nearby within the table and select the > symbol that appears. Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see'' ''[[Author_Instructions]]'' ''and [[Frequently Asked Questions (FAQs)|FAQs]] as well as contact your [[Leadership|Associate Editor]] or [mailto:CCGA@cancergenomics.org Technical Support])''

==Primary Author(s)*==

Kathleen Bone, PhD, Medical College of Wisconsin

==WHO Classification of Disease==

{| class="wikitable"

!Structure

!Disease

|-

|Book

|Genetic Tumor Syndromes (5th ed.)

|-

|Category

|DNA repair and genomic instability

|-

|Family

|Chromosomal and non-dysjunction (aneuploidy) syndromes

|-

|Type

|N/A

|-

|Subtype(s)

|Turner Syndrome

|}

==Definition / Description of Disease==

Turner Syndrome (TS) is a rare chromosomal disorder resulting from complete or partial loss of the second sex chromosome. The most common clinical manifestations include short stature, ovarian failure, primary or secondary amenorrhea associated with hypergonadotropic hypogonadism, congenital lymphedema of the hands and feet, Madelung deformity of the forearm and wrist, webbed neck, cardiac anomalies such as coarctation of the aorta, bicuspid aortic valves, mitral valve prolapse, hypertension, ischemic heart disease and arteriosclerosis, impaired glucose tolerance, thyroid disease and hearing loss.<ref name=":0">{{Cite journal|last=Gravholt|first=Claus H.|date=2005-11|title=Clinical practice in Turner syndrome|url=https://pubmed.ncbi.nlm.nih.gov/16929365|journal=Nature Clinical Practice. Endocrinology & Metabolism|volume=1|issue=1|pages=41–52|doi=10.1038/ncpendmet0024|issn=1745-8366|pmid=16929365}}</ref><ref>{{Cite journal|last=Bondy|first=Carolyn A.|last2=Bakalov|first2=Vladimir K.|date=2006-07|title=Investigation of cardiac status and bone mineral density in Turner syndrome|url=https://pubmed.ncbi.nlm.nih.gov/16624607|journal=Growth hormone & IGF research: official journal of the Growth Hormone Research Society and the International IGF Research Society|volume=16 Suppl A|pages=S103–108|doi=10.1016/j.ghir.2006.03.008|issn=1096-6374|pmid=16624607}}</ref><ref>{{Cite journal|last=Dhooge|first=Ingeborg J. M.|last2=De Vel|first2=E.|last3=Verhoye|first3=C.|last4=Lemmerling|first4=M.|last5=Vinck|first5=B.|date=2005-03|title=Otologic disease in turner syndrome|url=https://pubmed.ncbi.nlm.nih.gov/15793396|journal=Otology & Neurotology: Official Publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology|volume=26|issue=2|pages=145–150|doi=10.1097/00129492-200503000-00003|issn=1531-7129|pmid=15793396}}</ref><ref>{{Cite journal|last=Güngör|first=N.|last2=Böke|first2=B.|last3=Belgin|first3=E.|last4=Tunçbilek|first4=E.|date=2000-10|title=High frequency hearing loss in Ullrich-Turner syndrome|url=https://pubmed.ncbi.nlm.nih.gov/11039128|journal=European Journal of Pediatrics|volume=159|issue=10|pages=740–744|doi=10.1007/pl00008338|issn=0340-6199|pmid=11039128}}</ref><ref>{{Cite journal|last=Zinn|first=A. R.|last2=Tonk|first2=V. S.|last3=Chen|first3=Z.|last4=Flejter|first4=W. L.|last5=Gardner|first5=H. A.|last6=Guerra|first6=R.|last7=Kushner|first7=H.|last8=Schwartz|first8=S.|last9=Sybert|first9=V. P.|date=1998-12|title=Evidence for a Turner syndrome locus or loci at Xp11.2-p22.1|url=https://pubmed.ncbi.nlm.nih.gov/9837829|journal=American Journal of Human Genetics|volume=63|issue=6|pages=1757–1766|doi=10.1086/302152|issn=0002-9297|pmc=1377648|pmid=9837829}}</ref><ref>{{Cite journal|last=Sävendahl|first=L.|last2=Davenport|first2=M. L.|date=2000-10|title=Delayed diagnoses of Turner's syndrome: proposed guidelines for change|url=https://pubmed.ncbi.nlm.nih.gov/11035820|journal=The Journal of Pediatrics|volume=137|issue=4|pages=455–459|doi=10.1067/mpd.2000.107390|issn=0022-3476|pmid=11035820}}</ref> Despite considerable phenotypic variability, short stature and gonadal dysgenesis are the most consistent findings. While individuals with TS may experience impairments in nonverbal developmental skills, they generally have normal intellectual ability.<ref>{{Cite journal|last=Kesler|first=Shelli R.|date=2007-07|title=Turner syndrome|url=https://pubmed.ncbi.nlm.nih.gov/17562588|journal=Child and Adolescent Psychiatric Clinics of North America|volume=16|issue=3|pages=709–722|doi=10.1016/j.chc.2007.02.004|issn=1056-4993|pmc=2023872|pmid=17562588}}</ref> Turner syndrome should be suspected prenatally when a prenatal ultrasound reveals fetal hydrops, cystic hygroma, or cardiac defects. Approximately 50% of TS patients have monosomy X (45,X), while the remaining 50% exhibit various structural abnormalities of the X chromosome or mosaicism with a normal female or normal male cell line.

[[File:45,X.png|center|thumb|G-banded chromosome analysis of a PHA-stimulated peripheral blood specimen from a patient with Turner Syndrome and a 45,X karyotype; Courtesy of Wisconsin Diagnostics Laboratories]]

[[File:Ring(X).tif|center|thumb|G-banded chromosome analysis of a PHA-stimulated peripheral blood specimen from a patient with variant Turner syndrome and a karyotype of 46,X,r(X)(p21q22)/45,X; Courtesy of Wisconsin Diagnostics Laboratories]]

In individuals with mosaic TS and Y chromosomal material, external genitalia may vary from normal male to ambiguous to female with TS characteristics. The Y chromosome, if present, may also be structurally abnormal. A patient with TS showing evidence of virilization is more likely to be mosaic for a Y-containing cell line, which increases the risk for gonadoblastoma.<ref name=":0" /><ref name=":1">{{Cite journal|last=Gravholt|first=Claus H.|last2=Andersen|first2=Niels H.|last3=Christin-Maitre|first3=Sophie|last4=Davis|first4=Shanlee M.|last5=Duijnhouwer|first5=Anthonie|last6=Gawlik|first6=Aneta|last7=Maciel-Guerra|first7=Andrea T.|last8=Gutmark-Little|first8=Iris|last9=Fleischer|first9=Kathrin|date=2024-06-05|title=Clinical practice guidelines for the care of girls and women with Turner syndrome|url=https://pubmed.ncbi.nlm.nih.gov/38748847|journal=European Journal of Endocrinology|volume=190|issue=6|pages=G53–G151|doi=10.1093/ejendo/lvae050|issn=1479-683X|pmid=38748847}}</ref> Molecular screening for Y chromosomal material is recommended in such cases.

==Synonyms / Terminology==

45,X Syndrome, Monosomy X, Variant Turner Syndrome, Mosaic Turner Syndrome, Congenital Ovarian Hypoplasia Syndrome (historical), Ullrich-Turner Syndrome (historical), Bonnevie-Ullrich syndrome (historical), 45,XO (historical, not recommended)

==Epidemiology / Prevalence==

TS and its variants occur in approximately 1 in 2000 to 1 in 2500 live-born females.<ref>{{Cite journal|last=Cui|first=Xiaoxiao|last2=Cui|first2=Yazhou|last3=Shi|first3=Liang|last4=Luan|first4=Jing|last5=Zhou|first5=Xiaoyan|last6=Han|first6=Jinxiang|date=2018-11|title=A basic understanding of Turner syndrome: Incidence, complications, diagnosis, and treatment|url=https://pubmed.ncbi.nlm.nih.gov/30560013|journal=Intractable & Rare Diseases Research|volume=7|issue=4|pages=223–228|doi=10.5582/irdr.2017.01056|issn=2186-3644|pmc=6290843|pmid=30560013}}</ref><ref>{{Cite journal|last=Nielsen|first=J.|last2=Wohlert|first2=M.|date=1991-05|title=Chromosome abnormalities found among 34,910 newborn children: results from a 13-year incidence study in Arhus, Denmark|url=https://pubmed.ncbi.nlm.nih.gov/2037286|journal=Human Genetics|volume=87|issue=1|pages=81–83|doi=10.1007/BF01213097|issn=0340-6717|pmid=2037286}}</ref> However, TS is among the most common chromosomal disorders, affecting 1–2% of conceptions, with approximately 99% of affected pregnancies resulting in pregnancy loss.<ref>{{Cite journal|last=Urbach|first=Achia|last2=Benvenisty|first2=Nissim|date=2009|title=Studying early lethality of 45,XO (Turner's syndrome) embryos using human embryonic stem cells|url=https://pubmed.ncbi.nlm.nih.gov/19137066|journal=PloS One|volume=4|issue=1|pages=e4175|doi=10.1371/journal.pone.0004175|issn=1932-6203|pmc=2613558|pmid=19137066}}</ref> The true prevalence of TS is difficult to ascertain, as many individuals remain undiagnosed or are only diagnosed later in adulthood.<ref>{{Cite journal|last=Gunther|first=Daniel F.|last2=Eugster|first2=Erica|last3=Zagar|first3=Anthony J.|last4=Bryant|first4=Constance G.|last5=Davenport|first5=Marsha L.|last6=Quigley|first6=Charmian A.|date=2004-09|title=Ascertainment bias in Turner syndrome: new insights from girls who were diagnosed incidentally in prenatal life|url=https://pubmed.ncbi.nlm.nih.gov/15342833|journal=Pediatrics|volume=114|issue=3|pages=640–644|doi=10.1542/peds.2003-1122-L|issn=1098-4275|pmid=15342833}}</ref>

==Genetic Abnormalities: Germline==

{| class="wikitable sortable"

|-

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|'''Notes'''

|-

|<~~span class~~=~~"blue~~-~~text">EXAMPLE~~:</~~span~~> ~~BRCA~~

|''SHOX''

|<~~span class~~="~~blue-text~~">~~EXAMPLE~~:</~~span~~> ~~Biallelic~~ inactivation ~~variants~~

|Whole or partial X chromosome loss encompassing gene

|<~~span class~~="~~blue-text~~">~~EXAMPLE~~:</~~span~~> ~~Second hit mutation can occur as copy neutral LOH, inactivating mutation, deletion, promoter hypermethylation,~~ or ~~a structural abnormality disrupting the gene.~~

|Haploinsufficiency

|

|''De novo'', complete penetrance, complete expressivity

|

|The ''short stature homeobox'' (''SHOX'') gene belongs to the paired homeobox family and is located in the pseudoautosomal region 1 (PAR1) on the short arms of the X (Xp22.3) and Y (Yp11.3) chromosomes.<ref>{{Cite journal|last=Rao|first=E.|last2=Weiss|first2=B.|last3=Fukami|first3=M.|last4=Rump|first4=A.|last5=Niesler|first5=B.|last6=Mertz|first6=A.|last7=Muroya|first7=K.|last8=Binder|first8=G.|last9=Kirsch|first9=S.|date=1997-05|title=Pseudoautosomal deletions encompassing a novel homeobox gene cause growth failure in idiopathic short stature and Turner syndrome|url=https://pubmed.ncbi.nlm.nih.gov/9140395|journal=Nature Genetics|volume=16|issue=1|pages=54–63|doi=10.1038/ng0597-54|issn=1061-4036|pmid=9140395}}</ref> It plays a crucial role in skeletal development, particularly in the growth plates of bones, where it regulates the proliferation and differentiation of chondrocytes, the cells responsible for cartilage formation. ''SHOX'' is vital for normal bone growth and stature, and pathogenic variants or deletions in this gene are associated with TS and other syndromes, including Leri-Weill dyschondrosteosis, and idiopathic short stature.<ref name=":2">{{Cite journal|last=Binder|first=Gerhard|date=2011-02|title=Short stature due to SHOX deficiency: genotype, phenotype, and therapy|url=https://pubmed.ncbi.nlm.nih.gov/21325865|journal=Hormone Research in Paediatrics|volume=75|issue=2|pages=81–89|doi=10.1159/000324105|issn=1663-2826|pmid=21325865}}</ref> Both males and females typically have two copies of the ''SHOX'' gene, as it escapes X chromosome inactivation.<ref name=":2" /><ref>{{Cite journal|last=Berletch|first=Joel B.|last2=Yang|first2=Fan|last3=Xu|first3=Jun|last4=Carrel|first4=Laura|last5=Disteche|first5=Christine M.|date=2011-08|title=Genes that escape from X inactivation|url=https://pubmed.ncbi.nlm.nih.gov/21614513|journal=Human Genetics|volume=130|issue=2|pages=237–245|doi=10.1007/s00439-011-1011-z|issn=1432-1203|pmc=3136209|pmid=21614513}}</ref>

|}

==Genetic Abnormalities: Somatic==

N/A

{| class="wikitable sortable"

|-

|'''Gene'''

|'''Genetic Variant or Variant Type'''

|'''Molecular Pathogenesis'''

|'''Inheritance, Penetrance, Expressivity'''

|'''Notes'''

|-

|~~EXAMPLE:<~~/~~span> BRCA~~

|N/A

|~~EXAMPLE:<~~/~~span> Gain~~

|N/A

|~~EXAMPLE:<~~/~~span>After exposure to certain therapies (e.g. PARP inhibitors), a second mutation may restore gene function as a resistance mechanism.~~

|N/A

|

|N/A

|

|N/A

|}

==Genes and Main Pathways Involved==

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==Genetic Diagnostic Testing Methods==

~~Put your text here~~

TS can be diagnosed prenatally through chorionic villus sampling (CVS) or amniocentesis, followed by G-banded chromosome analysis or karyotyping. Postnatal confirmation requires chromosome analysis of a phytohemagglutinin (PHA)-stimulated peripheral blood (PB) specimen. In cases of mosaicism, the karyotype may appear normal, so additional diagnostic methods may be necessary.

If TS is strongly suspected, a fluorescence in situ hybridization (FISH) study using an X chromosome centromere probe may be performed alongside karyotyping. Furthermore, if clinical suspicion remains high despite normal results from chromosome analysis and FISH, a chromosome analysis of a skin fibroblast culture may be indicated.

In patients with TS who exhibit signs of virilization, the presence of Y chromosomal material is a significant concern, as it increases the risk for the development of gonadoblastoma, a type of germ cell tumor.<ref name=":1" /> To detect Y chromosomal material, polymerase chain reaction (PCR) is a sensitive and specific molecular method used for screening. PCR involves amplifying DNA sequences specific to the Y chromosome, such as SRY (sex-determining region Y), TSPY (testis-specific protein Y-encoded), or other Y-specific markers.<ref>{{Cite journal|last=Mendes|first=J. R.|last2=Strufaldi|first2=M. W.|last3=Delcelo|first3=R.|last4=Moisés|first4=R. C.|last5=Vieira|first5=J. G.|last6=Kasamatsu|first6=T. S.|last7=Galera|first7=M. F.|last8=Andrade|first8=J. A.|last9=Verreschi|first9=I. T.|date=1999-01|title=Y-chromosome identification by PCR and gonadal histopathology in Turner's syndrome without overt Y-mosaicism|url=https://pubmed.ncbi.nlm.nih.gov/10341852|journal=Clinical Endocrinology|volume=50|issue=1|pages=19–26|doi=10.1046/j.1365-2265.1999.00607.x|issn=0300-0664|pmid=10341852}}</ref> This technique can identify even low levels of mosaicism, which might not be detectable by conventional karyotyping or FISH. When Y chromosomal material is confirmed, preventive measures, such as gonadectomy, are typically recommended to reduce the risk of malignancy.<ref name=":1" /> PCR is particularly valuable in cases where clinical findings and standard cytogenetic testing are inconclusive but there is strong clinical suspicion of Y chromosomal mosaicism. This molecular approach complements cytogenetic methods, providing a comprehensive evaluation for patients with TS and virilization.

==Additional Information==

Put your text here

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 {{Under Construction}}
-__TOC__
+<span style="color:#0070C0">(''General Instructions – The focus of these pages is the clinically significant genetic alterations in each disease type. This is based on up-to-date knowledge from multiple resources such as PubMed and the WHO classification books. The CCGA is meant to be a supplemental resource to the WHO classification books; the CCGA captures in a continually updated wiki-stye manner the current genetics/genomics knowledge of each disease, which evolves more rapidly than books can be revised and published. If the same disease is described in multiple WHO classification books, the genetics-related information for that disease will be consolidated into a single main page that has this template (other pages would only contain a link to this main page). Use [https://www.genenames.org/ <u>HUGO-approved gene names and symbols</u>] (italicized when appropriate), [https://varnomen.hgvs.org/ <u>HGVS-based nomenclature for variants</u>], as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples); to add (or move) a row or column in a table, click nearby within the table and select the > symbol that appears. Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see'' </span><u>''[[Author_Instructions]]''</u><span style="color:#0070C0"> ''and [[Frequently Asked Questions (FAQs)|<u>FAQs</u>]] as well as contact your [[Leadership|<u>Associate Editor</u>]] or [mailto:CCGA@cancergenomics.org <u>Technical Support</u>].)''</span>
-<span style="color:#0070C0">(''General Instructions – The focus of these pages is the clinically significant genetic alterations in each disease type, which is based on current knowledge within the WHO classification books and using resources such as PubMed for the latest information. If the same disease is described in multiple WHO classification books, the genetics-related information for that disease will be consolidated into a single main page that has this template (other pages would only contain a link to this main page). Use [https://www.genenames.org/ <u>HUGO-approved gene names and symbols</u>] (italicized when appropriate), [https://varnomen.hgvs.org/ HGVS-based nomenclature for variants], as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples); to add (or move) a row or column in a table, click nearby within the table and select the > symbol that appears to be given options. Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see'' </span><u>''[[Author_Instructions]]''</u><span style="color:#0070C0"> ''and [[Frequently Asked Questions (FAQs)|<u>FAQs</u>]] as well as contact your [[Leadership|<u>Associate Editor</u>]] or [mailto:CCGA@cancergenomics.org <u>Technical Support</u>])''</span>
 ==Primary Author(s)*==
 Put your text here<span style="color:#0070C0"> (''<span class="blue-text">EXAMPLE:</span>'' Jane Smith, PhD) </span>
 ==WHO Classification of Disease==
-<span style="color:#0070C0">(''Instructions: This table’s content will be autogenerated.'')</span>
+<span style="color:#0070C0">(''Instructions: This table’s content from the WHO book will be <u>autocompleted</u>.'')</span>
 {| class="wikitable"
 !Structure
@@ Line 25: / Line 24: @@
 |
 |}
-==Definition / Description of Disease==
+==Related Terminology==
-Put your text here <span style="color:#0070C0">(''Instructions: Include a brief general clinical description, diagnostic criteria, and differential diagnosis if applicable. Include disease context relative to other WHO classification categories, i.e. describe any organ-specific information pertinent to the genetic aspects of the disease across all applicable WHO classification books.'') </span>
+<span style="color:#0070C0">(''Instructions: This table will have the related terminology from the WHO book <u>autocompleted</u>.)''</span>
-==Synonyms / Terminology==
+{| class="wikitable"
-Put your text here <span style="color:#0070C0">(''Instructions: Include currently used terms and major historical ones, adding “(historical)” after the latter.'') </span>
+|+
-==Epidemiology / Prevalence==
+|Acceptable
+|
+|-
+|Not Recommended
+|
+|}
+==Definition/Description of Disease==
+Put your text here <span style="color:#0070C0">(''Instructions: Include a brief general clinical description, diagnostic criteria, and differential diagnosis if applicable. Include disease context relative to other WHO classification categories, i.e. describe any information relevant to the genetic aspects of the disease from all WHO classification books in which the syndrome is described.'')</span>
+==Epidemiology/Prevalence==
 Put your text here
 ==Genetic Abnormalities: Germline==
-Put your text here and fill in the table <span style="color:#0070C0">(''Instruction: Can include references in the table. Do not delete table. If multiple causes of the syndrome, include relative prevalence of genetic contributions to that syndrome. In the notes, include additional details about most common mutations including founder mutations, mechanisms of molecular pathogenesis, alteration-specific prognosis and any other important genetic-related information with key references.'')</span>
+Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Describe germline alteration(s) that cause the syndrome. In the notes, include additional details about most common mutations including founder mutations, mechanisms of molecular pathogenesis, alteration-specific prognosis and any other important genetics-related information. If multiple causes of the syndrome, include relative prevalence of genetic contributions to that syndrome. Please include references throughout the table. Do not delete the table.'')</span>
 {| class="wikitable sortable"
 |-
-|'''Gene'''
+!Gene!!Genetic Variant or Variant Type!!Molecular Pathogenesis!!Inheritance, Penetrance, Expressivity
-|'''Genetic Variant or Variant Type'''
+!Notes
-|'''Molecular Pathogenesis'''
-|'''Inheritance, Penetrance, Expressivity'''
-|'''Notes'''
 |-
-|<span class="blue-text">EXAMPLE:</span> BRCA1||<span class="blue-text">EXAMPLE:</span> Many||<span class="blue-text">EXAMPLE:</span> Multiple variant types leading to loss of function||
+|<span class="blue-text">EXAMPLE:</span> ''BRCA1''||<span class="blue-text">EXAMPLE:</span> Many||<span class="blue-text">EXAMPLE:</span> Multiple variant types leading to loss of function||<span class="blue-text">EXAMPLE:</span> Autosomal recessive,
+~30% penetrant for carriers
 |
 |-
 |<span class="blue-text">EXAMPLE:</span> Gene X
 |<span class="blue-text">EXAMPLE:</span> List the specific mutation
+|
+|
+|
+|-
+|
+|
 |
 |
@@ Line 51: / Line 63: @@
 |}
 ==Genetic Abnormalities: Somatic==
-Put your text here and fill in the table <span style="color:#0070C0">(''Instruction: Describe significant second hit mutations, or somatic variants that present as a germline syndrome. Can include references in the table. Do not delete table. In the notes, include details about most common mutations, mechanisms of molecular pathogenesis, alteration-specific prognosis and any other important genetic-related information with key references.'') </span>
+Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Describe significant second hit mutations, or somatic variants that present as a germline syndrome. In the notes, include details about most common mutations, mechanisms of molecular pathogenesis, alteration-specific prognosis and any other important genetic-related information. Please include references throughout the table. Do not delete the table.'')</span>
+{| class="wikitable sortable"
+|-
+!Gene!!Genetic Variant or Variant Type!!Molecular Pathogenesis!!Inheritance, Penetrance, Expressivity
+!Notes
+|-
+|<span class="blue-text">EXAMPLE:</span> ''BRCA1''||<span class="blue-text">EXAMPLE:</span> Biallelic inactivation variants||<span class="blue-text">EXAMPLE:</span> Second hit mutation can occur as copy neutral LOH, inactivating mutation, deletion, promoter hypermethylation, or a structural abnormality disrupting the gene.||
+|
+|-
+|<span class="blue-text">EXAMPLE:</span> ''BRCA1''
+|<span class="blue-text">EXAMPLE:</span> Reversion mutation
+|<span class="blue-text">EXAMPLE:</span> After exposure to certain therapies (e.g. PARP inhibitors), a second mutation may restore gene function as a resistance mechanism.
+|
+|
+|-
+|
+|
+|
+|
+|
+|}
+==Genes and Main Pathways Involved==
+Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Please include references throughout the table. Do not delete the table.)''</span>
+{| class="wikitable sortable"
+|-
+!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
+|-
+|<span class="blue-text">EXAMPLE:</span> ''BRAF'' and ''MAP2K1''; Activating mutations
+|<span class="blue-text">EXAMPLE:</span> MAPK signaling
+|<span class="blue-text">EXAMPLE:</span> Increased cell growth and proliferation
+|-
+|<span class="blue-text">EXAMPLE:</span> ''CDKN2A''; Inactivating mutations
+|<span class="blue-text">EXAMPLE:</span> Cell cycle regulation
+|<span class="blue-text">EXAMPLE:</span> Unregulated cell division
+|-
+|<span class="blue-text">EXAMPLE:</span> ''KMT2C'' and ''ARID1A''; Inactivating mutations
+|<span class="blue-text">EXAMPLE:</span> Histone modification, chromatin remodeling
+|<span class="blue-text">EXAMPLE:</span> Abnormal gene expression program
+|-
+|
+|
+|
+|}
+==Genetic Diagnostic Testing Methods==
+Put your text here <span style="color:#0070C0">(''Instructions: Include recommended testing type(s) to identify the clinically significant genetic alterations.'')</span>
+==Additional Information==
+Put your text here
+==Links==
+Put a link here or anywhere appropriate in this page <span style="color:#0070C0">(''Instructions: Highlight the text to which you want to add a link in this section or elsewhere, select the "Link" icon at the top of the wiki page, and search the name of the internal page to which you want to link this text, or enter an external internet address by including the "<nowiki>http://www</nowiki>." portion.'')</span>
+==References==
+(use the "Cite" icon at the top of the page) <span style="color:#0070C0">(''Instructions: Add each reference into the text above by clicking where you want to insert the reference, selecting the “Cite” icon at the top of the wiki page, and using the “Automatic” tab option to search by PMID to select the reference to insert. If a PMID is not available, such as for a book, please use the “Cite” icon, select “Manual” and then “Basic Form”, and include the entire reference. To insert the same reference again later in the page, select the “Cite” icon and “Re-use” to find the reference; DO NOT insert the same reference twice using the “Automatic” tab as it will be treated as two separate references. The reference list in this section will be automatically generated and sorted''</span><span style="color:#0070C0">''.''</span><span style="color:#0070C0">)</span>
+==Notes==
+<nowiki>*</nowiki>Primary authors will typically be those that initially create and complete the content of a page.  If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the [[Leadership|''<u>Associate Editor</u>'']] or other CCGA representative.  When pages have a major update, the new author will be acknowledged at the beginning of the page, and those who contributed previously will be acknowledged below as a prior author.
+Prior Author(s):
+[[Category:GTS5]][[Category:DISEASE]]
+THIS IS WEHRE THE OLD TEMPLATE BEGINS
+{{Under Construction}}
+<span style="color:#0070C0">(''General Instructions – The focus of these pages is the clinically significant genetic alterations in each disease type, which is based on current knowledge within the WHO classification books and using resources such as PubMed for the latest information. If the same disease is described in multiple WHO classification books, the genetics-related information for that disease will be consolidated into a single main page that has this template (other pages would only contain a link to this main page). Use [https://www.genenames.org/ <u>HUGO-approved gene names and symbols</u>] (italicized when appropriate), [https://varnomen.hgvs.org/ HGVS-based nomenclature for variants], as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples); to add (or move) a row or column in a table, click nearby within the table and select the > symbol that appears. Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see'' </span><u>''[[Author_Instructions]]''</u><span style="color:#0070C0"> ''and [[Frequently Asked Questions (FAQs)|<u>FAQs</u>]] as well as contact your [[Leadership|<u>Associate Editor</u>]] or [mailto:CCGA@cancergenomics.org <u>Technical Support</u>])''</span>
+==Primary Author(s)*==
+Kathleen Bone, PhD, Medical College of Wisconsin
+==WHO Classification of Disease==
+{| class="wikitable"
+!Structure
+!Disease
+|-
+|Book
+|Genetic Tumor Syndromes (5th ed.)
+|-
+|Category
+|DNA repair and genomic instability
+|-
+|Family
+|Chromosomal and non-dysjunction (aneuploidy) syndromes
+|-
+|Type
+|N/A
+|-
+|Subtype(s)
+|Turner Syndrome
+|}
+==Definition / Description of Disease==
+Turner Syndrome (TS) is a rare chromosomal disorder resulting from complete or partial loss of the second sex chromosome. The most common clinical manifestations include short stature, ovarian failure, primary or secondary amenorrhea associated with hypergonadotropic hypogonadism, congenital lymphedema of the hands and feet, Madelung deformity of the forearm and wrist, webbed neck, cardiac anomalies such as coarctation of the aorta, bicuspid aortic valves, mitral valve prolapse, hypertension, ischemic heart disease and arteriosclerosis, impaired glucose tolerance, thyroid disease and hearing loss.<ref name=":0">{{Cite journal|last=Gravholt|first=Claus H.|date=2005-11|title=Clinical practice in Turner syndrome|url=https://pubmed.ncbi.nlm.nih.gov/16929365|journal=Nature Clinical Practice. Endocrinology & Metabolism|volume=1|issue=1|pages=41–52|doi=10.1038/ncpendmet0024|issn=1745-8366|pmid=16929365}}</ref><ref>{{Cite journal|last=Bondy|first=Carolyn A.|last2=Bakalov|first2=Vladimir K.|date=2006-07|title=Investigation of cardiac status and bone mineral density in Turner syndrome|url=https://pubmed.ncbi.nlm.nih.gov/16624607|journal=Growth hormone & IGF research: official journal of the Growth Hormone Research Society and the International IGF Research Society|volume=16 Suppl A|pages=S103–108|doi=10.1016/j.ghir.2006.03.008|issn=1096-6374|pmid=16624607}}</ref><ref>{{Cite journal|last=Dhooge|first=Ingeborg J. M.|last2=De Vel|first2=E.|last3=Verhoye|first3=C.|last4=Lemmerling|first4=M.|last5=Vinck|first5=B.|date=2005-03|title=Otologic disease in turner syndrome|url=https://pubmed.ncbi.nlm.nih.gov/15793396|journal=Otology & Neurotology: Official Publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology|volume=26|issue=2|pages=145–150|doi=10.1097/00129492-200503000-00003|issn=1531-7129|pmid=15793396}}</ref><ref>{{Cite journal|last=Güngör|first=N.|last2=Böke|first2=B.|last3=Belgin|first3=E.|last4=Tunçbilek|first4=E.|date=2000-10|title=High frequency hearing loss in Ullrich-Turner syndrome|url=https://pubmed.ncbi.nlm.nih.gov/11039128|journal=European Journal of Pediatrics|volume=159|issue=10|pages=740–744|doi=10.1007/pl00008338|issn=0340-6199|pmid=11039128}}</ref><ref>{{Cite journal|last=Zinn|first=A. R.|last2=Tonk|first2=V. S.|last3=Chen|first3=Z.|last4=Flejter|first4=W. L.|last5=Gardner|first5=H. A.|last6=Guerra|first6=R.|last7=Kushner|first7=H.|last8=Schwartz|first8=S.|last9=Sybert|first9=V. P.|date=1998-12|title=Evidence for a Turner syndrome locus or loci at Xp11.2-p22.1|url=https://pubmed.ncbi.nlm.nih.gov/9837829|journal=American Journal of Human Genetics|volume=63|issue=6|pages=1757–1766|doi=10.1086/302152|issn=0002-9297|pmc=1377648|pmid=9837829}}</ref><ref>{{Cite journal|last=Sävendahl|first=L.|last2=Davenport|first2=M. L.|date=2000-10|title=Delayed diagnoses of Turner's syndrome: proposed guidelines for change|url=https://pubmed.ncbi.nlm.nih.gov/11035820|journal=The Journal of Pediatrics|volume=137|issue=4|pages=455–459|doi=10.1067/mpd.2000.107390|issn=0022-3476|pmid=11035820}}</ref> Despite considerable phenotypic variability, short stature and gonadal dysgenesis are the most consistent findings. While individuals with TS may experience impairments in nonverbal developmental skills, they generally have normal intellectual ability.<ref>{{Cite journal|last=Kesler|first=Shelli R.|date=2007-07|title=Turner syndrome|url=https://pubmed.ncbi.nlm.nih.gov/17562588|journal=Child and Adolescent Psychiatric Clinics of North America|volume=16|issue=3|pages=709–722|doi=10.1016/j.chc.2007.02.004|issn=1056-4993|pmc=2023872|pmid=17562588}}</ref> Turner syndrome should be suspected prenatally when a prenatal ultrasound reveals fetal hydrops, cystic hygroma, or cardiac defects. Approximately 50% of TS patients have monosomy X (45,X), while the remaining 50% exhibit various structural abnormalities of the X chromosome or mosaicism with a normal female or normal male cell line.
+[[File:45,X.png|center|thumb|G-banded chromosome analysis of a PHA-stimulated peripheral blood specimen from a patient with Turner Syndrome and a 45,X karyotype; Courtesy of Wisconsin Diagnostics Laboratories]]
+<br />
+[[File:Ring(X).tif|center|thumb|G-banded chromosome analysis of a PHA-stimulated peripheral blood specimen from a patient with variant Turner syndrome and a karyotype of 46,X,r(X)(p21q22)/45,X; Courtesy of Wisconsin Diagnostics Laboratories]]
+In individuals with mosaic TS and Y chromosomal material, external genitalia may vary from normal male to ambiguous to female with TS characteristics. The Y chromosome, if present, may also be structurally abnormal. A patient with TS showing evidence of virilization is more likely to be mosaic for a Y-containing cell line, which increases the risk for gonadoblastoma.<ref name=":0" /><ref name=":1">{{Cite journal|last=Gravholt|first=Claus H.|last2=Andersen|first2=Niels H.|last3=Christin-Maitre|first3=Sophie|last4=Davis|first4=Shanlee M.|last5=Duijnhouwer|first5=Anthonie|last6=Gawlik|first6=Aneta|last7=Maciel-Guerra|first7=Andrea T.|last8=Gutmark-Little|first8=Iris|last9=Fleischer|first9=Kathrin|date=2024-06-05|title=Clinical practice guidelines for the care of girls and women with Turner syndrome|url=https://pubmed.ncbi.nlm.nih.gov/38748847|journal=European Journal of Endocrinology|volume=190|issue=6|pages=G53–G151|doi=10.1093/ejendo/lvae050|issn=1479-683X|pmid=38748847}}</ref> Molecular screening for Y chromosomal material is recommended in such cases.
+==Synonyms / Terminology==
+,X Syndrome, Monosomy X, Variant Turner Syndrome, Mosaic Turner Syndrome, Congenital Ovarian Hypoplasia Syndrome (historical), Ullrich-Turner Syndrome (historical), Bonnevie-Ullrich syndrome (historical), 45,XO (historical, not recommended)
+==Epidemiology / Prevalence==
+TS and its variants occur in approximately 1 in 2000 to 1 in 2500 live-born females.<ref>{{Cite journal|last=Cui|first=Xiaoxiao|last2=Cui|first2=Yazhou|last3=Shi|first3=Liang|last4=Luan|first4=Jing|last5=Zhou|first5=Xiaoyan|last6=Han|first6=Jinxiang|date=2018-11|title=A basic understanding of Turner syndrome: Incidence, complications, diagnosis, and treatment|url=https://pubmed.ncbi.nlm.nih.gov/30560013|journal=Intractable & Rare Diseases Research|volume=7|issue=4|pages=223–228|doi=10.5582/irdr.2017.01056|issn=2186-3644|pmc=6290843|pmid=30560013}}</ref><ref>{{Cite journal|last=Nielsen|first=J.|last2=Wohlert|first2=M.|date=1991-05|title=Chromosome abnormalities found among 34,910 newborn children: results from a 13-year incidence study in Arhus, Denmark|url=https://pubmed.ncbi.nlm.nih.gov/2037286|journal=Human Genetics|volume=87|issue=1|pages=81–83|doi=10.1007/BF01213097|issn=0340-6717|pmid=2037286}}</ref> However, TS is among the most common chromosomal disorders, affecting 1–2% of conceptions, with approximately 99% of affected pregnancies resulting in pregnancy loss.<ref>{{Cite journal|last=Urbach|first=Achia|last2=Benvenisty|first2=Nissim|date=2009|title=Studying early lethality of 45,XO (Turner's syndrome) embryos using human embryonic stem cells|url=https://pubmed.ncbi.nlm.nih.gov/19137066|journal=PloS One|volume=4|issue=1|pages=e4175|doi=10.1371/journal.pone.0004175|issn=1932-6203|pmc=2613558|pmid=19137066}}</ref> The true prevalence of TS is difficult to ascertain, as many individuals remain undiagnosed or are only diagnosed later in adulthood.<ref>{{Cite journal|last=Gunther|first=Daniel F.|last2=Eugster|first2=Erica|last3=Zagar|first3=Anthony J.|last4=Bryant|first4=Constance G.|last5=Davenport|first5=Marsha L.|last6=Quigley|first6=Charmian A.|date=2004-09|title=Ascertainment bias in Turner syndrome: new insights from girls who were diagnosed incidentally in prenatal life|url=https://pubmed.ncbi.nlm.nih.gov/15342833|journal=Pediatrics|volume=114|issue=3|pages=640–644|doi=10.1542/peds.2003-1122-L|issn=1098-4275|pmid=15342833}}</ref>
+==Genetic Abnormalities: Germline==
 {| class="wikitable sortable"
 |-
@@ Line 60: / Line 170: @@
 |'''Notes'''
 |-
-|<span class="blue-text">EXAMPLE:</span> BRCA
+|''SHOX''
-|<span class="blue-text">EXAMPLE:</span> Biallelic inactivation variants
+|Whole or partial X chromosome loss encompassing gene
-|<span class="blue-text">EXAMPLE:</span> Second hit mutation can occur as copy neutral LOH, inactivating mutation, deletion, promoter hypermethylation, or a structural abnormality disrupting the gene.
+|Haploinsufficiency
-|
+|''De novo'', complete penetrance, complete expressivity
-|
+|The ''short stature homeobox'' (''SHOX'') gene belongs to the paired homeobox family and is located in the pseudoautosomal region 1 (PAR1) on the short arms of the X (Xp22.3) and Y (Yp11.3) chromosomes.<ref>{{Cite journal|last=Rao|first=E.|last2=Weiss|first2=B.|last3=Fukami|first3=M.|last4=Rump|first4=A.|last5=Niesler|first5=B.|last6=Mertz|first6=A.|last7=Muroya|first7=K.|last8=Binder|first8=G.|last9=Kirsch|first9=S.|date=1997-05|title=Pseudoautosomal deletions encompassing a novel homeobox gene cause growth failure in idiopathic short stature and Turner syndrome|url=https://pubmed.ncbi.nlm.nih.gov/9140395|journal=Nature Genetics|volume=16|issue=1|pages=54–63|doi=10.1038/ng0597-54|issn=1061-4036|pmid=9140395}}</ref> It plays a crucial role in skeletal development, particularly in the growth plates of bones, where it regulates the proliferation and differentiation of chondrocytes, the cells responsible for cartilage formation. ''SHOX'' is vital for normal bone growth and stature, and pathogenic variants or deletions in this gene are associated with TS and other syndromes, including Leri-Weill dyschondrosteosis, and idiopathic short stature.<ref name=":2">{{Cite journal|last=Binder|first=Gerhard|date=2011-02|title=Short stature due to SHOX deficiency: genotype, phenotype, and therapy|url=https://pubmed.ncbi.nlm.nih.gov/21325865|journal=Hormone Research in Paediatrics|volume=75|issue=2|pages=81–89|doi=10.1159/000324105|issn=1663-2826|pmid=21325865}}</ref> Both males and females typically have two copies of the ''SHOX'' gene, as it escapes X chromosome inactivation.<ref name=":2" /><ref>{{Cite journal|last=Berletch|first=Joel B.|last2=Yang|first2=Fan|last3=Xu|first3=Jun|last4=Carrel|first4=Laura|last5=Disteche|first5=Christine M.|date=2011-08|title=Genes that escape from X inactivation|url=https://pubmed.ncbi.nlm.nih.gov/21614513|journal=Human Genetics|volume=130|issue=2|pages=237–245|doi=10.1007/s00439-011-1011-z|issn=1432-1203|pmc=3136209|pmid=21614513}}</ref>
+|}
+==Genetic Abnormalities: Somatic==
+N/A
+{| class="wikitable sortable"
+|-
+|'''Gene'''
+|'''Genetic Variant or Variant Type'''
+|'''Molecular Pathogenesis'''
+|'''Inheritance, Penetrance, Expressivity'''
+|'''Notes'''
 |-
-|<span class="blue-text">EXAMPLE:</span> BRCA
+|N/A
-|<span class="blue-text">EXAMPLE:</span> Gain
+|N/A
-|<span class="blue-text">EXAMPLE:</span>After exposure to certain therapies (e.g. PARP inhibitors), a second mutation may restore gene function as a resistance mechanism.
+|N/A
-|
+|N/A
-|
+|N/A
 |}
 ==Genes and Main Pathways Involved==
@@ Line 91: / Line 211: @@
 |}
 ==Genetic Diagnostic Testing Methods==
-Put your text here
+TS can be diagnosed prenatally through chorionic villus sampling (CVS) or amniocentesis, followed by G-banded chromosome analysis or karyotyping. Postnatal confirmation requires chromosome analysis of a phytohemagglutinin (PHA)-stimulated peripheral blood (PB) specimen. In cases of mosaicism, the karyotype may appear normal, so additional diagnostic methods may be necessary.
+If TS is strongly suspected, a fluorescence in situ hybridization (FISH) study using an X chromosome centromere probe may be performed alongside karyotyping. Furthermore, if clinical suspicion remains high despite normal results from chromosome analysis and FISH, a chromosome analysis of a skin fibroblast culture may be indicated.
+In patients with TS who exhibit signs of virilization, the presence of Y chromosomal material is a significant concern, as it increases the risk for the development of gonadoblastoma, a type of germ cell tumor.<ref name=":1" /> To detect Y chromosomal material, polymerase chain reaction (PCR) is a sensitive and specific molecular method used for screening. PCR involves amplifying DNA sequences specific to the Y chromosome, such as SRY (sex-determining region Y), TSPY (testis-specific protein Y-encoded), or other Y-specific markers.<ref>{{Cite journal|last=Mendes|first=J. R.|last2=Strufaldi|first2=M. W.|last3=Delcelo|first3=R.|last4=Moisés|first4=R. C.|last5=Vieira|first5=J. G.|last6=Kasamatsu|first6=T. S.|last7=Galera|first7=M. F.|last8=Andrade|first8=J. A.|last9=Verreschi|first9=I. T.|date=1999-01|title=Y-chromosome identification by PCR and gonadal histopathology in Turner's syndrome without overt Y-mosaicism|url=https://pubmed.ncbi.nlm.nih.gov/10341852|journal=Clinical Endocrinology|volume=50|issue=1|pages=19–26|doi=10.1046/j.1365-2265.1999.00607.x|issn=0300-0664|pmid=10341852}}</ref> This technique can identify even low levels of mosaicism, which might not be detectable by conventional karyotyping or FISH. When Y chromosomal material is confirmed, preventive measures, such as gonadectomy, are typically recommended to reduce the risk of malignancy.<ref name=":1" /> PCR is particularly valuable in cases where clinical findings and standard cytogenetic testing are inconclusive but there is strong clinical suspicion of Y chromosomal mosaicism. This molecular approach complements cytogenetic methods, providing a comprehensive evaluation for patients with TS and virilization.
 ==Additional Information==
 Put your text here