|Synonyms||XXY syndrome, Klinefelter's syndrome, Klinefelter-Reifenstein-Albright syndrome|
|Usual onset||At birth|
|Causes||Two or more X chromosomes in males|
|Risk factors||Older mother|
|Diagnostic method||Genetic testing (karyotype)|
|Treatment||Physical therapy, speech and language therapy, counselling|
|Prognosis||Nearly normal life expectancy|
|Frequency||1:500 to 1:1,000 males|
Klinefelter syndrome (KS) also known as 47,XXY or XXY, is the set of symptoms that result from two or more X chromosomes in males. The primary features are sterility and small testicles. Often symptoms may be subtle and many people do not realize they are affected. Sometimes symptoms are more prominent and may include weaker muscles, greater height, poor coordination, less body hair, breast growth, and less interest in sex. Often it is only at puberty that these symptoms are noticed. Intelligence is usually normal; however, reading difficulties and problems with speech are more common. Symptoms are typically more severe if three or more X chromosomes are present.
Klinefelter syndrome usually occurs randomly. An older mother may have a slightly increased risk of a child with Klinefelter syndrome. The condition is not typically inherited from one's parents. The underlying mechanisms involves at least one extra X chromosome in addition to a Y chromosome such that there is a total of 47 or more chromosomes rather than the usual 46. KS is diagnosed by the genetic test known as a karyotype.
While there is no cure, a number of treatments may help. Physical therapy, speech and language therapy, counselling, and adjustments of teaching methods may be useful. Testosterone replacement may be used in those who have significantly lower levels. Enlarged breasts may be removed by surgery. About half of affected males have a chance of fathering children with the help of assisted reproductive technology, but this is expensive and not risk free. Males appear to have a higher risk of breast cancer than typical but still lower than that of females. The condition has a nearly normal life expectancy.
Klinefelter syndrome is one of the most common chromosomal disorders, occurring in 1:500 to 1:1,000 live male births. It is named after Harry Klinefelter who identified the condition in the 1940s. In 1956 identification of the extra X chromosome was first noticed. Mice can also have the XXY syndrome, making them a useful research model.
Signs and symptoms
While it is possible to characterise XXY males based on physical characteristics, substantial variation in physical and developmental traits mean the only reliable method of positive or negative identification is karyotype testing.
As babies and children, XXY males may have weaker muscles and reduced strength. As they grow older, they tend to become taller than average. They may have less muscle control and coordination than other boys of their age.
During puberty, the physical traits of the syndrome become more evident; because these boys do not produce as much testosterone as other boys, they have a less muscular body, less facial and body hair, and broader hips. As teens, XXY males may develop breast tissue and also have weaker bones, and a lower energy level than other males.
By adulthood, XXY males look similar to males without the condition, although they are often taller. In adults, possible characteristics vary widely and include 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 to some extent in about a third of affected individuals, a slightly higher percentage than in the XY population. About 10% of XXY males have gynecomastia noticeable enough that they may choose to have cosmetic surgery.
The term hypogonadism in XXY symptoms is often misinterpreted to mean "small testicles" when it means decreased testicular hormone/endocrine function. Because of this (primary) hypogonadism, individuals will often have a low serum testosterone level but high serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels. Despite this misunderstanding of the term, however, it is true that XXY men may also have microorchidism (i.e., small testicles).
XXY males are also more likely than other men to have certain health problems that typically affect females, such as autoimmune disorders, breast cancer, venous thromboembolic disease, and osteoporosis. In contrast to these potentially increased risks, it is currently thought that rare X-linked recessive conditions occur less frequently in XXY males than in normal XY males, 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.
Cognitive and developmental
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. There may also be delays in motor development which can be addressed through occupational therapy and physical therapy. XXY males may sit up, crawl, and walk later than other infants; they may also struggle in school, both academically and with sports.
The extra chromosome is retained because of a nondisjunction event during paternal or maternal meiosis I (gametogenesis). Nondisjunction 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 offspring (Klinefelter). Fertilizing a double X egg with a normal sperm also produces an XXY offspring (Klinefelter).
Another mechanism for retaining the extra chromosome is through a nondisjunction event during meiosis II in the egg. Nondisjunction will occur when sister chromatids on the sex chromosome, in this case an X and an X, fail to separate. (meiosis) An XX egg is produced which, when fertilized with a Y sperm, yields XXY offspring. This XXY chromosome arrangement is one of the most common genetic variations from the XY karyotype, occurring in about 1 in 500 live male births. See also Triple X syndrome.
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.
48,XXYY and 48,XXXY occur in 1 in 18,000–50,000 male births. The incidence of 49,XXXXY is 1 in 85,000 to 100,000 male births. These variations are extremely rare. Additional chromosomal material can contribute to cardiac, neurological, orthopedic and other anomalies.
Males with Klinefelter syndrome may have a mosaic 47,XXY/46,XY constitutional karyotype and varying degrees of spermatogenic failure. Mosaicism 47,XXY/46,XX with clinical features suggestive of Klinefelter syndrome is very rare. Thus far, only about 10 cases have been described in literature.
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 Klinefelter syndrome, because a color gene involved in cat tabby coloration is on the X chromosome.
About 10% of Klinefelter cases are found by prenatal diagnosis. The first clinical features may appear in early childhood or, more frequently, during puberty, such as lack of secondary sexual characteristics and aspermatogenesis. Despite the presence of small testes, only a quarter of the affected males are recognized as having Klinefelter syndrome at puberty. Another quarter receive their diagnosis in late adulthood. About 64% of affected individuals are never recognized. Often the diagnosis is made incidentally as a result of examinations and medical visits for reasons not linked to the condition.
The standard diagnostic method is the analysis of the chromosomes' karyotype on lymphocytes. In the past, the observation of the Barr body was common practice as well. To confirm mosaicism, it is also possible to analyze the karyotype using dermal fibroblasts or testicular tissue.
Other methods may be: research of high serum levels of gonadotropins (follicle-stimulating hormone and luteinizing hormone), presence of azoospermia, determination of the sex chromatin, and prenatally via chorionic villus sampling or amniocentesis. A 2002 literature review of elective abortion rates found that approximately 58% of pregnancies in the United States with a diagnosis of Klinefelter syndrome were terminated.
The symptoms of Klinefelter syndrome are often variable; therefore, a karyotype analysis should be ordered when small testes, infertility, gynecomastia, long legs/arms, developmental delay, speech/language deficits, learning disabilities/academic issues and/or behavioral issues are present in an individual. The differential diagnosis for the Klinefelter syndrome can include the following conditions: fragile X syndrome, Kallmann syndrome and Marfan syndrome. The cause of hypogonadism can be attributed to many other different medical conditions.
There have been some reports of individuals with Klinefelter syndrome who also have other chromosome abnormalities, such as Down syndrome.
The genetic variation is irreversible, however, individuals who want to look more masculine can take testosterone. Treating adolescents with implants of controlled release testosterone has shown good results when appropriately monitored. Hormone therapy is also useful in preventing the onset of osteoporosis.
Often individuals that have noticeable breast tissue or hypogonadism experience depression and/or social anxiety because they are outside of social norms. An academic term for this is psychosocial morbidity. At least one study indicates that planned and timed support should be provided for young men with Klinefelter syndrome to ameliorate current poor psychosocial outcomes. The surgical removal of the breasts may be considered for both the psychological reasons and to reduce the risk of breast cancer.
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.
By 2010 over 100 successful pregnancies have been reported using IVF technology with surgically removed sperm material from males with Klinefelter syndrome. Microdissection testicular sperm extraction in adult men with Klinefelter syndrome reported success rates of up to 45%.
Children with XXY differ little from other children. Although they can face problems during adolescence, often emotional and behavioral, and difficulties at school, most of them can achieve full independence from their families in adulthood. Most can lead a normal, healthy life.
The results of a study carried out on 87 Australian adults with the syndrome shows that those who have had a diagnosis and appropriate treatment from a very young age had a significant benefit with respect to those who had been diagnosed in adulthood.
There is research suggesting Klinefelter syndrome substantially decreases life expectancy among affected individuals, though the evidence is not definitive. A 1985 publication identified a greater mortality mainly due to diseases of the aortic valve, development of tumors and possible subarachnoid hemorrhages, reducing life expectancy by about 5 years. Later studies have reduced this estimated reduction to an average of 2.1 years. These results are still questioned data, are not absolute, and will need further testing.
This syndrome, evenly spread in all ethnic groups, has a prevalence of 1-2 subjects per every 1000 males in the general population. 3.1% of infertile males have Klinefelter syndrome. The syndrome is also the main cause of male hypogonadism.
According to 2008 meta-analysis, the prevalence of the syndrome has increased over the past decades; however, this does not appear to be related to increased age of the mother at conception, as no increase was observed in the rates of other trisomies of sex chromosomes (XXX and XYY). The National Institutes of Health; however, state that older mothers might have a slightly increased risk.
The syndrome was named after 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. 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.
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 Klinefelter syndrome. Jacobs described her discovery of this first reported human or mammalian chromosome aneuploidy in her 1981 William Allan Memorial Award address.
- "What are common symptoms of Klinefelter syndrome (KS)?". Eunice Kennedy Shriver National Institute of Child Health and Human Development. 2013-10-25. Archived from the original on 2 April 2015. Retrieved 15 March 2015.
- "Klinefelter Syndrome (KS): Overview". nichd.nih.gov. Eunice Kennedy Shriver National Institute of Child Health and Human Development. 2013-11-15. Archived from the original on 18 March 2015. Retrieved 15 March 2015.
- "How many people are affected by or at risk for Klinefelter syndrome (KS)?". Eunice Kennedy Shriver National Institute of Child Health and Human Development. 2012-11-30. Archived from the original on 17 March 2015. Retrieved 15 March 2015.
- "How do health care providers diagnose Klinefelter syndrome (KS)?". Eunice Kennedy Shriver National Institute of Child Health and Human Development. 2012-11-30. Archived from the original on 17 March 2015. Retrieved 15 March 2015.
- "What are the treatments for symptoms in Klinefelter syndrome (KS)?". Eunice Kennedy Shriver National Institute of Child Health and Human Development. 2013-10-25. Archived from the original on 15 March 2015. Retrieved 15 March 2015.
- "Is there a cure for Klinefelter syndrome (KS)?". Eunice Kennedy Shriver National Institute of Child Health and Human Development. 2012-11-30. Archived from the original on 17 March 2015. Retrieved 16 March 2015.
- "Klinefelter syndrome". Genetics Home Reference. National Library of Medicine. 2012-10-30. Archived from the original on 2012-11-15. Retrieved 2012-11-02.
- Visootsak, Jeannie; Graham, John M. (24 October 2006). "Klinefelter syndrome and other sex chromosomal aneuploidies". Orphanet Journal of Rare Diseases. 1: 42. doi:10.1186/1750-1172-1-42. ISSN 1750-1172.
- Visootsak J, Graham JM; Graham Jr (2006). "Klinefelter syndrome and other sex chromosomal aneuploidies". Orphanet Journal of Rare Diseases. 1: 42. doi:10.1186/1750-1172-1-42. PMC . PMID 17062147.
- Brinton, LA (June 2011). "Breast cancer risk among patients with Klinefelter syndrome". Acta paediatrica (Oslo, Norway : 1992). 100 (6): 814–8. doi:10.1111/j.1651-2227.2010.02131.x. PMC . PMID 21241366.
- "Klinefelter Syndrome (KS): Condition Information". nichd.nih.gov. 2013-11-15. Archived from the original on 18 March 2015. Retrieved 15 March 2015.
- Odom, Samuel L. (2009). Handbook of developmental disabilities (Pbk. ed.). New York: Guilford. p. 113. ISBN 9781606232484. Archived from the original on 2017-09-10.
- Conn, P. Michael (2013). Animal models for the study of human disease (First ed.). San Diego: Elsevier Science & Technology Books. p. 780. ISBN 9780124159129. Archived from the original on 2017-09-10.
- "Klinefelter Syndrome". Eunice Kennedy Shriver National Institute of Child Health and Human Development. 2007-05-24. Archived from the original on November 27, 2012.
- "47, XXY (Klinefelter syndrome)". University of Utah. Archived from the original on 30 July 2014. Retrieved 15 June 2014.
- Klinefelter HF (1986). "Klinefelter syndrome: historical background and development". South Med J. 79 (9): 1089–1093. doi:10.1097/00007611-198609000-00012. PMID 3529433.
- Bock, Robert (August 1993). "Understanding Klinefelter Syndrome: A Guide for XXY Males and their Families". NIH Pub. No. 93-3202. Eunice Kennedy Shriver National Institute of Child Health and Human Development. Retrieved 2007-04-07.
- Denschlag D, Tempfer C, Kunze M, Wolff G, Keck C; Clemens, Tempfer, MD; Kunze, Myriam, MD; Wolff, Gerhard, MD; Keck, Christoph, MD (October 2004). "Assisted reproductive techniques in patients with Klinefelter syndrome: A critical review". Fertility and Sterility. 82 (4): 775–779. doi:10.1016/j.fertnstert.2003.09.085. PMID 15482743.
- Leask, Kathryn (October 2005). "Klinefelter syndrome". National Library for Health, Specialist Libraries, Clinical Genetics. National Library for Health. Archived from the original on 2007-09-27. Retrieved 2007-04-07.
- "Archived copy". Archived from the original on 2017-08-24. Retrieved 2017-07-01.
- Smyth, Cynthia M.; Bremner, William J. (22 June 1998). "Klinefelter Syndrome". Archives of Internal Medicine. 158 (12): 1309. doi:10.1001/archinte.158.12.1309.
- Hultborn R, Hanson C, Köpf I, Verbiené I, Warnhammar E, Weimarck A; Hanson, C; Kopf, I; Verbiene, I; Warnhammar, E; Weimarck, A (November–December 1997). "Prevalence of Klinefelter syndrome in male breast cancer patients". Anticancer Res. 17 (6D): 4293–7. PMID 9494523.
- Graham JM, Bashir AS, Stark RE, Silbert A, Walzer S; Bashir, AS; Stark, RE; Silbert, A; Walzer, S (June 1988). "Oral and written language abilities of XXY boys: implications for anticipatory guidance". Pediatrics. 81 (6): 795–806. PMID 3368277.
- Boone KB, Swerdloff RS, Miller BL, Geschwind DH, Razani J, Lee A, Gonzalo IG, Haddal A, Rankin K, Lu P, Paul L (May 2001). "Neuropsychological profiles of adults with Klinefelter syndrome". J Int Neuropsychol Soc. 7 (4): 446–56. PMID 11396547.
- Samango-Sprouse C (2010). "Expansion of the phenotypic profile of the young child with XXY". Pediatric endocrinology reviews : PER. 8 Suppl 1: 160–168. PMID 21217608.
- "Klinefelter Syndrome - Inheritence Pattern". NIH - Genetics Home Reference. NIH. Archived from the original on 30 January 2017. Retrieved 27 January 2017.
- Chow JC, Yen Z, Ziesche SM, Brown CJ (2005). "Silencing of the mammalian X chromosome". Annu Rev Genomics Hum Genet. 6: 69–92. doi:10.1146/annurev.genom.6.080604.162350. PMID 16124854.
- Blaschke RJ, Rappold G (2006). "The pseudoautosomal regions, SHOX and disease. Curr Opin Genet Dev". Jun;. 16 (3): 233–9. doi:10.1016/j.gde.2006.04.004. PMID 16650979.
- Linden MG, Bender BG, Robinson A (1995). "Sex chromosome tetrasomy and pentasomy". Pediatrics. 96 (4 Pt 1): 672–682. PMID 7567329.
- Velissariou V, Christopoulou S, Karadimas C, Pihos I, Kanaka-Gantenbein C, Kapranos N, Kallipolitis G, Hatzaki A (2006). "Rare XXY/XX mosaicism in a phenotypic male with Klinefelter syndrome: case report". Eur J Med Genet. 49 (4): 331–337. doi:10.1016/j.ejmg.2005.09.001. PMID 16829354.
- Centerwall WR, Benirschke K (1975). "An animal model for the XXY Klinefelter's syndrome in man: Tortoiseshell and calico male cats". American journal of veterinary research. 36 (9): 1275–1280. PMID 1163864.
- Bojesen A, Gravholt CH (April 2007). "Klinefelter syndrome in clinical practice". Nat Clin Pract Urol. 4 (4): 192–204. doi:10.1038/ncpuro0775. PMID 17415352. Archived from the original on 2013-02-19.
- Abramsky L, Chapple J (April 1997). "47,XXY (Klinefelter syndrome) and 47,XYY: estimated rates of and indication for postnatal diagnosis with implications for prenatal counselling". Prenat Diagn. 17 (4): 363–8. doi:10.1002/(SICI)1097-0223(199704)17:4<363::AID-PD79>3.0.CO;2-O. PMID 9160389.
- Klinefelter HF Jr; Reifenstein EC Jr; Albright F. (1942). "Syndrome characterized by gynecomastia, aspermatogenesis without a-Leydigism and increased excretion of follicle-stimulating hormone". J Clin Endocrinol Metab. 2 (11): 615–624. doi:10.1210/jcem-2-11-615.
- Bojesen A, Juul S, Gravholt CH; Juul; Gravholt (Feb 2003). "Prenatal and postnatal prevalence of Klinefelter syndrome: a national registry study". Clin Endocrinol Metab. 88 (2): 622–6. doi:10.1210/jc.2002-021491. PMID 12574191.
- Kamischke A, Baumgardt A, Horst J, Nieschlag E; Baumgardt; Horst; Nieschlag (Jan–Feb 2003). "Clinical and diagnostic features of patients with suspected Klinefelter syndrome". J Androl. 24 (1): 41–8. PMID 12514081.
- Smyth CM, Bremner WJ; Bremner (22 June 1998). "Klinefelter syndrome". Arch Intern Med. 158 (12): 1309–14. doi:10.1001/archinte.158.12.1309. PMID 9645824.
- Grzywa-Celińska A, Rymarz E, Mosiewicz J; Rymarz; Mosiewicz (October 2009). "[Diagnosis differential of Klinefelter's syndrome in a 24-year old male hospitalized with sudden dyspnoea--case report]". Pol. Merkur. Lekarski (in Polish). 27 (160): 331–3. PMID 19928664.
- Kurková S, Zemanová Z, Hána V, Mayerová K, Pacovská K, Musilová J, Stĕpán J, Michalová K; Zemanová; Hána; Mayerová; Pacovská; Musilová; Stĕpán; Michalová (April 1999). "[Molecular cytogenetic diagnosis of Klinefelter's syndrome in men more frequently detects sex chromosome mosaicism than classical cytogenetic methods]". Cas. Lek. Cesk. (in Czech). 138 (8): 235–8. PMID 10510542.
- Kleinheinz A, Schulze W; Schulze (1994). "Klinefelter's syndrome: New and rapid diagnosis by PCR analysis of XIST gene expression". Andrologia. 26 (3): 127–129. doi:10.1111/j.1439-0272.1994.tb00773.x. PMID 8085664.
- Mansfield C, Hopfer S, Marteau TM; Hopfer; Marteau (1999). "Termination rates after prenatal diagnosis of Down syndrome, spina bifida, anencephaly, and Turner and Klinefelter syndromes: A systematic literature review". Prenatal Diagnosis. 19 (9): 808–812. doi:10.1002/(SICI)1097-0223(199909)19:9<808::AID-PD637>3.0.CO;2-B. PMID 10521836.
- Sanz-Cortés M, Raga F, Cuesta A, Claramunt R, Bonilla-Musoles F; Raga; Cuesta; Claramunt; Bonilla-Musoles (November 2006). "Prenatally detected double trisomy: Klinefelter and Down syndrome". Prenat. Diagn. 26 (11): 1078–80. doi:10.1002/pd.1561. PMID 16958145.
- Wikström AM, Dunkel L (2011). "Klinefelter syndrome". Best Pract. Res. Clin. Endocrinol. Metab. 25 (2): 239–50. doi:10.1016/j.beem.2010.09.006. PMID 21397196.
- Moskovic DJ, Freundlich RE, Yazdani P, Lipshultz LI, Khera M (2012). "Subcutaneous implantable testosterone pellets overcome noncompliance in adolescents with Klinefelter syndrome". J. Androl. 33 (4): 570–3. doi:10.2164/jandrol.111.013979. PMID 21940986.
- Simm PJ, Zacharin MR; Zacharin (April 2006). "The psychosocial impact of Klinefelter syndrome--a 10 year review". J. Pediatr. Endocrinol. Metab. 19 (4): 499–505. PMID 16759035.
- Gabriele R, Borghese M, Conte M, Egidi F (2002). "[Clinical-therapeutic features of gynecomastia]". G Chir (in Italian). 23 (6-7): 250–2. PMID 12422780.
- Harold Chen. "Klinefelter Syndrome - Treatment". medscape.com. Archived from the original on 2 July 2012. Retrieved 4 September 2012.
- Fullerton G, Hamilton M, Maheshwari A; Hamilton; Maheshwari (2010). "Should non-mosaic Klinefelter syndrome men be labelled as infertile in 2009?". Hum. Reprod. 25 (3): 588–97. doi:10.1093/humrep/dep431. PMID 20085911.
- Ramasamy, R; Ricci, JA; Palermo, GD; Gosden, LV; Rosenwaks, Z; Schlegel, PN (September 2009). "Successful fertility treatment for Klinefelter's syndrome". The Journal of Urology. 182 (3): 1108–13. doi:10.1016/j.juro.2009.05.019. PMID 19616796.
- Herlihy AS, McLachlan RI, Gillam L, Cock ML, Collins V, Halliday JL; McLachlan; Gillam; Cock; Collins; Halliday (July 2011). "The psychosocial impact of Klinefelter syndrome and factors influencing quality of life". Genet. Med. 13 (7): 632–42. doi:10.1097/GIM.0b013e3182136d19. PMID 21546843.
- Swerdlow AJ, Higgins CD, Schoemaker MJ, Wright AF, Jacobs PA; Higgins; Schoemaker; Wright; Jacobs; United Kingdom Clinical Cytogenetics Group (December 2005). "Mortality in patients with Klinefelter syndrome in Britain: a cohort study". J. Clin. Endocrinol. Metab. 90 (12): 6516–22. doi:10.1210/jc.2005-1077. PMID 16204366.
- Price WH, Clayton JF, Wilson J, Collyer S, De Mey R; Clayton; Wilson; Collyer; De Mey (December 1985). "Causes of death in X chromatin positive males (Klinefelter's syndrome)". J Eppmidemiol Community Health. 39 (4): 330–6. doi:10.1136/jech.39.4.330. PMC . PMID 4086964.
- Bojesen A, Juul S, Birkebaek N, Gravholt CH; Juul; Birkebaek; Gravholt (August 2004). "Increased mortality in Klinefelter syndrome". J. Clin. Endocrinol. Metab. 89 (8): 3830–4. doi:10.1210/jc.2004-0777. PMID 15292313.
- Jacobs PA (1979). "Recurrence risks for chromosome abnormalities". Birth Defects Orig Artic Ser. 15 (5C): 71–80. PMID 526617.
- MACLEAN N, HARNDEN DG, COURT BROWN WM; Harnden; Court Brown (Aug 1961). "Abnormalities of sex chromosome constitution in newborn babies". Lancet. 2 (7199): 406–8. doi:10.1016/S0140-6736(61)92486-2. PMID 13764957.
- Visootsak J, Aylstock M, Graham JM; Aylstock; Graham Jr (Dec 2001). "Klinefelter syndrome and its variants: an update and review for the primary pediatrician". Clin Pediatr (Phila). 40 (12): 639–51. doi:10.1177/000992280104001201. PMID 11771918.
- Matlach J, Grehn F, Klink T; Grehn; Klink (Jan 2012). "Klinefelter Syndrome Associated With Goniodysgenesis". J Glaucoma. 22 (5): e7–8. doi:10.1097/IJG.0b013e31824477ef. PMID 22274665.
- Morris JK, Alberman E, Scott C, Jacobs P; Alberman; Scott; Jacobs (Feb 2008). "Is the prevalence of Klinefelter syndrome increasing?". Eur J Hum Genet. 16 (2): 163–70. doi:10.1038/sj.ejhg.5201956. PMID 18000523.
- The Klinefelter-Reifenstein-Albright syndrome. on biomedsearch.com, retrieved 26 August 2017
- JACOBS PA, STRONG JA (January 31, 1959). "A case of human intersexuality having a possible XXY sex-determining mechanism". Nature. 183 (4657): 302–3. doi:10.1038/183302a0. PMID 13632697.
- Jacobs PA (September 1982). "The William Allan Memorial Award address: human population cytogenetics: the first twenty-five years". Am J Hum Genet. 34 (5): 689–98. PMC . PMID 6751075.
- Virginia Isaacs Cover (2012). Living with Klinefelter Syndrome, Trisomy X and 47,XYY: A Guide for Families and Individuals Affected by Extra X and Y Chromosomes. ISBN 978-0-615-57400-4.