GTS5:Klinefelter syndrome: Difference between revisions
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<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-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> | ||
==Primary Author(s)*== | ==Primary Author(s)*== | ||
Kathleen M. Bone, PhD, Medical College of Wisconsin | |||
==WHO Classification of Disease== | ==WHO Classification of Disease== | ||
<span style="color:#0070C0">(''Instructions: This table’s content from the WHO book will be <u>autocompleted</u>.'')</span> | <span style="color:#0070C0">(''Instructions: This table’s content from the WHO book will be <u>autocompleted</u>.'')</span> | ||
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|+ | |+ | ||
|Acceptable | |Acceptable | ||
| | |47,XXY Syndrome | ||
|- | |- | ||
|Not Recommended | |Not Recommended | ||
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==Definition/Description of Disease== | ==Definition/Description of Disease== | ||
Klinefelter syndrome (KS) is a genetic condition affecting males and results from the presence of an extra X chromosome (47,XXY). KS can lead to a range of physical, developmental and reproductive issues, including tall stature, reduced muscle mass, gynecomastia, small testes, infertility, azoospermia and learning difficulties.<ref>{{Cite journal|last=Bearelly|first=Priyanka|last2=Oates|first2=Robert|date=2019|title=Recent advances in managing and understanding Klinefelter syndrome|url=https://pubmed.ncbi.nlm.nih.gov/30755791|journal=F1000Research|volume=8|pages=F1000 Faculty Rev–112|doi=10.12688/f1000research.16747.1|issn=2046-1402|pmc=6352920|pmid=30755791}}</ref> There is a high incidence of symptom variability, and many individuals remain undiagnosed. KS should be suspected in adolescence in males with incomplete or delayed puberty, eunuchoid body habitus (disproportionately long arms and legs), gynecomastia, small and firm testes, low muscle mass, and psychosocial difficulties, and in adults with primary hypogonadism (small testes low testosterone, high FSH/LH), azoospermia, reduced libido or erectile dysfunction, osteoporosis, and mild cognitive or language difficulties.<ref>{{Cite journal|last=Bojesen|first=Anders|last2=Gravholt|first2=Claus H.|date=2007-04|title=Klinefelter syndrome in clinical practice|url=https://pubmed.ncbi.nlm.nih.gov/17415352|journal=Nature Clinical Practice. Urology|volume=4|issue=4|pages=192–204|doi=10.1038/ncpuro0775|issn=1743-4289|pmid=17415352}}</ref><ref name=":0">{{Cite journal|last=Groth|first=Kristian A.|last2=Skakkebæk|first2=Anne|last3=Høst|first3=Christian|last4=Gravholt|first4=Claus Højbjerg|last5=Bojesen|first5=Anders|date=2013-01|title=Clinical review: Klinefelter syndrome--a clinical update|url=https://pubmed.ncbi.nlm.nih.gov/23118429|journal=The Journal of Clinical Endocrinology and Metabolism|volume=98|issue=1|pages=20–30|doi=10.1210/jc.2012-2382|issn=1945-7197|pmid=23118429}}</ref> | |||
==Epidemiology/Prevalence== | ==Epidemiology/Prevalence== | ||
The incidence of KS is approximately 1 in 500 to 1000 male births.<ref name=":0" /><ref>{{Cite journal|last=Berglund|first=Agnethe|last2=Stochholm|first2=Kirstine|last3=Gravholt|first3=Claus Højbjerg|date=2020-06|title=The epidemiology of sex chromosome abnormalities|url=https://pubmed.ncbi.nlm.nih.gov/32506765|journal=American Journal of Medical Genetics. Part C, Seminars in Medical Genetics|volume=184|issue=2|pages=202–215|doi=10.1002/ajmg.c.31805|issn=1552-4876|pmid=32506765}}</ref> However, some studies suggest the prevalence could be as high as 1:600 due to under diagnosis, as many individuals have mild or unnoticed symptoms.<ref>{{Cite journal|last=Bojesen|first=Anders|last2=Juul|first2=Svend|last3=Gravholt|first3=Claus Højbjerg|date=2003-02|title=Prenatal and postnatal prevalence of Klinefelter syndrome: a national registry study|url=https://pubmed.ncbi.nlm.nih.gov/12574191|journal=The Journal of Clinical Endocrinology and Metabolism|volume=88|issue=2|pages=622–626|doi=10.1210/jc.2002-021491|issn=0021-972X|pmid=12574191}}</ref> Only about 10% of cases are diagnosed before puberty, and many individuals remain undiagnosed. The median age of diagnosis is in the mid-30s.<ref name=":0" /> There is a significant association with advanced maternal age: around 50-60% of cases result from maternal non-disjunction during meiosis I, while the remaining cases arise from paternal non-disjunction during meiosis II or postzygotic mitotic errors, which are not associated with parental age.<ref>{{Cite journal|last=Thomas|first=N. S.|last2=Hassold|first2=T. J.|date=2003|title=Aberrant recombination and the origin of Klinefelter syndrome|url=https://pubmed.ncbi.nlm.nih.gov/12926525|journal=Human Reproduction Update|volume=9|issue=4|pages=309–317|doi=10.1093/humupd/dmg028|issn=1355-4786|pmid=12926525}}</ref> | |||
KS also carriers an increased risk for breast cancer and extragonadal germ cell tumors. Males with KS have a 20-30-fold increased risk of developing breast cancer over the average male population risk of approximately 1 in 726.<ref>{{Cite journal|last=Swerdlow|first=Anthony J.|last2=Schoemaker|first2=Minouk J.|last3=Higgins|first3=Craig D.|last4=Wright|first4=Alan F.|last5=Jacobs|first5=Patricia A.|last6=UK Clinical Cytogenetics Group|date=2005-08-17|title=Cancer incidence and mortality in men with Klinefelter syndrome: a cohort study|url=https://pubmed.ncbi.nlm.nih.gov/16106025|journal=Journal of the National Cancer Institute|volume=97|issue=16|pages=1204–1210|doi=10.1093/jnci/dji240|issn=1460-2105|pmid=16106025}}</ref> There is also an increased incidence of mediastinal germ cell tumors (M-GCTs) in KS patients, which can lead to precocious puberty due to human chorionic gonadotropin (hCG)-producing M-GCTs.<ref>{{Cite journal|last=Hasle|first=H.|last2=Jacobsen|first2=B. B.|last3=Asschenfeldt|first3=P.|last4=Andersen|first4=K.|date=1992-10|title=Mediastinal germ cell tumour associated with Klinefelter syndrome. A report of case and review of the literature|url=https://pubmed.ncbi.nlm.nih.gov/1425792|journal=European Journal of Pediatrics|volume=151|issue=10|pages=735–739|doi=10.1007/BF01959079|issn=0340-6199|pmid=1425792}}</ref><ref>{{Cite journal|last=Völkl|first=Thomas M. K.|last2=Langer|first2=Thorsten|last3=Aigner|first3=Thomas|last4=Greess|first4=Holger|last5=Beck|first5=Jörn D.|last6=Rauch|first6=Anita M.|last7=Dörr|first7=Helmuth G.|date=2006-03-01|title=Klinefelter syndrome and mediastinal germ cell tumors|url=https://pubmed.ncbi.nlm.nih.gov/16470792|journal=American Journal of Medical Genetics. Part A|volume=140|issue=5|pages=471–481|doi=10.1002/ajmg.a.31103|issn=1552-4825|pmid=16470792}}</ref> The pathophysiology is unclear, but is thought to be related to genes the extra X chromosome.<ref>{{Cite journal|last=Rapley|first=E. A.|last2=Crockford|first2=G. P.|last3=Teare|first3=D.|last4=Biggs|first4=P.|last5=Seal|first5=S.|last6=Barfoot|first6=R.|last7=Edwards|first7=S.|last8=Hamoudi|first8=R.|last9=Heimdal|first9=K.|date=2000-02|title=Localization to Xq27 of a susceptibility gene for testicular germ-cell tumours|url=https://pubmed.ncbi.nlm.nih.gov/10655070|journal=Nature Genetics|volume=24|issue=2|pages=197–200|doi=10.1038/72877|issn=1061-4036|pmid=10655070}}</ref> | |||
==Genetic Abnormalities: Germline== | ==Genetic Abnormalities: Germline== | ||
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> | 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> | ||
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Prior Author(s): | Prior Author(s): | ||
[[Category:GTS5]][[Category:DISEASE]] | [[Category:GTS5]] | ||
[[Category:DISEASE]] | |||
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