Changes

{{Under Construction}}

{{Under Construction}}

<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. 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-style 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>

==Primary Author(s)*==

==Primary Author(s)*==

Put your text here<span style="color:#0070C0"> (''<span class="blue-text">EXAMPLE:</span>'' Jane Smith, PhD) </span>

Kathleen M. Bone, PhD, Medical College of Wisconsin

==WHO Classification of Disease==

==WHO Classification of Disease==

{| class="wikitable"

{| class="wikitable"

!Structure

!Structure

|-

|-

|Book

|Book

|

|Genetic Tumor Syndromes (5th ed.)

|-

|-

|Category

|Category

|

|DNA repair and genomic instability

|-

|-

|Family

|Family

|

|Chromosomal and non-dysjunction (aneuploidy) syndromes

|-

|-

|Type

|Type

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|N/A

|-

|-

|Subtype(s)

|Subtype(s)

|

|Turner Syndrome

|}

|}

==Related Terminology==

==Related Terminology==

{| class="wikitable"

{| class="wikitable"

|+

|+

|Acceptable

|Acceptable

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|45,X syndrome; Ullrich-Turner syndrome

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|Not Recommended

|Not Recommended

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|45,XO syndrome

|}

|}

==Definition/Description of Disease==

==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>

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> TS 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]]

[[File:I(X)(q10).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,i(X)(q10); Courtesy of Wisconsin Diagnostics Laboratories]]

[[File:46,X,del(X)(q21.3).png|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,del(X)(q21.3)/45,X; Courtesy of Wisconsin Diagnostics Laboratories]]

 

 

In 45,X females, ovarian tissue is generally replaced with streak gonads, and most TS individuals are thus infertile. While spontaneous pregnancies have been reported in ~2-8% of TS females, it has been speculated that a normal cell line is present in the gonads of such individuals.<ref>{{Cite journal|last=Pasquino|first=A. M.|last2=Passeri|first2=F.|last3=Pucarelli|first3=I.|last4=Segni|first4=M.|last5=Municchi|first5=G.|date=1997-06|title=Spontaneous pubertal development in Turner's syndrome. Italian Study Group for Turner's Syndrome|url=https://pubmed.ncbi.nlm.nih.gov/9177387|journal=The Journal of Clinical Endocrinology and Metabolism|volume=82|issue=6|pages=1810–1813|doi=10.1210/jcem.82.6.3970|issn=0021-972X|pmid=9177387}}</ref><ref>{{Cite journal|last=Hovatta|first=O.|date=1999-04|title=Pregnancies in women with Turner's syndrome|url=https://pubmed.ncbi.nlm.nih.gov/10344582|journal=Annals of Medicine|volume=31|issue=2|pages=106–110|issn=0785-3890|pmid=10344582}}</ref><ref>{{Cite journal|last=Hadnott|first=Tracy N.|last2=Gould|first2=Harley N.|last3=Gharib|first3=Ahmed M.|last4=Bondy|first4=Carolyn A.|date=2011-06|title=Outcomes of spontaneous and assisted pregnancies in Turner syndrome: the U.S. National Institutes of Health experience|url=https://pubmed.ncbi.nlm.nih.gov/21496813|journal=Fertility and Sterility|volume=95|issue=7|pages=2251–2256|doi=10.1016/j.fertnstert.2011.03.085|issn=1556-5653|pmc=3130000|pmid=21496813}}</ref><ref>{{Cite journal|last=Birkebaek|first=N. H.|last2=Crüger|first2=D.|last3=Hansen|first3=J.|last4=Nielsen|first4=J.|last5=Bruun-Petersen|first5=G.|date=2002-01|title=Fertility and pregnancy outcome in Danish women with Turner syndrome|url=https://pubmed.ncbi.nlm.nih.gov/11903353|journal=Clinical Genetics|volume=61|issue=1|pages=35–39|doi=10.1034/j.1399-0004.2002.610107.x|issn=0009-9163|pmid=11903353}}</ref> 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> Screening for Y chromosomal material, by fluorescence in situ hybridization (FISH) or a molecular method, is recommended in such cases.

 

==Epidemiology/Prevalence==

==Epidemiology/Prevalence==

==Genetic Abnormalities: Germline==

==Genetic Abnormalities: Germline==

{| class="wikitable sortable"

{| class="wikitable sortable"

|-

|-

!Notes

!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> Autosomal recessive,

|''SHOX''||Whole or partial X chromosome loss encompassing 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 name=":3" /> 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" /> Both males and females typically have two copies of the ''SHOX'' gene, as it escapes X chromosome inactivation.<ref name=":2" /><ref name=":4" />

|-

|-

|<span class="blue-text">EXAMPLE:</span> Gene X

|''SRY''

|<span class="blue-text">EXAMPLE:</span> List the specific mutation

|

|

|

|The presence of Y chromosomal material, specifically the ''sex-determining region Y'' (''SRY)'' gene carries a risk of developing gonadoblastoma, with reported incidences ranging from 7% to 33%.<ref>{{Cite journal|last=Gravholt|first=C. H.|last2=Fedder|first2=J.|last3=Naeraa|first3=R. W.|last4=Müller|first4=J.|date=2000-09|title=Occurrence of gonadoblastoma in females with Turner syndrome and Y chromosome material: a population study|url=https://pubmed.ncbi.nlm.nih.gov/10999808|journal=The Journal of Clinical Endocrinology and Metabolism|volume=85|issue=9|pages=3199–3202|doi=10.1210/jcem.85.9.6800|issn=0021-972X|pmid=10999808}}</ref><ref>{{Cite journal|last=Mazzanti|first=Laura|last2=Cicognani|first2=Alessandro|last3=Baldazzi|first3=Lilia|last4=Bergamaschi|first4=Rosalba|last5=Scarano|first5=Emanuela|last6=Strocchi|first6=Simona|last7=Nicoletti|first7=Annalisa|last8=Mencarelli|first8=Francesca|last9=Pittalis|first9=Mariacarla|date=2005-06-01|title=Gonadoblastoma in Turner syndrome and Y-chromosome-derived material|url=https://pubmed.ncbi.nlm.nih.gov/15880570|journal=American Journal of Medical Genetics. Part A|volume=135|issue=2|pages=150–154|doi=10.1002/ajmg.a.30569|issn=1552-4825|pmid=15880570}}</ref><ref>{{Cite journal|last=Kwon|first=Ahreum|last2=Hyun|first2=Sei Eun|last3=Jung|first3=Mo Kyung|last4=Chae|first4=Hyun Wook|last5=Lee|first5=Woo Jung|last6=Kim|first6=Tae Hyuk|last7=Kim|first7=Duk Hee|last8=Kim|first8=Ho-Seong|date=2017-06|title=Risk of Gonadoblastoma Development in Patients with Turner Syndrome with Cryptic Y Chromosome Material|url=https://pubmed.ncbi.nlm.nih.gov/28349385|journal=Hormones & Cancer|volume=8|issue=3|pages=166–173|doi=10.1007/s12672-017-0291-8|issn=1868-8500|pmc=PMC10355848|pmid=28349385}}</ref> The risk is higher with the presence of the ''testis-specific protein Y-linked 1'' (''TSPY1)'' gene, which promotes germ cell proliferation, increasing the risk for tumor development.<ref>{{Cite journal|last=Bianco|first=Bianca|last2=Lipay|first2=Mônica|last3=Guedes|first3=Alexis|last4=Oliveira|first4=Kelly|last5=Verreschi|first5=Ieda T. N.|date=2009-03|title=SRY gene increases the risk of developing gonadoblastoma and/or nontumoral gonadal lesions in Turner syndrome|url=https://pubmed.ncbi.nlm.nih.gov/19188812|journal=International Journal of Gynecological Pathology: Official Journal of the International Society of Gynecological Pathologists|volume=28|issue=2|pages=197–202|doi=10.1097/PGP.0b013e318186a825|issn=1538-7151|pmid=19188812}}</ref> TSPY1 expression can synergize with other tumor-promoting factors, such as octamer-binding transcription factor 4 (OCT4), KIT proto-oncogene, receptor tyrosine kinase (c-KIT), and KIT ligand (KITLG), maintaining germ cells in a proliferative, undifferentiated state.<ref>{{Cite journal|last=Li|first=Yunmin|last2=Tabatabai|first2=Z. Laura|last3=Lee|first3=Tin-Lap|last4=Hatakeyama|first4=Shingo|last5=Ohyama|first5=Chikara|last6=Chan|first6=Wai-Yee|last7=Looijenga|first7=Leendert H. J.|last8=Lau|first8=Yun-Fai Chris|date=2007-10|title=The Y-encoded TSPY protein: a significant marker potentially plays a role in the pathogenesis of testicular germ cell tumors|url=https://pubmed.ncbi.nlm.nih.gov/17521702|journal=Human Pathology|volume=38|issue=10|pages=1470–1481|doi=10.1016/j.humpath.2007.03.011|issn=0046-8177|pmc=2744854|pmid=17521702}}</ref>

|-

|

|

|

|

|

|}

|}

==Genetic Abnormalities: Somatic==

==Genetic Abnormalities: Somatic==

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>

N/A

{| class="wikitable sortable"

{| class="wikitable sortable"

|-

|-

!Notes

!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.||

|N/A||N/A||N/A||N/A

|N/A

|<span class="blue-text">EXAMPLE:</span> ''BRCA1''

|<span class="blue-text">EXAMPLE:</span> Reversion mutation

|}

|}

==Genes and Main Pathways Involved==

==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>

N/A

{| class="wikitable sortable"

{| class="wikitable sortable"

|-

|-

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

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

|-

|-

|<span class="blue-text">EXAMPLE:</span> ''BRAF'' and ''MAP2K1''; Activating mutations

|N/A

|<span class="blue-text">EXAMPLE:</span> MAPK signaling

|N/A

|<span class="blue-text">EXAMPLE:</span> Increased cell growth and proliferation

|N/A

|}

|}

==Genetic Diagnostic Testing Methods==

==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>

 

 

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), ''TSPY1'' (testis-specific protein Y-encoded), or other Y-specific markers.<ref name=":5" /> This technique can identify even low levels of mosaicism, which might not be detectable by conventional karyotyping or FISH. FISH can also be used to screen for SRY. 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.

[[File:SRY in 45,X-46,XY.tif|center|thumb|Metaphase fluorescence in situ hybridization (FISH) analysis for SRY (red) and the X chromosome centromere (green) in an individual with Turner syndrome and a 45,X/46,XY karyotype.]]

[[File:Interphase SRY.tif|center|thumb|Interphase fluorescence in situ hybridization (FISH) analysis for SRY (red) and the X chromosome centromere (green) in an individual with Turner syndrome and a 45,X/46,XY karyotype.]]

<br />

==Additional Information==

==Additional Information==

Put your text here

Put your text here

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>

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==

==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>

<references />

==Notes==

==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.  

<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):  

Prior Author(s):  

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

[[Category:GTS5]]

[[Category:DISEASE]]

==Primary Author(s)*==

==Primary Author(s)*==

Kathleen Bone, PhD, Medical College of Wisconsin

Kathleen Bone, PhD, Medical College of Wisconsin

{| class="wikitable sortable"

{| class="wikitable sortable"

|-

|-

|Haploinsufficiency

|Haploinsufficiency

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

|''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>

|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 name=":3">{{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 name=":4">{{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>

|}

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==Genetic Abnormalities: Somatic==

==Genetic Abnormalities: Somatic==

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.

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.

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 name=":5">{{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==

==Additional Information==