Medicine:Klinefelter syndrome

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Short description: Human chromosomal condition
Klinefelter syndrome
Other namesXXY syndrome, Klinefelter's syndrome, Klinefelter-Reifenstein-Albright syndrome
Human chromosomesXXY01.png
47,XXY karyotype
Pronunciation
SpecialtyMedical genetics
SymptomsVaried; include above average height, weaker muscles, poor coordination, less body hair, breast growth, small testicle size, less interest in sex, infertility.[1]
ComplicationsInfertility, intellectual disability,[2] autoimmune disorders, breast cancer, venous thromboembolic disease, osteoporosis
Usual onsetAt fertilisation[3]
DurationLifelong
CausesTwo X chromosomes in a male[4]
Risk factorsOlder age of mother[5]
Diagnostic methodGenetic testing (karyotype)[6]
PreventionNone
TreatmentPhysical therapy, speech and language therapy, counseling[7]
PrognosisNearly normal life expectancy[8]
Frequency1 in 500–1000 [5][9]

Klinefelter syndrome (KS), also known as 47,XXY, is an aneuploid genetic condition where the recipient has an additional copy of the X chromosome. As the presence of a Y chromosome denotes male sex, people with Klinefelter syndrome are still genetically male, although they occasionally suffer health complications.[4] These complications commonly include infertility and small, poorly functioning testicles (if present). These symptoms are often noticed only at puberty, although this is one of the most common chromosomal disorders, occurring in one to two per 1,000 live births. It is named after American endocrinologist Harry Klinefelter, who identified the condition in the 1940s.[10][5][11]

The syndrome is defined by the presence of at least one extra X chromosome in addition to a Y chromosome yielding a total of 47 or more chromosomes rather than the usual 46. Klinefelter syndrome occurs randomly. The extra X chromosome comes from the father and mother nearly equally. An older mother may have a slightly increased risk of a child with KS. The syndrome is diagnosed by the genetic test known as a karyotype.[10][6][12][13]

Signs and symptoms

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.

The 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. Whereas some other times 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.[10][6][14]

Prenatal

An estimated 60% of pregnancies with fetuses having Klinefelter syndrome spontaneously abort. 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).[15]

Physical manifestations

As babies and children, those with XXY chromosomes may have weaker muscles and reduced strength. They may sit up, crawl, and walk later than other infants. In average KS children will start walking at 18 months of age. They also have less muscle control and coordination than other children of their age.[16]

During puberty, they show less muscular body, less facial and body hair, and broader hips. This is a direct consequence of the low levels of testosterone produced by KS subjects. 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 of those affected are usually less than 2 cm in length (and always shorter than 3.5 cm), 1 cm in width, and 4ml in volume. Those with XXY chromosomes may also have microorchidism (i.e., small testicles).[16][17]

By adulthood, they tend to become taller than average; with proportionally longer arms and legs, less-muscular bodies, more belly fat, wider hips, narrower shoulders. Some will show little to no sign of affectedness, a lanky, youthful build and facial appearance, or a rounded body type with some degree of gynecomastia (increased breast tissue). Gynecomastia is present in approximately a third of affected individuals, a slightly higher percentage than in the XY population. Approximately 10% of males with XXY chromosomes have gynecomastia noticeable enough that they may choose to have surgery. Those affected 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.[11][18]

Psychological characteristics

Cognitive development

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.[19][20]

The overall IQ tends to be lower than average. Language milestones may also be delayed, particularly when compared to other people their age. Between 25% to 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.[16][21]

Behavior and personality traits

Compared to individuals with a normal number of chromosomes, males affected by Klinefelter syndrome may display behavioral abnormalities. These are phenotypically displayed as higher level of anxiety and depression, mood dysregulation, impaired social skills, emotional immaturity during childhood or difficulty with frustration.[22][23][24] These neurocognitive abnormalities 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.[25]

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.[21][26]

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 the feminine characteristics that their bodies display.[10][21]

Concomitant illness

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 still below the normal risk for women. These patients are also more prone to develop a cardiovascular disease due to the predominance of metabolic abnormalities such as dyslipidemia and type 2 diabetes. Interestingly, its has not been demonstrated that hypertension is related with KS.[27][28][29]

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.[30]

Cause

Birth of a cell with karyotype XXY due to a nondisjunction event of one X chromosome from a Y chromosome during meiosis I in the male
Birth of a cell with karyotype XXY due to a nondisjunction event of one X chromosome during meiosis II in the female

Klinefelter syndrome is not an inherited condition. The extra X chromosome comes from the mother in approximately 50% of the cases and the other 50% comes from the father. 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.[13][31][32]

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.[31][33]

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.[10][12][33]

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.[34][35]

Variations

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.[36] These variations are extremely rare. Additional chromosomal material can contribute to cardiac, neurological, orthopedic, urinogenital and other anomalies.[citation needed]

Approximately 15–20%[37] 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.[37] 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.[38]

Random Versus Skewed X-inactivation

Main page: Biology: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.[39]

Pathogenesis

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.[40] Despite this misunderstanding of the term, testicular growth is arrested.[40]

Diagnosis

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.[41] 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.[29] 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.[13] 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.[42]

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.[10]

Prognosis

The lifespan of individuals with Klinefelter syndrome appears to be reduced by around 2.1 years compared to the general male population.[43] These results are still questioned data, are not absolute, and need further testing.[44]

Treatment

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.[45] 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 both the psychological reasons and to reduce the risk of breast cancer.[46][47]

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.[48]

Intracytoplasmic sperm injection

Infertility treatment

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.[49] By 2010, over 100 successful pregnancies have been reported using IVF technology with surgically removed sperm material from males with KS.[50]

History

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.[11][51] 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.[52] In 1956, Klinefelter syndrome was found to result from an extra chromosome.[53] 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.[54] 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.[54] 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.[55]

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.[56] In 2021, investigation of the individual buried with the Suontaka sword, previously assumed to be a woman, concluded he was a male with Klinefelter syndrome.[57]

Epidemiology

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.[32][58][59][60] However, it is estimated that only 25% of the individuals with Klinefelter syndrome are diagnosed throughout their lives.[45] The rate of Klinefelter syndrome among infertile males is 3.1%. The syndrome is also the main cause of male hypogonadism.[61]

See also

References

  1. ↑ "What are common symptoms of Klinefelter syndrome (KS)?". Eunice Kennedy Shriver National Institute of Child Health and Human Development. 25 October 2013. http://www.nichd.nih.gov/health/topics/klinefelter/conditioninfo/Pages/symptoms.aspx. 
  2. ↑ "Intelligence Quotient Variability in Klinefelter Syndrome Is Associated With GTPBP6 Expression Under Regulation of X-Chromosome Inactivation Pattern". Frontiers in Genetics 12: 724625. 2021. doi:10.3389/fgene.2021.724625. PMID 34616429. 
  3. ↑ "Klinefelter syndrome". https://rarediseases.info.nih.gov/diseases/8705/klinefelter-syndrome/cases/31312. 
  4. ↑ 4.0 4.1 "Klinefelter syndrome". National Health Service. 20 February 2023. Archived from the original on 17 January 2024. https://web.archive.org/web/20240117022701/https://www.nhs.uk/conditions/klinefelters-syndrome/. 
  5. ↑ 5.0 5.1 5.2 "How many people are affected by or at risk for Klinefelter syndrome (KS)?". Eunice Kennedy Shriver National Institute of Child Health and Human Development. 30 November 2012. http://www.nichd.nih.gov/health/topics/klinefelter/conditioninfo/Pages/risk.aspx. 
  6. ↑ 6.0 6.1 6.2 "How do health care providers diagnose Klinefelter syndrome (KS)?". Eunice Kennedy Shriver National Institute of Child Health and Human Development. 2012-11-30. http://www.nichd.nih.gov/health/topics/klinefelter/conditioninfo/Pages/diagnosed.aspx. 
  7. ↑ "What are the treatments for symptoms in Klinefelter syndrome (KS)?". Eunice Kennedy Shriver National Institute of Child Health and Human Development. 2013-10-25. http://www.nichd.nih.gov/health/topics/klinefelter/conditioninfo/Pages/treatments.aspx. 
  8. ↑ "Is there a cure for Klinefelter syndrome (KS)?". Eunice Kennedy Shriver National Institute of Child Health and Human Development. 30 November 2012. http://www.nichd.nih.gov/health/topics/klinefelter/conditioninfo/Pages/cure.aspx. 
  9. ↑ "Klinefelter syndrome". National Library of Medicine. 30 October 2012. http://ghr.nlm.nih.gov/condition/klinefelter-syndrome. 
  10. ↑ 10.0 10.1 10.2 10.3 10.4 10.5 "Klinefelter syndrome and other sex chromosomal aneuploidies". Orphanet Journal of Rare Diseases 1: 42. October 2006. doi:10.1186/1750-1172-1-42. PMID 17062147. 
  11. ↑ 11.0 11.1 11.2 "Klinefelter's syndrome: historical background and development". Southern Medical Journal 79 (9): 1089–1093. September 1986. doi:10.1097/00007611-198609000-00012. PMID 3529433. 
  12. ↑ 12.0 12.1 "Klinefelter Syndrome". Mayo Clinic. https://www.mayoclinic.org/diseases-conditions/klinefelter-syndrome/symptoms-causes/syc-20353949. 
  13. ↑ 13.0 13.1 13.2 "Klinefelter syndrome: more than hypogonadism". Metabolism 86: 135–144. September 2018. doi:10.1016/j.metabol.2017.09.017. PMID 29382506. 
  14. ↑ "Klinefelter Syndrome (KS): Overview". Eunice Kennedy Shriver National Institute of Child Health and Human Development. 2013-11-15. http://www.nichd.nih.gov/health/topics/klinefelter/Pages/default.aspx. 
  15. ↑ Klinefelter Syndrome. January 31, 2022. Drugs & Diseases: Pediatrics: Genetics and Metabolic Disease. https://emedicine.medscape.com/article/945649-overview#a6?form=fpf. 
  16. ↑ 16.0 16.1 16.2 "Klinefelter Syndrome". 24 May 2007. http://www.nichd.nih.gov/health/topics/klinefelter_syndrome.cfm. 
  17. ↑ "Klinefelter's Syndrome: XXY Males". U.S. Pharmacist (West Palm Beach, Florida) 8: 43–51. August 25, 2006. https://www.uspharmacist.com/article/klinefelters-syndrome-xxy-males. 
  18. ↑ "Assisted reproductive techniques in patients with Klinefelter syndrome: a critical review". Fertility and Sterility 82 (4): 775–779. October 2004. doi:10.1016/j.fertnstert.2003.09.085. PMID 15482743. 
  19. ↑ "Oral and written language abilities of XXY boys: implications for anticipatory guidance". Pediatrics 81 (6): 795–806. June 1988. doi:10.1542/peds.81.6.795. PMID 3368277. 
  20. ↑ "Neuropsychological profiles of adults with Klinefelter syndrome". Journal of the International Neuropsychological Society 7 (4): 446–456. May 2001. doi:10.1017/S1355617701744013. PMID 11396547. https://resolver.caltech.edu/CaltechAUTHORS:20210301-123913869. 
  21. ↑ 21.0 21.1 21.2 GenePool (October 17, 2005). "Klinefelter syndrome". http://www.library.nhs.uk/genepool/ViewResource.aspx?resID=104897. 
  22. ↑ "Anxiety and depression in Klinefelter syndrome: The impact of personality and social engagement". PLOS ONE 13 (11): e0206932. November 9, 2018. doi:10.1371/journal.pone.0206932. PMID 30412595. Bibcode: 2018PLoSO..1306932S. 
  23. ↑ "The role of genes, intelligence, personality, and social engagement in cognitive performance in Klinefelter syndrome". Brain and Behavior 7 (3): e00645. March 2017. doi:10.1002/brb3.645. PMID 28293480. 
  24. ↑ "Mental Health of a Large Group of Adults With Disorders of Sex Development in Six European Countries". Psychosomatic Medicine 81 (7): 629–640. September 2019. doi:10.1097/PSY.0000000000000718. PMID 31232913. 
  25. ↑ Animal models for the study of human disease (First ed.). San Diego: Elsevier Science & Technology Books. 2013. p. 780. doi:10.1016/C2011-0-05225-0. ISBN 9780124159129. https://books.google.com/books?id=dVLVLIV8rD0C&pg=PA780. Retrieved February 9, 2017. 
  26. ↑ "Psychosocial adaptation of 39 adolescents with sex chromosome abnormalities". Pediatrics 96 (2 Pt 1): 302–308. August 1995. doi:10.1542/peds.96.2.302. PMID 7630689. 
  27. ↑ "Prevalence of Klinefelter's syndrome in male breast cancer patients". Anticancer Research 17 (6D): 4293–4297. 1997. PMID 9494523. https://pubmed.ncbi.nlm.nih.gov/9494523/. 
  28. ↑ "Klinefelter syndrome, cardiovascular system, and thromboembolic disease: review of literature and clinical perspectives". European Journal of Endocrinology 175 (1): R27–R40. July 2016. doi:10.1530/EJE-15-1025. PMID 26850445. 
  29. ↑ 29.0 29.1 "Klinefelter syndrome: the commonest form of hypogonadism, but often overlooked or untreated". Deutsches Arzteblatt International 110 (20): 347–353. May 2013. doi:10.3238/arztebl.2013.0347. PMID 23825486. 
  30. ↑ "Klinefelter Syndrome: Integrating Genetics, Neuropsychology, and Endocrinology". Endocrine Reviews 39 (4): 389–423. August 2018. doi:10.1210/er.2017-00212. PMID 29438472. 
  31. ↑ 31.0 31.1 "Klinefelter Syndrome – Inheritance Pattern". NIH. July 10, 2023. https://ghr.nlm.nih.gov/condition/klinefelter-syndrome#inheritance. 
  32. ↑ 32.0 32.1 "Prenatal and postnatal prevalence of Klinefelter syndrome: a national registry study". The Journal of Clinical Endocrinology and Metabolism 88 (2): 622–626. February 2003. doi:10.1210/jc.2002-021491. PMID 12574191. 
  33. ↑ 33.0 33.1 "Novel genetic aspects of Klinefelter's syndrome". Molecular Human Reproduction 16 (6): 386–395. June 2010. doi:10.1093/molehr/gaq019. PMID 20228051. 
  34. ↑ "Silencing of the mammalian X chromosome". Annual Review of Genomics and Human Genetics 6 (1): 69–92. 2005-09-01. doi:10.1146/annurev.genom.6.080604.162350. PMID 16124854. 
  35. ↑ "The pseudoautosomal regions, SHOX and disease". Current Opinion in Genetics & Development. Genetics of disease 16 (3): 233–239. June 2006. doi:10.1016/j.gde.2006.04.004. PMID 16650979. 
  36. ↑ "Sex chromosome tetrasomy and pentasomy". Pediatrics 96 (4 Pt 1): 672–682. October 1995. doi:10.1542/peds.96.4.672. PMID 7567329. 
  37. ↑ 37.0 37.1 "Phenotypic differences in mosaic Klinefelter patients as compared with non-mosaic Klinefelter patients". Fertility and Sterility 101 (4): 950–955. April 2014. doi:10.1016/j.fertnstert.2013.12.051. PMID 24502895. https://www.fertstert.org/article/S0015-0282(13)03487-0/pdf. Retrieved 13 June 2020. 
  38. ↑ "Rare XXY/XX mosaicism in a phenotypic male with Klinefelter syndrome: case report". European Journal of Medical Genetics 49 (4): 331–337. 2006. doi:10.1016/j.ejmg.2005.09.001. PMID 16829354. 
  39. ↑ "Random X chromosome inactivation in patients with Klinefelter syndrome". Molecular and Cellular Pediatrics 7 (1): 1. January 2020. doi:10.1186/s40348-020-0093-x. PMID 31974854. 
  40. ↑ 40.0 40.1 "Klinefelter syndrome". National Library for Health. October 2005. http://www.library.nhs.uk/genepool/ViewResource.aspx?resID=104897. 
  41. ↑ "Clinical and diagnostic features of patients with suspected Klinefelter syndrome". Journal of Andrology 24 (1): 41–48. Jan–Feb 2003. doi:10.1002/j.1939-4640.2003.tb02638.x. PMID 12514081. 
  42. ↑ "47,XXY (Klinefelter syndrome) and 47,XYY: estimated rates of and indication for postnatal diagnosis with implications for prenatal counselling". Prenatal Diagnosis 17 (4): 363–368. April 1997. doi:10.1002/(SICI)1097-0223(199704)17:4<363::AID-PD79>3.0.CO;2-O. PMID 9160389. 
  43. ↑ "Increased mortality in Klinefelter syndrome". The Journal of Clinical Endocrinology and Metabolism 89 (8): 3830–3834. August 2004. doi:10.1210/jc.2004-0777. PMID 15292313. 
  44. ↑ "Mortality in patients with Klinefelter syndrome in Britain: a cohort study". The Journal of Clinical Endocrinology and Metabolism 90 (12): 6516–6522. December 2005. doi:10.1210/jc.2005-1077. PMID 16204366. 
  45. ↑ 45.0 45.1 "Clinical review: Klinefelter syndrome--a clinical update". The Journal of Clinical Endocrinology and Metabolism 98 (1): 20–30. January 2013. doi:10.1210/jc.2012-2382. PMID 23118429. 
  46. ↑ "[Clinical-therapeutic features of gynecomastia]" (in it). Il Giornale di Chirurgia 23 (6–7): 250–252. 2002. PMID 12422780. 
  47. ↑ "What are the treatments for symptoms in Klinefelter syndrome (KS)?" (in en). December 2016. https://www.nichd.nih.gov/health/topics/klinefelter/conditioninfo/treatments. 
  48. ↑ Harold Chen. "Klinefelter Syndrome – Treatment". medscape.com. http://emedicine.medscape.com/article/945649-treatment#showall. 
  49. ↑ "Sperm recovery and ICSI outcomes in Klinefelter syndrome: a systematic review and meta-analysis". Human Reproduction Update 23 (3): 265–275. May 2017. doi:10.1093/humupd/dmx008. PMID 28379559. 
  50. ↑ "Should non-mosaic Klinefelter syndrome men be labelled as infertile in 2009?". Human Reproduction 25 (3): 588–597. March 2010. doi:10.1093/humrep/dep431. PMID 20085911. 
  51. ↑ "Syndrome characterized by gynecomastia, aspermatogenesis without a-Leydigism and increased excretion of follicle-stimulating hormone". The Journal of Clinical Endocrinology & Metabolism 2 (11): 615–624. 1942. doi:10.1210/jcem-2-11-615. 
  52. ↑ "The Klinefelter-Reifenstein-Albright syndrome". Biomedsearch.com. http://www.biomedsearch.com/nih/Klinefelter-Reifenstein-Albright-syndrome/21002506.html. 
  53. ↑ Handbook of developmental disabilities (Pbk. ed.). New York: Guilford. 2009. p. 113. ISBN 9781606232484. https://books.google.com/books?id=U4VpCKVomHkC&pg=PA113. Retrieved 2017-09-02. 
  54. ↑ 54.0 54.1 "A case of human intersexuality having a possible XXY sex-determining mechanism". Nature 183 (4657): 302–303. January 1959. doi:10.1038/183302a0. PMID 13632697. Bibcode: 1959Natur.183..302J. 
  55. ↑ "The William Allan Memorial Award address: human population cytogenetics: the first twenty-five years". American Journal of Human Genetics 34 (5): 689–698. September 1982. PMID 6751075. 
  56. ↑ "A 1000-year-old case of Klinefelter's syndrome diagnosed by integrating morphology, osteology, and genetics". Lancet 400 (10353): 691–692. August 2022. doi:10.1016/S0140-6736(22)01476-3. PMID 36030812. 
  57. ↑ "A Woman with a Sword? – Weapon Grave at Suontaka Vesitorninmäki, Finland" (in en). European Journal of Archaeology (Cambridge University Press) 25: 42–60. 2021-07-15. doi:10.1017/eaa.2021.30. ISSN 1461-9571. 
  58. ↑ "Recurrence risks for chromosome abnormalities". Birth Defects Original Article Series 15 (5C): 71–80. 1979. PMID 526617. 
  59. ↑ "Abnormalities of sex chromosome constitution in newborn babies". Lancet 2 (7199): 406–408. August 1961. doi:10.1016/S0140-6736(61)92486-2. PMID 13764957. 
  60. ↑ "Klinefelter syndrome and its variants: an update and review for the primary pediatrician". Clinical Pediatrics 40 (12): 639–651. December 2001. doi:10.1177/000992280104001201. PMID 11771918. 
  61. ↑ "Klinefelter syndrome associated with goniodysgenesis". Journal of Glaucoma 22 (5): e7–e8. Jan 2012. doi:10.1097/IJG.0b013e31824477ef. PMID 22274665. 

Further reading

  • Living with Klinefelter Syndrome, Trisomy X and 47,XYY: A Guide for Families and Individuals Affected by Extra X and Y Chromosomes. Virginia Isaacs Cover. 2012. ISBN 978-0-615-57400-4. 

https://genetic.org/wp-content/uploads/2016/08/LivingWithKlinefelterSyndromeTrisomyX47XYY.pdf

External links

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