Klinefelter syndrome in children and adolescents (review)

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Klinefelter syndrome is the most common sex chromosomal abnormality and the most frequent form of primary male hypogonadism. The presence of additional X-chromosome in karyotype leads to such most frequent manifestations as infertility, azoospermia, small testicular volume, high levels of gonadotropins and low testosterone level, tall stature with disproportional body shape, learning difficulties and speech-language disorders. Despite the high incidence of the syndrome, only 25% of patients learn about their disease during life. Late diagnosis and untimely treatment are often caused by severe clinical disease polymorphism, different symptom onset times in patients, and a high incidence of associated conditions, in connection with which patients can be observed by different specialists without knowing the underlying diagnosis.

This review presents data on the history of the study, the etiology of the syndrome, clinical and laboratory parameters characteristic of childhood, adolescence and adulthood. The most common concomitant diseases are highlighted and current data on their prevalence, as well as the effect of testosterone replacement therapy on them, are presented.

About the authors

Daria Bespalyuk


Author for correspondence.
Email: dariabespalyuk@gmail.com
ORCID iD: 0000-0002-4900-6652
SPIN-code: 7129-8794

clinical fellow institute of pediatric endocrinology FSBI NMRC of endocrinology of ministry of health of russia

Russian Federation, 117036, 11, Uliyanova street, Moscow, Russia


  1. Bojesen A, Juul S, Gravholt CH. Prenatal and postnatal prevalence of Klinefelter syndrome: a national registry study. J Clin Endocrinol Metab. 2003; 88 (2): 622– 626. doi: 10.1210/jc.2002-021491
  2. Herlihy AS, Halliday JL, Cock ML, et al. The prevalence and diagnosis rates of Klinefelter syndrome: an Australian comparison. Med J Aust. 2011; 194 (1): 24 –28.
  3. Groth KA, Skakkebæk A, Høst C, et al. Clinical review: Klinefelter syndrome - a clinical update. J Clin Endocrinol Metab. 2013; 98(1):20–30. doi: 10.1210/jc.2012-2382.
  4. Klinefelter HF, Reifenstein EC, Albright F. Syndrome characterized by gynecomastia, aspermatogenesis without A-Leydigism, and increased excretion of follicle-stimulating hormone. Jour Clin Endocrinol. 1942; 2 (11): 615-627.
  5. Barr ML, Bertram EG. A morphological distinction between neurones of the male and female, and the behaviour of the nucleolar satellite during accelerated nucleoprotein synthesis. Nature. 1949; 163(4148):676.
  6. Moore KL, Barr ML. Smears from the oral mucosa in the detection of chromosomal sex. Lancet. 1955; 269(6880):57–8.
  7. Bradbury JT, Bunge RG, Boccabella RA. Chromatin test in Klinefelter’s syndrome. J Clin Endocrinol Metab. 1956; 16(5):689. doi: 10.1210/jcem-16-5-689
  8. Jacobs PA, Strong JA. A case of human intersexuality having a possible XXY sex-determining mechanism. Nature. 1959; 183(4657): 302–3.
  9. Thomas NS, Hassold TJ. Aberrant recombination and the origin of Klinefelter syndrome. Hum Reprod Update. 2003; 9(4): 309–17.
  10. Simpson JL, de la Cruz F, Swerdloff RS, et al. Klinefelter syndrome: expanding the phenotype and identifying new research directions. Genet Med. 2003; 5(6): doi: 10.109701.GIM.0000095626.54201.D0
  11. Tüttelmann F, Gromoll J. Novel genetic aspects of Klinefelter's syndrome. Mol Hum Reprod. 2010; 16 (6): 386-395. doi: 10.1093/molehr/gaq019
  12. Visootsak J, Graham JM.Jr. Klinefelter syndrome and other sex chromosomal aneuploidies. Orphanet J Rare Dis. 2006; 1(42): 1-5. doi: 10.1186/1750-1172-1-42
  13. Lahlou N, Fennoy I, Ross JL, et al. Clinical and hormonal status of infants with nonmosaic XXY karyotype. Acta Paediatr. 2011; 100 (6): 824–829. doi: 10.1111/j.1651-2227.2011.02280.x
  14. Ross JL, Samango-Sprouse C, Lahlou N, et al. Early androgen deficiency in infants and young boys with 47,XXY Klinefelter syndrome. Horm Res. 2005; 64 (1): 39–45. doi: 10.1159/000087313
  15. Samango-Sprouse C. Mental development in polysomy X Klinefelter Syndrome (47,XXY; 48,XXXY): effects of incomplete X inactivation. Semin Reprod Med. 2001; 19 (2): 193-202. doi: 10.1055/s-2001-15400
  16. Davis S, Howell S, Wilson R, et al. Advances in the Interdisciplinary Care of Children with Klinefelter Syndrome. Adv Pediatr. 2016; 63 (1): 15-46. doi: 10.1016/j.yapd.2016.04.020
  17. Davis S, Lahlou N, Bardsley M et al. Gonadal function is associated with cardiometabolic health in pre-pubertal boys with Klinefelter syndrome. Andrology. 2016; 4 (6): 1169–1177. doi: 10.1111/andr.12275
  18. Close S, Fennoy I, Smaldone A, et al. Phenotype and Adverse Quality of Life in Boys with Klinefelter Syndrome. J Pediatr. 2016; 167 (3): 650-657. doi: 10.1016/j.jpeds.2015.06.037
  19. Bruining H, Swaab H, Kas M, et al. Psychiatric characteristics in a self-selected sample of boys with Klinefelter syndrome. Pediatrics. 2009; 123 (5): 865-870. doi: 10.1542/peds.2008-1954
  20. Davis SM, Rogol AD, Ross JL. Testis Development and Fertility Potential in Boys with Klinefelter Syndrome. Endocrinol Metab Clin North Am. 2015; 44 (4): 843–865. doi: 10.1016/j.ecl.2015.07.008
  21. Lahlou N, Fennoy I, Carel JC, et al. Inhibin B and anti-Müllerian hormone, but not testosterone levels, are normal in infants with nonmosaic Klinefelter syndrome. J Clin Endocrinol Metab. 2004; 9. (4):1864–1868. doi: 10.1210/jc.2003-031624
  22. Aksglaede L, Petersen JH, Main KM, et al. High normal testosterone levels in infants with non-mosaic Klinefelter’s syndrome. Eur J Endocrinol. 2007; 157 (3): 345–350. doi: 10.1530/EJE-07-0310
  23. Chang S, Skakkebæk A, Trolle C, et al. Anthropometry in Klinefelter syndrome -multifactorial influences due to CAG length, testosterone treatment and possibly intrauterine hypogonadism. J Clin Endocrinol Metab. 2015; 100 (3):508–517. doi: 10.1210/jc.2014-2834
  24. Kanakis GA, Nieschlag E. Klinefelter syndrome: more than hypogonadism. Metab Clin Exp. 2018; doi: 10.1016/j.metabol.2017.09.017.
  25. Bonomi M, Rochira V, Pasquali D, et al. Klinefelter syndrome (KS): genetics, clinical phenotype and hypogonadism. J Endocrinol Invest. 2017; 40 (2):123-134. doi: 10.1007/s40618-016-0541-6
  26. Aksglaede L, Skakkebaek NE, Almstrup K, et al. Clinical and biological parameters in 166 boys, adolescents and adults with nonmosaic Klinefelter syndrome: a Copenhagen experience. Acta Paediatr. 2011;100(6):793–806. doi: 10.1111/j.1651-2227.2011.02246.x
  27. Pacenza N, Pasqualini T, Gottlieb S, et al. Clinical Presentation of Klinefelter’s Syndrome: Differences According to Age. Int J Endocrinol. 2012; 2012:324835. doi: 10.1155/2012/324835
  28. Rohayem J, Nieschlag E, Zitzmann M, et al. Testicular function during puberty and young adulthood in patients with Klinefelter’s syndrome with and without spermatozoa in seminal fluid. Andrology. 2016; 4 (6): 1178-1186. doi: 10.1111/andr.12249
  29. Christiansen P, Andersson AM, Skakkebaek NE. Longitudinal studies of inhibin B levels in boys and young adults with Klinefelter syndrome. J Clin Endocrinol Metab. 2003; 88 (2):888–891. doi: 10.1210/jc.2002-021379
  30. Radicioni AF, Ferlin A, Balercia G, et al. Consensus statement on diagnosis and clinical management of Klinefelter syndrome. J Endocrinol Invest. 2010; 33 (11):839–850. doi: 10.1007/BF03350351
  31. Wikström AM, Dunkel L. Klinefelter Syndrome. Best Pract Res Clin Endocrinol Metab. 2011; 25 (2):239-250. doi: 10.1016/j.beem.2010.09.006
  32. Lanfranco F, Kamischke A, Zitzmann M, еt al. Klinefelter’s syndrome. Lancet. 2004; 364: 273-283. doi: 10.1016/S0140-6736(04)16678-6
  33. Bojesen A, Gravholt C.H. Morbidity and mortality in Klinefelter syndrome (47,XXY). Acta Paediatr. 2011; 100 (6):807–813. doi: 10.1111/j.1651-2227.2011.02274.x
  34. Роживанов Р.В. Опыт применения пролонгированного препарата тестостерона ундеканоата при гипогонадизме, ожирении и метаболическом синдроме у мужчин // Ожирение и метаболизм — 2012. — №4. — С.10-13. [Rozhivanov RV. Opyit primeneniya prolongirovannogo preparata testosterona undekanoata pri gipogonadizme, ojirenii i metabolicheskom sindrome u mujchin. Obesity and metabolism. 2012; (4):10-13. (In Russ).]
  35. Дедов И.И., Мельниченко Г.А., Бутрова С.А.. Жировая ткань как эндокринный орган // Ожирение и метаболизм. – 2006. – Т. 3. – №1. – C. 6-13. [Dedov II, Mel'nichenko GA, Butrova SA. Zhirovaya tkan' kak endokrinnyy organ. Obesity and metabolism. 2006; 3(1):6-13. (In Russ.)] doi: 10.14341/2071-8713-49375.
  36. Leenen R, Van der Kooy K, Seidell J.C, et al. Visceral fat accumulation in relation to sex hormones in obese men and women undergoing weight loss therapy. J Clin Endocrinol Metab. 1994; 78. (6):1515-1520. doi: 10.1210/jcem.78.6.8200956
  37. Bojesen A, Juul S, Birkebaek NH, et al. Morbidity in Klinefelter syndrome: a Danish register study based on hospital discharge diagnoses. J Clin Endocrinol Metab. 2006; 91 (4): 1254-1260. doi: 10.1210/jc.2005-0697
  38. Ishikawa T, Yamaguchi K, Kondo Y, et al. Metabolic Syndrome in Men with Klinefelter’s Syndrome. Urology. 2008; 71 (6):1109–1113. doi: 10.1016/j.urology.2008.01.051
  39. Jiang-Feng M, Hong-Li X, Xue-Yan W, et al. Prevalence and risk factors of diabetes in patients with Klinefelter syndrome: a longitudinal observational study. Fertil Steril. 2012; 98 (5):1331–1335. doi: 10.1016/j.fertnstert.2012.07.1122
  40. Selice R, Caretta N, Di Mambro A, et al. Prostate volume and growth during testosterone replacement therapy is related to visceral obesity in Klinefelter syndrome. Eur J Endocrinol. 2013; 169 (6): 743–749. doi: 10.1530/EJE-13-0488
  41. Jo DG, Lee HS, Joo YM, et al. Effect of testosterone replacement therapy on bone mineral density in patients with Klinefelter syndrome. Yonsei Med J. 2013; 54 (6): 1331–1335. doi: 10.3349/ymj.2013.54.6.1331
  42. Aksglaede L, Molgaard C, Skakkebaek NE, et al. Normal bone mineral content but unfavourable muscle/fat ratio in Klinefelter syndrome. Arch Dis Child. 2008; 93 (1): 30–34. doi: 10.1136/adc.2007.120675
  43. Bardsley MZ, Falkner B, Kowal K, et al. Insulin resistance and metabolic syndrome in prepubertal boys with Klinefelter syndrome. Acta Paediatr. 2011; 100 (6): 866-870. doi: 10.1111/j.1651-2227.2011.02161.x
  44. The IDF consensus worldwide definition of the metabolic syndrome. International diabetes federation, 2006. Available from: http://www.idf.org/webdata/docs/IDF_Meta_def_final.pdf.
  45. Yesilova Z, Oktenli C, Sanisoglu SY, et al. Evaluation of insulin sensitivity in patients with Klinefelter’s syndrome: a hyperinsulinemic euglycemic clamp study. Endocrine. 2005; 27 (1): 11-15. doi: 10.1385/ENDO:27:1:011
  46. Pasquali D, Arcopinto M, Renzullo A, et al. Cardiovascular abnormalities in Klinefelter syndrome. Int J Cardiol. 2013; 168 (2): 754–759. doi: 10.1016/j.ijcard.2012.09.215
  47. Swerdlow AJ, Higgins CD, Schoemaker MJ, et al. Mortality in patients with Klinefelter syndrome in Britain: a cohort study. J Clin Endocrinol Metab. 2005; 90: 6516-6522. doi: 10.1210/jc.2005-1077
  48. Ota K, Suehiro T, Ikeda Y. Diabetes mellitus associated with Klinefelter’s syndrome: a case report and review in Japan. Intern Med. 2002; 41 (10): 842–847. doi: 10.2169/internalmedicine.41.842
  49. Han SJ, Kim KS, Kim W, et al. Obesity and Hyperglycemia in Korean Men with Klinefelter Syndrome: The Korean Endocrine Society Registry. Endocrinol Metab (Seoul). 2016;.31 (4): 598–603. doi: 10.3803/EnM.2016.31.4.598
  50. Salzano A, D’Assante R, Heaney LM, et al. Klinefelter syndrome, insulin resistance, metabolic syndrome, and diabetes: review of literature and clinical perspective. Endocrine. 2018 — doi: 10.1007/s12020-018-1584-6.
  51. Gravholt CH, Chang S, Wallentin M, et al. Klinefelter syndrome - integrating genetics, neuropsychology and endocrinology. Endocr Rev. 2018. doi: 10.1210/er.2017-00212.
  52. Breuil V, Euller-Ziegler L. Gonadal dysgenesis and bone metabolism. Joint Bone Spine. 2001; 68(1): 26–33. doi: 10.1016/S1297-319X(00)00235-9
  53. Stepan JJ, Burckhardt P, Hána V. The effects of three-month intravenous ibandronate on bone mineral density and bone remodeling in Klinefelter’s syndrome: the influence of vitamin D deficiency and hormonal status. Bone. 2003; 33 (4): 589–596. doi: 10.1016/S8756-3282(03)00205-9
  54. Ferlin A, Schipilliti M, Vinanzi C, et al. Bone mass in subjects with Klinefelter syndrome: role of testosterone levels and androgen receptor gene CAG polymorphism. J Clin Endocrinol Metab. 2011; 96 (4):739-745. doi: 10.1210/jc.2010-1878
  55. Цораева ФЗ., Скородок ЮЛ., Нагорная ИИ и соавт. Влияние заместительной терапии половыми стероидами на метаболизм костной ткани у мальчиков с синдромом Клайнфельтера // Педиатрия — 2015. — Том 94 — № 5 — С.26-29. [Coraeva FZ Skorodok Yul. Нagornaya-ii Vliyanie-zamestitelnoj terapii-polovymi- teroidami na metabolism kostnoj-tkani-u-malchikov-s-sindromom-klajnfelter.
  56. Kübler A, Schulz G, Cordes U, et al. The influence of testosterone substitution on bone mineral density in patients with Klinefelter’s syndrome. Exp Clin Endocrinol. 1992; 100 (3): 129-132. doi: 10.1055/s-0029-1211192
  57. Ferlin A, Selice R, Di Mambro A, et al. Role of vitamin D levels and vitamin D supplementation on bone mineral density in Klinefelter syndrome. Osteoporos Int. 2015; 26 (8): 2193–2202. doi: 10.1007/s00198-015-3136-8
  58. Overvad S, Bay K, Bojesen A, et al. Low INSL3 in Klinefelter syndrome is related to osteocalcin, testosterone treatment and body composition, as well as measures of the hypothalamic-pituitary-gonadal axis. Andrology. 2014; 2 (3):421–427. doi: 10.1111/j.2047-2927.2014.00204.x

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Abstract: 104


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