Klinefelter syndrome#Cause

{{multiple image

| align = right

| image1 = Bodymorphproj mkg modA001 20070325 pos03.jpg

| width1 = 150

| alt1 =

| caption1 =

| image2 = Bodymorphproj mkg modA001 20070325 pos04.jpg

| width2 = 132

| alt2 =

| caption2 =

| footer = A person with typical untreated Klinefelter 46,XY/47,XXY mosaic, diagnosed at age 19 – a scar from biopsy is on his right breast above the nipple.

}}

Klinefelter syndrome has different manifestations and these will vary from one patient to another. Among the primary features are infertility and small, poorly functioning testicles. Often, symptoms may be subtle and many people do not realize they are affected. In other cases, symptoms are more prominent and may include weaker muscles, greater height, poor motor coordination, less body hair, gynecomastia (breast growth), and low libido. In the majority of the cases, these symptoms are noticed only at puberty.{{cite web |date=2013-11-15 |title=Klinefelter Syndrome (KS): Overview |url=http://www.nichd.nih.gov/health/topics/klinefelter/Pages/default.aspx |url-status=live |archive-url=https://web.archive.org/web/20150318011309/http://www.nichd.nih.gov/health/topics/klinefelter/Pages/default.aspx |archive-date=18 March 2015 |access-date=15 March 2015 |website=nichd.nih.gov |publisher=Eunice Kennedy Shriver National Institute of Child Health and Human Development}}

Chromosomal abnormalities, including Klinefelter syndrome, are the most common cause of spontaneous abortion.{{Cite web |last=Puscheck |first=Elizabeth |date=June 16, 2023 |title=Early Pregnancy Loss |url=https://reference.medscape.com/article/266317-overview?form=fpf |access-date=June 28, 2024 |website=Medscape}} Generally, the severity of the malformations is proportional to the number of extra X chromosomes present in the karyotype. For example, patients with 49 chromosomes (XXXXY) have a lower IQ and more severe physical manifestations than those with 48 chromosomes (XXXY).{{Cite journal | vauthors = Defendi GL |date=January 31, 2022 | veditors = Rohena LO |title=Klinefelter Syndrome |url=https://emedicine.medscape.com/article/945649-overview#a6?form=fpf |website=Medscape |at=Drugs & Diseases: Pediatrics: Genetics and Metabolic Disease}}

As babies and children, those with XXY chromosomes may have lower muscle tone and reduced strength. They may sit up, crawl, and walk later than other infants. An average KS child will start walking at 19 months of age. They may also have less muscle control and coordination than other children of their age.{{cite web |date=24 May 2007 |title=Klinefelter Syndrome |url=http://www.nichd.nih.gov/health/topics/klinefelter_syndrome.cfm |url-status=dead |archive-url=https://web.archive.org/web/20121127030744/http://www.nichd.nih.gov/health/topics/klinefelter_syndrome.cfm |archive-date=27 November 2012 |access-date=November 28, 2023 |website=Eunice Kennedy Shriver National Institute of Child Health and Human Development}}

During puberty, KS subjects show less muscular body, less facial and body hair, and broader hips as a consequence of low levels of testosterone. Delays in motor development may occur, which can be addressed through occupational and physical therapies. As teens, males with XXY may develop breast tissue, have weaker bones, and a lower energy level than others. Testicles are affected and are usually less than 2 cm in length (and always shorter than 3.5 cm), 1 cm in width, and 4ml in volume.{{Cite journal | vauthors = Zierler-Browm SL |date=August 25, 2006 |title=Klinefelter's Syndrome: XXY Males |url=https://www.uspharmacist.com/article/klinefelters-syndrome-xxy-males |journal=U.S. Pharmacist |publication-place=West Palm Beach, Florida |volume=8 |pages=43–51}}

By adulthood, individuals with KS tend to become taller than average, with proportionally longer arms and legs, less-muscular bodies, more belly fat, wider hips, and narrower shoulders. Some will show little to no symptomology, a lanky, youthful build and facial appearance, or a rounded body type. Gynecomastia (increased breast tissue) in males is common, affecting up to 80% of cases.{{Cite journal |last=Raheem |first=Amr Abdel |date=February 12, 2021 |title=The Impact and Management of Gynaecomastia in Klinefelter Syndrome |journal=Frontiers in Reproductive Health |volume=3 |doi=10.3389/frph.2021.629673 |doi-access=free |pmid=36303983 |pmc=9580767 }} Approximately 10% of males with XXY chromosomes have gynecomastia noticeable enough that they may choose to have surgery.{{citation needed|date=June 2024}}

Individuals with KS are often infertile or have reduced fertility. Advanced reproductive assistance is sometimes possible in order to produce an offspring since approximately 50% of males with Klinefelter syndrome can produce sperm.{{cite journal |last=Klinefelter |first=Harry Fitch Jr. |date=September 1986 |title=Klinefelter's syndrome: historical background and development |journal=Southern Medical Journal |volume=79 |issue=9 |pages=1089–1093 |doi=10.1097/00007611-198609000-00012 |pmid=3529433}}{{cite journal | vauthors = Denschlag D, Tempfer C, Kunze M, Wolff G, Keck C | title = Assisted reproductive techniques in patients with Klinefelter syndrome: a critical review | journal = Fertility and Sterility | volume = 82 | issue = 4 | pages = 875–879 | date = October 2004 | pmid = 15482743 | doi = 10.1016/j.fertnstert.2003.09.085 | doi-access = free}}

Some degree of language learning or reading impairment may be present, and neuropsychological testing often reveals deficits in executive functions, although these deficits can often be overcome through early intervention. It is estimated that 10% of those with Klinefelter syndrome are autistic. Additional abnormalities may include impaired attention, reduced organizational and planning abilities, deficiencies in judgment (often presented as a tendency to interpret non-threatening stimuli as threatening), and dysfunctional decision processing.{{cite journal | vauthors = Graham JM, Bashir AS, Stark RE, Silbert A, Walzer S | title = Oral and written language abilities of XXY boys: implications for anticipatory guidance | journal = Pediatrics | volume = 81 | issue = 6 | pages = 795–806 | date = June 1988 | pmid = 3368277 | doi = 10.1542/peds.81.6.795 | s2cid = 26098458 }}{{cite journal | vauthors = Boone KB, Swerdloff RS, Miller BL, Geschwind DH, Razani J, Lee A, Gonzalo IG, Haddal A, Rankin K, Lu P, Paul L | display-authors = 6 | title = Neuropsychological profiles of adults with Klinefelter syndrome | journal = Journal of the International Neuropsychological Society | volume = 7 | issue = 4 | pages = 446–456 | date = May 2001 | pmid = 11396547 | doi = 10.1017/S1355617701744013 | s2cid = 145642384 | url = https://resolver.caltech.edu/CaltechAUTHORS:20210301-123913869 }}

The overall IQ tends to be lower than average{{specify|date=April 2025}}. Language milestones may also be delayed, particularly when compared to other people their age. Between 25% and 85% of males with XXY have some kind of language problem, such as delay in learning to speak, trouble using language to express thoughts and needs, problems reading, and trouble processing what they hear. They may also have a harder time doing work that involves reading and writing, but most hold jobs and have successful careers.{{Cite web |last=GenePool |date=October 17, 2005 |title=Klinefelter syndrome |url=http://www.library.nhs.uk/genepool/ViewResource.aspx?resID=104897 |url-status= |archive-url=https://web.archive.org/web/20070927011423/http://www.library.nhs.uk/genepool/ViewResource.aspx?resID=104897 |archive-date=September 27, 2007 |access-date=November 29, 2023 |website=Clinical Genetics Specialist Library}}

Compared to individuals with a normal number of chromosomes, males affected by Klinefelter syndrome may display behavioral differences. These are phenotypically displayed as higher levels of anxiety and depression, mood dysregulation, impaired social skills, emotional immaturity during childhood, and low frustration tolerance.{{cite journal | vauthors = Skakkebæk A, Moore PJ, Pedersen AD, Bojesen A, Kristensen MK, Fedder J, Hertz JM, Østergaard JR, Wallentin M, Gravholt CH | display-authors = 6 | title = Anxiety and depression in Klinefelter syndrome: The impact of personality and social engagement | journal = PLOS ONE | volume = 13 | issue = 11 | pages = e0206932 | date = November 9, 2018 | pmid = 30412595 | pmc = 6226182 | doi = 10.1371/journal.pone.0206932 | doi-access = free | bibcode = 2018PLoSO..1306932S }}{{cite journal | vauthors = Skakkebæk A, Moore PJ, Pedersen AD, Bojesen A, Kristensen MK, Fedder J, Laurberg P, Hertz JM, Østergaard JR, Wallentin M, Gravholt CH | display-authors = 6 | title = The role of genes, intelligence, personality, and social engagement in cognitive performance in Klinefelter syndrome | journal = Brain and Behavior | volume = 7 | issue = 3 | pages = e00645 | date = March 2017 | pmid = 28293480 | pmc = 5346527 | doi = 10.1002/brb3.645 }}{{cite journal | vauthors = de Vries AL, Roehle R, Marshall L, Frisén L, van de Grift TC, Kreukels BP, Bouvattier C, Köhler B, Thyen U, Nordenström A, Rapp M, Cohen-Kettenis PT | display-authors = 6 | title = Mental Health of a Large Group of Adults With Disorders of Sex Development in Six European Countries | journal = Psychosomatic Medicine | volume = 81 | issue = 7 | pages = 629–640 | date = September 2019 | pmid = 31232913 | pmc = 6727927 | doi = 10.1097/PSY.0000000000000718 }} These neurocognitive disabilities are most likely due to the presence of the extra X chromosome, as indicated by studies carried out on animal models carrying an extra X chromosome.{{cite book | vauthors = Conn PM |url=https://books.google.com/books?id=dVLVLIV8rD0C&pg=PA780 |title=Animal models for the study of human disease |date=2013 |publisher=Elsevier Science & Technology Books |isbn=9780124159129 |edition=First |location=San Diego |page=780 |doi=10.1016/C2011-0-05225-0 |access-date=February 9, 2017 |archive-url=https://web.archive.org/web/20170910234047/https://books.google.com/books?id=dVLVLIV8rD0C&pg=PA780 |archive-date=September 10, 2017 |url-status=live}}

In 1995, a scientific study evaluated the psychosocial adaptation of 39 adolescents with sex chromosome abnormalities. It demonstrated that males with XXY tend to be quiet, shy and undemanding; they are less self-confident, less active, and more helpful and obedient than other children their age. They may struggle in school and sports, meaning they may have more trouble "fitting in" with other kids.{{cite journal | vauthors = Bender BG, Harmon RJ, Linden MG, Robinson A | title = Psychosocial adaptation of 39 adolescents with sex chromosome abnormalities | journal = Pediatrics | volume = 96 | issue = 2 Pt 1 | pages = 302–308 | date = August 1995 | pmid = 7630689 | doi = 10.1542/peds.96.2.302 | s2cid = 36072015 }}

As adults, they live lives similar to others without the condition; they have friends, families, and normal social relationships. Nonetheless, some individuals may experience social and emotional problems due to problems in childhood. They show a lower sex drive and low self-esteem, in most cases due to their feminine physical characteristics.

Those with XXY are more likely than others to have certain health problems, such as autoimmune disorders, breast cancer, venous thromboembolic disease, and osteoporosis. Nonetheless, the risk of breast cancer is still below the normal risk for women. These patients are also more prone to develop cardiovascular disease due to the predominance of metabolic abnormalities such as dyslipidemia and type 2 diabetes. It has not been demonstrated that hypertension is related with KS.{{cite journal | vauthors = Hultborn R, Hanson C, Köpf I, Verbiené I, Warnhammar E, Weimarck A | title = Prevalence of Klinefelter's syndrome in male breast cancer patients | journal = Anticancer Research | volume = 17 | issue = 6D | pages = 4293–4297 | date = 1997 | pmid = 9494523 | url = https://pubmed.ncbi.nlm.nih.gov/9494523/ }}{{cite journal | vauthors = Salzano A, Arcopinto M, Marra AM, Bobbio E, Esposito D, Accardo G, Giallauria F, Bossone E, Vigorito C, Lenzi A, Pasquali D, Isidori AM, Cittadini A | display-authors = 6 | title = Klinefelter syndrome, cardiovascular system, and thromboembolic disease: review of literature and clinical perspectives | journal = European Journal of Endocrinology | volume = 175 | issue = 1 | pages = R27–R40 | date = July 2016 | pmid = 26850445 | doi = 10.1530/EJE-15-1025 }}{{cite journal | vauthors = Nieschlag E | title = Klinefelter syndrome: the commonest form of hypogonadism, but often overlooked or untreated | journal = Deutsches Ärzteblatt International | volume = 110 | issue = 20 | pages = 347–353 | date = May 2013 | pmid = 23825486 | pmc = 3674537 | doi = 10.3238/arztebl.2013.0347 }}

In contrast to these potentially increased risks, rare X-linked recessive conditions are thought to occur less frequently in those with XXY than in those without, since these conditions are transmitted by genes on the X chromosome, and people with two X chromosomes are typically only carriers rather than affected by these X-linked recessive conditions.{{cite journal | vauthors = Gravholt CH, Chang S, Wallentin M, Fedder J, Moore P, Skakkebæk A | title = Klinefelter Syndrome: Integrating Genetics, Neuropsychology, and Endocrinology | journal = Endocrine Reviews | volume = 39 | issue = 4 | pages = 389–423 | date = August 2018 | pmid = 29438472 | doi = 10.1210/er.2017-00212 | doi-access = free }}

File:XXY syndrome M.svg event of one X chromosome from a Y chromosome during meiosis I in the male]]

File:XXY syndrome.svg in the female]]

Klinefelter syndrome is not an inherited condition. The extra X chromosome comes from the mother in approximately 50% of the cases. Maternal age is the only known risk factor. Women at 40 years have a four-times-higher risk of a child with Klinefelter syndrome than women aged 24 years.{{cite web |date=July 10, 2023 |title=Klinefelter Syndrome – Inheritance Pattern |url=https://ghr.nlm.nih.gov/condition/klinefelter-syndrome#inheritance |url-status=live |archive-url=https://web.archive.org/web/20170130031336/https://ghr.nlm.nih.gov/condition/klinefelter-syndrome#inheritance |archive-date=30 January 2017 |access-date=January 2, 2024 |website=Medline Plus |publisher=NIH}}{{cite journal | vauthors = Bojesen A, Juul S, Gravholt CH | title = Prenatal and postnatal prevalence of Klinefelter syndrome: a national registry study | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 88 | issue = 2 | pages = 622–626 | date = February 2003 | pmid = 12574191 | doi = 10.1210/jc.2002-021491 | doi-access = free }}

The extra chromosome is retained because of a nondisjunction event during paternal meiosis I, maternal meiosis I, or maternal meiosis II, also known as gametogenesis. The relevant nondisjunction in meiosis I occurs when homologous chromosomes, in this case the X and Y or two X sex chromosomes, fail to separate, producing a sperm with an X and a Y chromosome or an egg with two X chromosomes. Fertilizing a normal (X) egg with this sperm produces an XXY or Klinefelter offspring. Fertilizing a double X egg with a normal sperm also produces an XXY or Klinefelter offspring.{{cite journal | vauthors = Tüttelmann F, Gromoll J | title = Novel genetic aspects of Klinefelter's syndrome | journal = Molecular Human Reproduction | volume = 16 | issue = 6 | pages = 386–395 | date = June 2010 | pmid = 20228051 | doi = 10.1093/molehr/gaq019 | doi-access = free }}

Another mechanism for retaining the extra chromosome is through a nondisjunction event during meiosis II in the egg. Nondisjunction occurs when sister chromatids on the sex chromosome, in this case an X and an X, fail to separate. An XX egg is produced, which when fertilized with a Y sperm, yields an XXY offspring. This XXY chromosome arrangement is one of the most common genetic variations from the XY karyotype, occurring in approximately one in 500 live male births.

In mammals with more than one X chromosome, the genes on all but one X chromosome are not expressed; this is known as X inactivation. This happens in XXY males, as well as normal XX females. However, in XXY males, a few genes located in the pseudoautosomal regions of their X chromosomes have corresponding genes on their Y chromosome and are capable of being expressed.{{cite journal | vauthors = Chow JC, Yen Z, Ziesche SM, Brown CJ | title = Silencing of the mammalian X chromosome | journal = Annual Review of Genomics and Human Genetics | volume = 6 | issue = 1 | pages = 69–92 | date = 2005-09-01 | pmid = 16124854 | doi = 10.1146/annurev.genom.6.080604.162350 }}{{cite journal | vauthors = Blaschke RJ, Rappold G | title = The pseudoautosomal regions, SHOX and disease | journal = Current Opinion in Genetics & Development | volume = 16 | issue = 3 | pages = 233–239 | date = June 2006 | pmid = 16650979 | doi = 10.1016/j.gde.2006.04.004 | series = Genetics of disease }}

The condition 48,XXYY or 48,XXXY occurs in one in 18,000–50,000 male births. The incidence of 49,XXXXY is one in 85,000 to 100,000 male births.{{cite journal | vauthors = Linden MG, Bender BG, Robinson A | title = Sex chromosome tetrasomy and pentasomy | journal = Pediatrics | volume = 96 | issue = 4 Pt 1 | pages = 672–682 | date = October 1995 | pmid = 7567329 | doi = 10.1542/peds.96.4.672 }} These variations are extremely rare. Additional chromosomal material can contribute to cardiac, neurological, orthopedic, urinogenital and other anomalies.{{citation needed|date=September 2021}} Thirteen cases of individuals with a 47,XXY karyotype and a female phenotype have been described.{{cite journal |last1=Frühmesser |first1=A. |last2=Kotzot|first2=D.|title=Chromosomal Variants in Klinefelter Syndrome |journal=Sexual Development |date=29 April 2011 |volume=5 |issue=3 |pages=109–123 |doi=10.1159/000327324 |pmid=21540567 |url=https://karger.com/sxd/article/5/3/109/296351/Chromosomal-Variants-in-Klinefelter-Syndrome |access-date=24 April 2024}}

Approximately 15–20%{{cite journal |last1=Samplaski |first1=Mary K. |display-authors=etal |title=Phenotypic differences in mosaic Klinefelter patients as compared with non-mosaic Klinefelter patients |journal=Fertility and Sterility |date=April 2014 |volume=101 |issue=4 |pages=950–955 |doi=10.1016/j.fertnstert.2013.12.051 |pmid=24502895 |url=https://www.fertstert.org/article/S0015-0282(13)03487-0/pdf |accessdate=13 June 2020 |archive-date=11 October 2020 |archive-url=https://web.archive.org/web/20201011040314/https://www.fertstert.org/article/S0015-0282%2813%2903487-0/pdf |url-status=live|doi-access=free }} of males with KS may have a mosaic 47,XXY/46,XY constitutional karyotype and varying degrees of spermatogenic failure. Often symptoms are milder in mosaic cases, with regular male secondary sex characteristics and testicular volume even falling within typical adult ranges. Another possible mosaicism is 47,XXY/46,XX with clinical features suggestive of KS and male phenotype, but this is very rare. Thus far, only about 10 cases of 47,XXY/46,XX have been described in literature.{{cite journal | vauthors = Velissariou V, Christopoulou S, Karadimas C, Pihos I, Kanaka-Gantenbein C, Kapranos N, Kallipolitis G, Hatzaki A | display-authors = 6 | title = Rare XXY/XX mosaicism in a phenotypic male with Klinefelter syndrome: case report | journal = European Journal of Medical Genetics | volume = 49 | issue = 4 | pages = 331–7 | year = 2006 | pmid = 16829354 | doi = 10.1016/j.ejmg.2005.09.001}}

Analogous XXY syndromes are known to occur in cats—specifically, the presence of calico or tortoiseshell markings in male cats is an indicator of the relevant abnormal karyotype. As such, male cats with calico or tortoiseshell markings are a model organism for KS, because a color gene involved in cat tabby coloration is on the X chromosome.{{cite journal | vauthors = Centerwall WR, Benirschke K | title = An animal model for the XXY Klinefelter's syndrome in man: tortoiseshell and calico male cats | journal = American Journal of Veterinary Research | volume = 36 | issue = 9 | pages = 1275–80 | date = September 1975 | pmid = 1163864}}

Approximately 15–20% of males with KS may have a mosaic 47,XXY/46,XY constitutional karyotype and varying degrees of spermatogenic failure. Often, symptoms are milder in mosaic cases, with regular male secondary sex characteristics and testicular volume even falling within typical adult ranges. Another possible mosaicism is 47,XXY/46,XX with clinical features suggestive of KS and male phenotype, but this is very rare. Thus far, only approximately 10 cases of 47,XXY/46,XX have been described in literature.

{{main|X-inactivation}}

Women typically have two X chromosomes, with half of their X chromosomes switching off early in embryonic development. The same happens with people with Klinefelter's, including in both cases a small proportion of individuals with a skewed ratio between the two Xs.{{cite journal | vauthors = Kinjo K, Yoshida T, Kobori Y, Okada H, Suzuki E, Ogata T, Miyado M, Fukami M | title = Random X chromosome inactivation in patients with Klinefelter syndrome | journal = Molecular and Cellular Pediatrics | volume = 7 | issue = 1 | pages = 1 | date = January 2020 | pmid = 31974854 | pmc = 6979883 | doi = 10.1186/s40348-020-0093-x | doi-access = free }}

The term "hypogonadism" in XXY symptoms is often misinterpreted to mean "small testicles", when it instead means decreased testicular hormone/endocrine function. Because of (primary) hypogonadism, individuals often have a low serum testosterone level, but high serum follicle-stimulating hormone and luteinizing hormone levels, hypergonadotropic hypogonadism.{{cite web | vauthors = Leask K |date=October 2005 |title=Klinefelter syndrome |url=http://www.library.nhs.uk/genepool/ViewResource.aspx?resID=104897 |url-status=dead |archive-url= https://web.archive.org/web/20070927011423/http://www.library.nhs.uk/genepool/ViewResource.aspx?resID=104897 |archive-date=2007-09-27 |access-date=2007-04-07 |website=National Library for Health, Specialist Libraries, Clinical Genetics |publisher=National Library for Health}} Despite this misunderstanding of the term, testicular growth also is arrested.

Destruction and hyalinization of the seminiferous tubules cause a reduction in the function of Sertoli cells and Leydig cells, leading to decreased production of FSH and testosterone. This results in impaired spermatogenesis and further endocrine dysfunction.{{cite journal |vauthors=Samplaski MK, Lo KC, Grober ED, Millar A, Dimitromanolakis A, Jarvi KA |year=2014 |title=Phenotypic differences in mosaic Klinefelter patients as compared with non-mosaic Klinefelter patients |journal=Fertility and Sterility |volume=101 |issue=4 |pages=950–955 |doi=10.1016/j.fertnstert.2013.12.051 |pmid=24502895|doi-access=free }}

The standard diagnostic method is the analysis of the chromosomes' karyotype on lymphocytes. A small blood sample is sufficient as test material. In the past, the observation of the Barr body was common practice, as well.{{cite journal | vauthors = Kamischke A, Baumgardt A, Horst J, Nieschlag E | title = Clinical and diagnostic features of patients with suspected Klinefelter syndrome | journal = Journal of Andrology | volume = 24 | issue = 1 | pages = 41–48 | date = Jan–Feb 2003 | pmid = 12514081 | doi = 10.1002/j.1939-4640.2003.tb02638.x | s2cid = 25133531 | doi-access = free }} To investigate the presence of a possible mosaicism, analysis of the karyotype using cells from the oral mucosa is performed. Physical characteristics of a Klinefelter syndrome can be tall stature, low body hair, and occasionally an enlargement of the breast. Usually, a small testicle volume of 1–5 ml per testicle (standard values: 12–30 ml) occurs. During puberty and adulthood, low testosterone levels with increased levels of the pituitary hormones FSH and LH in the blood can indicate the presence of Klinefelter syndrome. A spermiogram can also be part of the further investigation. Often, an azoospermia is present, or rarely an oligospermia. Furthermore, Klinefelter syndrome can be diagnosed as a coincidental prenatal finding in the context of invasive prenatal diagnosis (amniocentesis, chorionic villus sampling). Approximately 10% of KS cases are found by prenatal diagnosis.{{cite journal | vauthors = Abramsky L, Chapple J | title = 47,XXY (Klinefelter syndrome) and 47,XYY: estimated rates of and indication for postnatal diagnosis with implications for prenatal counselling | journal = Prenatal Diagnosis | volume = 17 | issue = 4 | pages = 363–368 | date = April 1997 | pmid = 9160389 | doi = 10.1002/(SICI)1097-0223(199704)17:4<363::AID-PD79>3.0.CO;2-O | s2cid = 25935518 }}

The symptoms of KS are often variable, so a karyotype analysis should be ordered when small testes, infertility, gynecomastia, long arms/legs, developmental delay, speech/language deficits, learning disabilities/academic issues, and/or behavioral issues are present in an individual.

The lifespan of individuals with Klinefelter syndrome appears to be reduced by around 2.1 years compared to the general male population.{{cite journal | vauthors = Bojesen A, Juul S, Birkebaek N, Gravholt CH | title = Increased mortality in Klinefelter syndrome | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 89 | issue = 8 | pages = 3830–3834 | date = August 2004 | pmid = 15292313 | doi = 10.1210/jc.2004-0777 | doi-access = free }} These results are still questioned data, are not absolute, and need further testing.{{cite journal | vauthors = Swerdlow AJ, Higgins CD, Schoemaker MJ, Wright AF, Jacobs PA | title = Mortality in patients with Klinefelter syndrome in Britain: a cohort study | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 90 | issue = 12 | pages = 6516–6522 | date = December 2005 | pmid = 16204366 | doi = 10.1210/jc.2005-1077 | doi-access = free }}

As the genetic variation is irreversible, no causal therapy is available. From the onset of puberty, the existing testosterone deficiency can be compensated by appropriate hormone-replacement therapy.{{cite journal | vauthors = Groth KA, Skakkebæk A, Høst C, Gravholt CH, Bojesen A | title = Clinical review: Klinefelter syndrome--a clinical update | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 98 | issue = 1 | pages = 20–30 | date = January 2013 | pmid = 23118429 | doi = 10.1210/jc.2012-2382 | doi-access = free }} Testosterone preparations are available in the form of syringes, patches, or gel. If gynecomastia is present, the surgical removal of the breast may be considered for psychological benefits and to reduce the risk of breast cancer.{{cite journal | vauthors = Gabriele R, Borghese M, Conte M, Egidi F | title = [Clinical-therapeutic features of gynecomastia] | language = it | journal = Il Giornale di Chirurgia | volume = 23 | issue = 6–7 | pages = 250–252 | year = 2002 | pmid = 12422780 }}{{cite web|title=What are the treatments for symptoms in Klinefelter syndrome (KS)?|url=https://www.nichd.nih.gov/health/topics/klinefelter/conditioninfo/treatments|access-date=2020-07-14|website=nichd.nih.gov/|date=December 2016 |language=en|archive-date=2020-07-09|archive-url=https://web.archive.org/web/20200709203539/https://www.nichd.nih.gov/health/topics/klinefelter/conditioninfo/treatments|url-status=live}}

The use of behavioral therapy can mitigate any language disorders, difficulties at school, and socialization. An approach by occupational therapy is useful in children, especially those who have dyspraxia.{{cite web|url=http://emedicine.medscape.com/article/945649-treatment#showall|title=Klinefelter Syndrome – Treatment|author=Harold Chen|publisher=medscape.com|access-date=4 September 2012|url-status=live|archive-url=https://web.archive.org/web/20120702203635/http://emedicine.medscape.com/article/945649-treatment#showall|archive-date=2 July 2012}}

File:Icsi.JPG]]

Methods of reproductive medicine, such as intracytoplasmic sperm injection (ICSI) with previously conducted testicular sperm extraction (TESE), have led to men with Klinefelter syndrome producing biological offspring.{{cite journal | vauthors = Corona G, Pizzocaro A, Lanfranco F, Garolla A, Pelliccione F, Vignozzi L, Ferlin A, Foresta C, Jannini EA, Maggi M, Lenzi A, Pasquali D, Francavilla S | display-authors = 6 | title = Sperm recovery and ICSI outcomes in Klinefelter syndrome: a systematic review and meta-analysis | journal = Human Reproduction Update | volume = 23 | issue = 3 | pages = 265–275 | date = May 2017 | pmid = 28379559 | doi = 10.1093/humupd/dmx008 | doi-access = free | hdl = 2318/1633550 | hdl-access = free }} By 2010, over 100 successful pregnancies have been reported using in vitro fertilization technology with surgically removed sperm material from men with KS.{{cite journal | vauthors = Fullerton G, Hamilton M, Maheshwari A | title = Should non-mosaic Klinefelter syndrome men be labelled as infertile in 2009? | journal = Human Reproduction | volume = 25 | issue = 3 | pages = 588–597 | date = March 2010 | pmid = 20085911 | doi = 10.1093/humrep/dep431 | doi-access = free}}

The syndrome was named after American endocrinologist Harry Klinefelter, who in 1942 worked with Fuller Albright and E. C. Reifenstein at Massachusetts General Hospital in Boston, Massachusetts, and first described it in the same year.{{Cite journal| vauthors = Klinefelter Jr HF, Reifenstein Jr EC, Albright Jr F |year=1942|title=Syndrome characterized by gynecomastia, aspermatogenesis without a-Leydigism and increased excretion of follicle-stimulating hormone|journal=The Journal of Clinical Endocrinology & Metabolism|volume=2|issue=11|pages=615–624|doi=10.1210/jcem-2-11-615}} The account given by Klinefelter came to be known as Klinefelter syndrome as his name appeared first on the published paper, and seminiferous tubule dysgenesis was no longer used. Considering the names of all three researchers, it is sometimes also called Klinefelter–Reifenstein–Albright syndrome.{{cite web | url = http://www.biomedsearch.com/nih/Klinefelter-Reifenstein-Albright-syndrome/21002506.html | title = The Klinefelter-Reifenstein-Albright syndrome | archive-url = https://web.archive.org/web/20170827042954/http://www.biomedsearch.com/nih/Klinefelter-Reifenstein-Albright-syndrome/21002506.html | archive-date=2017-08-27 | work = Biomedsearch.com | access-date = 26 August 2017}} In 1956, Klinefelter syndrome was found to result from an extra chromosome.{{cite book | vauthors = Odom SL |url=https://books.google.com/books?id=U4VpCKVomHkC&pg=PA113 |title=Handbook of developmental disabilities |date=2009 |publisher=Guilford |isbn=9781606232484 |edition=Pbk. |location=New York |page=113 |access-date=2017-09-02 |archive-url=https://web.archive.org/web/20170910234047/https://books.google.com/books?id=U4VpCKVomHkC&pg=PA113 |archive-date=2017-09-10 |url-status=live}} Plunkett and Barr found the sex chromatin body in cell nuclei of the body. This was further clarified as XXY in 1959 by Patricia Jacobs and John Anderson Strong.{{cite journal | vauthors = Jacobs PA, Strong JA | title = A case of human intersexuality having a possible XXY sex-determining mechanism | journal = Nature | volume = 183 | issue = 4657 | pages = 302–303 | date = January 1959 | pmid = 13632697 |doi = 10.1038/183302a0 | s2cid = 38349997 | bibcode = 1959Natur.183..302J}} The first published report of a man with a 47,XXY karyotype was by Patricia Jacobs and John Strong at Western General Hospital in Edinburgh, Scotland, in 1959. This karyotype was found in a 24-year-old man who had signs of KS. Jacobs described her discovery of this first reported human or mammalian chromosome aneuploidy in her 1981 William Allan Memorial Award address.{{cite journal | vauthors = Jacobs PA | title = The William Allan Memorial Award address: human population cytogenetics: the first twenty-five years | journal = American Journal of Human Genetics | volume = 34 | issue = 5 | pages = 689–698 | date = September 1982 | pmid = 6751075 | pmc = 1685430}}

Klinefelter syndrome has been identified in ancient burials. In August 2022, a team of scientists published a study of a skeleton found in Bragança, north-eastern Portugal, of a man who died around 1000 AD and was discovered by their investigations to have a 47,XXY karyotype.{{cite journal | vauthors = Roca-Rada X, Tereso S, Rohrlach AB, Brito A, Williams MP, Umbelino C, Curate F, Deveson IW, Souilmi Y, Amorim A, Carvalho PC, Llamas B, Teixeira JC | display-authors = 6 | title = A 1000-year-old case of Klinefelter's syndrome diagnosed by integrating morphology, osteology, and genetics | journal = Lancet | volume = 400 | issue = 10353 | pages = 691–692 | date = August 2022 | pmid = 36030812 | doi = 10.1016/S0140-6736(22)01476-3 | hdl = 10316/101524 | s2cid = 251817711 | hdl-access = free}} In 2021, bioarchaeological investigation of the individual buried with the Suontaka sword, previously assumed to be a woman, concluded that person "whose gender identity may well have been non-binary", had Klinefelter syndrome.{{Cite journal| vauthors = Moilanen U, Kirkinen T, Saari NJ, Rohrlach AB, Krause J, Onkamo P, Salmela E |date=2021-07-15|title=A Woman with a Sword? – Weapon Grave at Suontaka Vesitorninmäki, Finland|journal=European Journal of Archaeology|volume=25 |publisher=Cambridge University Press|language=en|pages=42–60|doi=10.1017/eaa.2021.30|issn=1461-9571|doi-access=free|hdl=10138/340641|hdl-access=free}}

In many societies, the symptoms of Klinefelter syndrome have contributed to significant social stigma, particularly due to infertility and gynecomastia. Historically, these traits were often associated with a perceived lack of masculinity, which could result in social ostracism.{{citation needed|date= October 2024}} However, in recent years, increased awareness and advocacy have led to a reduction in stigma, with individuals diagnosed with KS more likely to receive proper medical care and support. Advocacy organizations, such as the American Association for Klinefelter Syndrome Information and Support (AAKSIS), have played a crucial role in promoting understanding and improving the quality of life for affected individuals.{{Cite journal |last1=Robinson |first1=Arthur |last2=Bender |first2=Bruce G. |last3=Linden |first3=Mary G. |date=1992 |title=Prognosis of prenatally diagnosed children with sex chromosome aneuploidy |url=http://dx.doi.org/10.1002/ajmg.1320440319 |journal=American Journal of Medical Genetics |volume=44 |issue=3 |pages=365–368 |doi=10.1002/ajmg.1320440319 |pmid=1488987 |issn=0148-7299|url-access=subscription }}

This syndrome, evenly distributed in all ethnic groups, has a prevalence of approximately four subjects per every 10,000 (0.04%) males in the general population.{{cite journal | vauthors = Jacobs PA | title = Recurrence risks for chromosome abnormalities | journal = Birth Defects Original Article Series | volume = 15 | issue = 5C | pages = 71–80 | year = 1979 | pmid = 526617}}{{cite journal | vauthors = Maclean N, Harnden DG, Court Brown WM | title = Abnormalities of sex chromosome constitution in newborn babies | journal = Lancet | volume = 2 | issue = 7199 | pages = 406–408 | date = August 1961 | pmid = 13764957 | doi = 10.1016/S0140-6736(61)92486-2}}{{cite journal | vauthors = Visootsak J, Aylstock M, Graham JM | title = Klinefelter syndrome and its variants: an update and review for the primary pediatrician | journal = Clinical Pediatrics | volume = 40 | issue = 12 | pages = 639–651 | date = December 2001 | pmid = 11771918 | doi = 10.1177/000992280104001201 | s2cid = 43040200}} However, it is estimated that only 25% of the individuals with Klinefelter syndrome are diagnosed throughout their lives. The rate of Klinefelter syndrome among infertile males is 3.1%. The syndrome is the main cause of male hypogonadism.{{cite journal | vauthors = Matlach J, Grehn F, Klink T | title = Klinefelter syndrome associated with goniodysgenesis | journal = Journal of Glaucoma | volume = 22 | issue = 5 | pages = e7–e8 | date = Jan 2012 | pmid = 22274665 | doi = 10.1097/IJG.0b013e31824477ef | s2cid = 30565002}} One survey in the United Kingdom found that the majority of people with KS identify as male, however, a significant number have a different gender identity.{{cite journal | last1=Cai | first1=Valerie | last2=Yap | first2=Tet | title=Gender Identity and Questioning in Klinefelter's Syndrome | journal=BJPsych Open | publisher=Royal College of Psychiatrists | volume=8 | issue=S1 | year=2022 | issn=2056-4724 | doi=10.1192/bjo.2022.176 | pages=S44–S45| pmc=9378311}} The prevalence of KS is higher than expected in transgender women.{{cite journal | last1=Liang | first1=Bonnie | last2=Cheung | first2=Ada S. | author2-link=Ada Cheung | last3=Nolan | first3=Brendan J. | title=Clinical features and prevalence of Klinefelter syndrome in transgender individuals: A systematic review | journal=Clinical Endocrinology | publisher=Wiley | volume=97 | issue=1 | date=2022-04-15 | issn=0300-0664 | doi=10.1111/cen.14734 | pages=3–12| pmid=35394664 | pmc=9540025}}

• Sex chromosome anomalies
• Aneuploidy
• Intersex
• Taurodontism
• Trisomy X
• Turner syndrome
• XYY syndrome
• XXYY syndrome

{{Reflist}}

• {{cite book | vauthors = Cover VI |year=2012 |title=Living with Klinefelter Syndrome, Trisomy X and 47,XYY: A Guide for Families and Individuals Affected by Extra X and Y Chromosomes |url=https://genetic.org/wp-content/uploads/2016/08/LivingWithKlinefelterSyndromeTrisomyX47XYY.pdf |publisher=Virginia Isaacs Cover |isbn=978-0-615-57400-4}}

{{Medical condition classification and resources

| ICD10 = {{ICD10|Q|98|0|q|90}}-{{ICD10|Q|98|4|q|90}}

| ICD9 = {{ICD9|758.7}}

| iseasesDB = 7189

| OMIM =

| MedlinePlus = 000382

| eMedicineSubj = ped

| eMedicineTopic = 1252

| MeshID = D007713

| SNOMED CT = 405770005

}}

{{Chromosomal abnormalities}}

{{Authority control}}

Category:Diseases named after discoverers

Category:Genetic anomalies

Category:Intersex variations

Category:Sex chromosome aneuploidies

Category:Wikipedia medicine articles ready to translate

Category:1940s neologisms