Skip to main content
SpringerLink
Log in

Consensus statement on diagnosis and clinical management of Klinefelter syndrome

  • Review Article
  • Published:
Journal of Endocrinological Investigation Aims and scope Submit manuscript

Abstract

Nearly 70 years after its description, Klinefelter syndrome (KS) remains a largely undiagnosed condition. As its clinical presentation may be subtle, many of those affected may be unaware or diagnosed only during evaluation for hypogonadism and/or infertility. In February 2010 an interdisciplinary panel of specialists met in Abano Terme (Padua, Italy) in a workshop on “Klinefelter Syndrome: diagnosis and clinical management”. The main aim of this meeting was to discuss several aspects related to the epidemiology, pathogenesis, and evaluation of KS and to develop a consensus defining its early diagnosis and treatment. In the present consensus we have highlighted the features that may prompt the physicians to look after patients with KS both for the syndrome and correlated diseases. We have provided evidences that, during the different phases of life, there might be some advantages in establishing the diagnosis and starting proper follow-up and treatment. The workshop was carried out under the auspices of the Italian Society of andrology and Sexual Medicine (SIAMS).

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Klinefelter HF, Reifenstein EC, Albright F. Syndrome characterized by gynecomastia, aspermatogenesis without a leydigism and increased excretion of follicle-stimulating hormone. J Clin Endocrinol Metab 1942, 2: 615–27.

    CAS  Google Scholar 

  2. Jacobs PA, Strong JA. A case of Human intersexuality having a possible XXY sex-determining mechanism. Nature 1959, 183: 302–3.

    PubMed  CAS  Google Scholar 

  3. Bojesen A, Juul S, Gravholt CH. Prenatal and postnatal prevalence of Klinefelter syndrome: a national registry study. J Clin Endocrinol Metab 2003, 88: 622–6.

    PubMed  CAS  Google Scholar 

  4. Abramsky L, Chappie J. 47, XXY (Klinefelter syndrome) and 47,XYY: estimated rates of and indication for postnatal diagnosis with implications for prenatal counseling. Prenat Diagn 1997, 17: 363–68.

    PubMed  CAS  Google Scholar 

  5. Nielsen J, Wohlert M. Sex chromosome abnormalities found among 34,910 newborn children: results from a 13-year incidence study in Arhus, Denmark. Birth Defects Orig Artic Ser 1990, 26: 209–23.

    PubMed  CAS  Google Scholar 

  6. 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: 6516–22.

    PubMed  CAS  Google Scholar 

  7. Ferlin A, Raicu F, Gatta V, Zuccarello D, Palka G, Foresta C. Male infertility: role of genetic background. Reprod Biomed Online 2007, 14: 734–45.

    PubMed  CAS  Google Scholar 

  8. Stemkens D, Broekmans FJ, Kastrop PM, Hochstenbach R, Smith BG, Giltay JC. Variant Klinefelter Syndrome 47,X,i(X)(q10),Y and Normal 47, XY Karyotype in Monozygotic Adult Twins. Am J Med Genet 2007; Part A 143A: 1906–1911

    PubMed  CAS  Google Scholar 

  9. Linden MG, Bender BG, Robinson A. Sex chromosome tetrasomy and pentasomy. Pediatrics 1995, 96: 672–82.

    PubMed  CAS  Google Scholar 

  10. Hassold TJ, Sherman SL, Pettay D, Page DC, Jacobs PA. XY chromosome nondisjunction in man is associated with diminished recombination in the pseudoautosomal region. Am J Hum Genet 1991, 49: 253–60.

    PubMed Central  PubMed  CAS  Google Scholar 

  11. MacDonald M, Hassold T, Harvey J, Wang LH, Morton NE, Jacobs P. The origin of 47, XXY and 47,XXX aneuploidy: heterogeneous mechanisms and role of aberrant recombination. Hum Mol Genet 1994, 3: 1365–71.

    PubMed  CAS  Google Scholar 

  12. litsuka Y, Bock A, Nguyen DD, Samango-Sprouse CA, Simpson JL, Bischoff FZ. Evidence of skewed X-chromosome inactivation in 47, XXY and 48,XXYY Klinefelter patients. Am J Med Genet 2001, 98: 25–31.

    Google Scholar 

  13. Bojesen A, Gravholt CH. Klinefelter syndrome in clinical practice. Nat Clin Pract Urol 2007, 4: 192–204.

    PubMed  Google Scholar 

  14. Lanfranco F, Kamischke A, Zitzmann M, Nieschlag E. Klinefelter’s syndrome. Lancet 2004, 364: 273–83.

    PubMed  CAS  Google Scholar 

  15. Simpson JL, de la Cruz F, Swerdloff RS, et al. Klinefelter syndrome: expanding the phenotype and identifying new research directions. Genet Med 2003, 5: 460–8.

    PubMed  Google Scholar 

  16. Ratcliffe SG. The sexual development of boys with the chromosome constitution 47, XXY (Klinefelter’s syndrome). Clin Endocrinol Metab 1982, 11: 703–16.

    PubMed  CAS  Google Scholar 

  17. Ross JL, Samango-Sprouse C, Lahlou N, Kowal K, Elder FF, Zinn A. Early androgen deficiency in infants and young boys with 47, XXY Klinefelter syndrome. Horm Res 2005, 64: 39–45.

    PubMed  CAS  Google Scholar 

  18. Linden. MG, Bender BG. Fifty-one prenatally diagnosed children and adolescents with sex chromosome abnormalities. Am J Med Genet 2002, 110: 11–8.

    PubMed  Google Scholar 

  19. Lee YS, Cheng AW, Ahmed SF, Shaw NJ, Hughes IA. Genital anomalies in Klinefelter’s syndrome. Horm Res 2007, 68: 150–5.

    PubMed  CAS  Google Scholar 

  20. Zeger MP, Zinn AR, Lahlou N, et al. Effect of ascertainment and genetic features on the phenotype of Klinefelter syndrome. J Pediatr 2008, 152: 716–22.

    PubMed  Google Scholar 

  21. Lahlou N, Roger M. Inhibin B in pubertal development and pubertal disorders. Semin Reprod Med 2004, 22: 165–75.

    PubMed  CAS  Google Scholar 

  22. Aksglaede L, Petersen JH, Main KM, Skakkebæk NE, Juul A. High normal testosterone levels in infants with non-mosaic Klinefelter’s syndrome. Eur J Endocrinol 2007, 157: 345–50.

    PubMed  CAS  Google Scholar 

  23. Girardin CM, Lemyre E, Alos N, Deal C, Huot C, Van Vliet G. Comparison of Adolescents with Klinefelter Syndrome according to the circumstances of diagnosis: amniocentesis versus clinical signs. Horm Res 2009, 72: 98–105.

    PubMed  CAS  Google Scholar 

  24. Ferlin A, Zuccarello D, Zuccarello B, Chirico MR, Zanon GF, Foresta C. Genetic alterations associated with cryptorchidism. JAMA 2008, 300: 2271–6.

    PubMed  CAS  Google Scholar 

  25. Ratcliffe S. Long-term outcome in children of sex chromosome abnormalities. Arch Dis Child 1999; 80: 192–5.

    PubMed Central  PubMed  CAS  Google Scholar 

  26. Topper E, Dickerman Z, Prager-Lewin R, Kaufman H, Maimon Z, Laron Z. Puberty in 24 patients with Klinefelter syndrome. Eur J Pediatr 1982, 139: 8–12.

    PubMed  CAS  Google Scholar 

  27. Salbenblatt JA, Bender BG, Puck MH, Robinson A, Faiman C, Winter JS. Pituitary-gonadal function in Klinefelter syndrome before and during puberty. Pediatr Res 1985, 19: 82–6.

    PubMed  CAS  Google Scholar 

  28. 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: 888–91.

    PubMed  CAS  Google Scholar 

  29. Wikström AM, Dunkel L, Wickman S, Norjavaara E, Ankarberg-Lindgren C, Raivio T. Are adolescent boys with Klinefelter syndrome androgen deficient? A longitudinal study of Finnish 47, XXY boys. Pediatric Research 2006, 59: 854–9.

    PubMed  Google Scholar 

  30. Wikström AM, Bay K, Hero M, et al. Serum insulin-like factor 3 levels during puberty in healthy boys and boys with Klinefelter syndrome. J Clin Endocrinol Metab 2006, 91: 4705–8.

    PubMed  Google Scholar 

  31. Aksglaede L, Wikström AM, Rajpert-De Meyts E, Dunkel L, Skakkebaek NE, Juul A. Natural history of seminiferous tubule degeneration in Klinefelter syndrome. Hum Reprod Update 2006, 12: 39–48.

    PubMed  Google Scholar 

  32. Marshall WA, Tanner JM. Variations in the pattern of pubertal changes in boys. Arch Dis Child 1970, 45: 13–23.

    PubMed Central  PubMed  CAS  Google Scholar 

  33. Castellino N, Bellone S, Rapa A, et al. Puberty onset in Northern Italy: a random sample of 3597 Italian children. J Endocrinol Invest 2005, 28: 589–94.

    PubMed  CAS  Google Scholar 

  34. Behre HM, Yeung%CH, Holstein AF, Weinbauer GF, Gassner P, Nieschlag E. Diagnosis of male infertility and hypogonadism. In: Nieschlag E, Behre HM, Nieschlag S, eds. Andrology: male reproductive health and dysfunction, 2nd ed. Berlin, Heidelberg, New York: Springer 2000, 90–124.

    Google Scholar 

  35. Ma NS, Geffner ME. Gynecomastia in prepubertal and pubertal men. Curr Opin Pediatr 2008, 20: 465–70.

    PubMed  Google Scholar 

  36. Smyth CM, Bremner WJ. Klinefelter syndrome. Arch Intern Med 1998, 158: 1309–14.

    PubMed  CAS  Google Scholar 

  37. Visootsak J, Aylstock M, Graham JM Jr. Kilnefelter syndrome and its variants: an update and review for the primary pediatrician clin pediatr (Phila) 2001, 40: 639–43.

    CAS  Google Scholar 

  38. Winter JS Androgen therapy in Klinefelter syndrome during adolescence. Birth Defects Orig Artic Ser 1990, 26: 235–45.

    PubMed  CAS  Google Scholar 

  39. Aksglaede L, Skakkebaek NE, Juul A. Abnormal sex chromosome constitution and longitudinal growth: serum levels of insulin-like growth factor (IGF)-I, IGF binding protein-3, luteinizing hormone, and testosterone in 109 males with 47, XXY, 47,XYY, or sex-determining region of the Y chromosome (SRY)-positive 46,XX karyotypes. J Clin Endocrinol Metab 2008, 93: 169–76.

    PubMed  CAS  Google Scholar 

  40. Radicioni AF, Anzuini A, De Marco E, Nofroni I, Castracane VD, Lenzi A. Changes in serum inhibin B during normal male puberty. Eur J Endocrinol 2005, 152: 403–9.

    PubMed  CAS  Google Scholar 

  41. Wikström AM, Raivio T, Hadziselimovic F, Wikström S, Tuuri T, Dunkel L. Klinefelter syndrome in adolescence: onset of puberty is associated with accelerated germ cell depletion. J Clin Endocrinol Metab 2004, 89: 2263–70.

    PubMed  Google Scholar 

  42. Ratcliffe SG, Murray L, Teague P. Edinburgh study of growth and development of children with sex chromosome abnormalities. III. Birth Defects Orig Artie Ser 1986, 22: 73–118.

    CAS  Google Scholar 

  43. Foresta C, Bettella A, Vinanzi C, et al. A novel circulating hormone of testis origin in humans. J Clin Endocrinol Metab 2004, 89: 5952–8.

    PubMed  CAS  Google Scholar 

  44. Bay K, Hartung S, Ivell R, et al. Insulin-like factor 3 serum levels in 135 normal men and 85 men with testicular disorders: relationship to the luteinizing hormone-testosterone axis. J Clin Endocrinol Metab 2005, 90: 3410–8.

    PubMed  CAS  Google Scholar 

  45. Ferlin A, Garolla A, Rigon F, Rasi Caldogno L, Lenzi A, Foresta C. Changes in serum insulin-like factor 3 during normal male puberty. J Clin Endocrinol Metab 2006, 91: 3426–31.

    PubMed  CAS  Google Scholar 

  46. Selice R, Di Mambro A, Garolla A, Ficarra V, Iafrate M, Ferlin A, Foresta C. Spermatogenesis in Klinefelter syndrome. J Endocrinol Invest 2010, Mar 22 [Epub ahead of print].

  47. Fullerton G, Hamilton M, Maheshwari A. Should non-mosaic Klinefelter syndrome men be labelled as infertile in 2009? Hum Reprod 2010, 25: 588–97.

    PubMed  CAS  Google Scholar 

  48. Bojesen A, Kristensen K, Birkebaek NH, et al. The metabolic syndrome is frequent in Klinefelter’s syndrome and is associated with abdominal obesity and hypogonadism. Diabetes Care 2006, 29: 1591–8.

    PubMed  Google Scholar 

  49. Kamischke A, Baumgardt A, Horst J, Nieschlag E. Clinical and diagnostic features of patients with suspected Klinefelter syndrome. J Androl 2003, 24: 41–8.

    PubMed  Google Scholar 

  50. Anawalt BD, Bebb RA, Matsumoto AM, et al. Serum inhibin B levels reflect Sertoli cell function in normal men and men with testicular dysfunction. J Clin Endocrinol Metab 1996, 81: 3341–5.

    PubMed  CAS  Google Scholar 

  51. Klingmüller D, Haidl G. Inhibin B in men with normal and disturbed spermatogenesis. Hum Reprod 1997, 12: 2376–8.

    PubMed  Google Scholar 

  52. Wang C, Nieschlag E, Swerdloff R, et al. Investigation, treatment and monitoring of late-onset hypogonadism in males. Int J Androl 2009, 32: 1–10.

    PubMed  Google Scholar 

  53. Ishikawa T, Yamaguchi K, Kondo Y, Takenaka A, Fujisawa M. Metabolic syndrome in men with Klinefelter’s syndrome. Urology 2008, 71: 1109–13.

    PubMed  Google Scholar 

  54. Ravaglia G, Forti P, Maioli F, et al. Metabolic Syndrome: prevalence and prediction of mortality in elderly individuals. Diabetes Care 2006, 29: 2471–6.

    PubMed  CAS  Google Scholar 

  55. Corona G, Mannucci E, Forti G, Maggi M. Hypogonadism, ED, metabolic syndrome and obesity: a patological link supporting cardiovascular diseases. Int J Androl 2009, 32: 587–98.

    PubMed  CAS  Google Scholar 

  56. Tsai EC, Boyko EJ, Leonetti DL, Fujimoto WY. Low serum testosterone level as a predictor of increased visceral fat in Japanese-American men. Int J Obes Relat Metab Disord 2000, 24: 485–91.

    PubMed  CAS  Google Scholar 

  57. Mårin P, Holmäng S, Jönsson L, et al. The effects of testosterone treatment on body composition and metabolism in middle-aged obese men. Int J Obes Relat Metab Disord 1992, 16: 991–7.

    PubMed  Google Scholar 

  58. Després JP, Lemieux I. Abdominal obesity and metabolic syndrome. Nature 2006, 444: 881–7.

    PubMed  Google Scholar 

  59. Aksglaede L, Molgaard C, Skakkebaek NE, Juul A. Normal bone mineral content but unfavourable muscle/fat ratio in Klinefelter syndrome. Arch Dis Child 2008, 93: 30–34.

    PubMed  CAS  Google Scholar 

  60. Yesilova Z, Oktenli C, Sanisoglu SY, et al. Evaluation of insulin sensitivity in patients with Klinefelter’s syndrome: a hyperinsulinemic euglycemic clamp study. Endocr 2005, 27: 11–5.

    CAS  Google Scholar 

  61. Andersen NH, Bojesen A, Kristensen K, et al. Left ventricular dysfunction in Klinefelter syndrome is associated to insulin resistance, abdominal adiposity and hypogonadism. Clin Endocrinol (Oxf) 2008, 69: 785–91.

    CAS  Google Scholar 

  62. Friedman JM, Halaas JL. Leptin and the regulation of body weight in mammals. Nature 1998, 395: 763–70.

    PubMed  CAS  Google Scholar 

  63. Laaksonen DE, Niskanen L, Punnonen K, et al. Sex hormones, inflammation and the metabolic syndrome: a population-based study. Eur J Endocrinol 2003, 149: 601–8.

    PubMed  CAS  Google Scholar 

  64. Díez JJ, Iglesias P. The role of the novel adipocyte-derived hormone adiponectin in human disease. Eur J Endocrinol 2003, 148: 293–300.

    PubMed  Google Scholar 

  65. Kapoor D, Goodwin E, Channer KS, Jones TH. Testosterone replacement therapy improves insulin resistance, glycaemic control, visceral adiposity and hypercholesterolaemia in hypogonadal men with type 2 diabetes. Eur J Endocrinol 2006, 154: 899–906.

    PubMed  CAS  Google Scholar 

  66. Saad F, Gooren LJ, Haider A, Yassin A. A dose-response study of testosterone on sexual dysfunction and features of the metabolic syndrome using testosterone gel and parenteral testosterone undecanoate. J Androl 2008, 29: 102–5.

    PubMed  CAS  Google Scholar 

  67. Corona G, Monami M, Rastrelli G, et al. Testosterone and metabolic syndrome: a meta-analysis study. J Sex Med 2010, in press.

  68. NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis and Therapy. Osteoporosis prevention, diagnosis and therapy. JAMA 2001, 285: 785–95.

    Google Scholar 

  69. Lombardi A, Ross PD. The assessment of bone mass in men. Calcif Tissue Int 2001, 69: 222–4.

    PubMed  CAS  Google Scholar 

  70. Jackson JA, Kleerekoper M. Osteoporosis in men: diagnosis, pathophysiology, and prevention. Medicine (Baltimore) 1990, 69: 137–52.

    CAS  Google Scholar 

  71. Kanis JA, Melton LJ 3rd, Christiansen C, Johnston CC, Khaltaev N. The diagnosis of osteoporosis. J Bone Miner Res 1994, 9: 1137–41.

    PubMed  CAS  Google Scholar 

  72. Kamel HK. Update on osteoporosis management in long-term care: focus on bisphosphonates. J Am Med Dir Assoc 2007, 8: 434–40.

    PubMed  Google Scholar 

  73. Horowitz M, Mordin BEC, Aaron JE (eds). Klinefelter’s Syndrome. Berlin: Springer-Verlag. 1984, 51–61.

    Google Scholar 

  74. Stepán JJ, Lachman M, Zvrina J, Pacovský V, Baylink DJ. Castrated men exhibit bone loss: effect of calcitonin treatment on biochemical indices of bone remodeling. J Clin Endocrinol Metab 1989, 69: 523–7.

    PubMed  Google Scholar 

  75. Breuil V, Euller-Ziegler L. Gonadal dysgenesis and bone metabolism. Joint, bone, spine: revue du rhumatisme 2001, 68: 26–33.

    CAS  Google Scholar 

  76. van den Bergh JP, Hermus AR, Spruyt AI, Sweep CG, Corstens FH, Smals AG. Bone mineral density and quantitative ultrasound parameters in patients with Klinefelter’s syndrome after long-term testosterone substitution. Osteoporos Int 2001, 12: 55–62.

    PubMed  Google Scholar 

  77. Fintini D, Grossi A, Brufani C, et al. Bone mineral density and body composition inmale children with hypogonadism. J Endocrinol Invest 2009, 32: 585–9.

    PubMed  CAS  Google Scholar 

  78. Seo JT, Lee JS, Oh TH, Joo KJ. The clinical significance of bone mineral density and testosterone levels in Korean men with nonmosaic Klinefelter’s syndrome. BJU Int 2007, 99: 141–6.

    PubMed  CAS  Google Scholar 

  79. Ferlin A, Schipilliti M, Di Mambro A, Vinanzi C, Foresta C. Osteoporosis in Klinefelter’s syndrome. Mol Hum Reprod 2010, 16: 402–10.

    PubMed  CAS  Google Scholar 

  80. Ringe JD, Faber H, Dorst A. Alendronate treatment of established primary osteoporosis in men: results of a 2-year prospective study. J Clin Endocrinol Metab 2001, 86: 5252–5.

    PubMed  CAS  Google Scholar 

  81. Shimon I, Eshed V, Doolman R, Sela BA, Karasik A, Vered I. Alendronate for osteoporosis in men with androgen-repleted hypogonadism. Osteoporos Int 2005, 16: 1591–6.

    PubMed  CAS  Google Scholar 

  82. Ringe JD, Faber H, Farahmand P, Dorst A. Efficacy of risedronate in men with primary and secondary osteoporosis: results of a 1-year study. Rheumatol Int 2006, 26: 427–31.

    PubMed  CAS  Google Scholar 

  83. Lyles KW, Colón-Emeric CS, Magaziner JS, et al; HORIZON Recurrent Fracture Trial. Zoledronic acid and clinical fracture and mortality after hip fracture. N Engl J Med 2007, 357: 1799–808.

    PubMed  CAS  Google Scholar 

  84. Orwoll ES, Scheele WH, Paul S, et al. The effect of teriparatide [human parathyroid hormone (1–34)] therapy on bone density in men with osteoporosis. J Bone Miner Res 2003, 18: 9–17.

    PubMed  CAS  Google Scholar 

  85. Geschwind DH, Boone KB, Miller BL, Swerdloff RS. Neurobehavioural phenotype of Klinefelter syndrome. Ment Retard Dev Disabil Res Rev 2000, 6: 107–16.

    PubMed  CAS  Google Scholar 

  86. Ratcliffe SG, Jenkins J, Teague P. Cognitive and behavioural development of the 47,XYY child. In: Berch DB, Bender BG, editors. Sex chromosome abnormalities and behavior: psychological studies. Boulder, CO, USA: Westview Press; 1990. pp. 161–84.

    Google Scholar 

  87. Bancroft J, Axworthy D, Ratcliffe S. The personality and psychosexual development of boys with 47, XXY chromosome constitution. J Child Psychol Psychiatry 1982, 23: 169–80.

    PubMed  CAS  Google Scholar 

  88. Temple CM, Sanfilippo PM. Executive skills in Klinefelter’s syndrome. Neuropsychologia 2003, 41: 1547–59.

    PubMed  Google Scholar 

  89. Liss M, Fein D, Allen D, et al. Executive functioning in high-functioning children with autism. J Child Psychol Psychiatry 2001, 42: 261–70.

    PubMed  CAS  Google Scholar 

  90. Samango-Sprouse CA, Rogol A. XXY: the hidden disability and a prototype for an infantile presentation of developmental dyspraxia (IDD). Infants Young Child 2002, 15: 11–18.

    Google Scholar 

  91. DeLisi LE, Maurizio AM, Svetina C, et al. Klinefelter’s syndrome (XXY) as a genetic model for psychotic disorders. Am J Med Genet B Neuropsychiatr Genet 2005, 135B: 15–23.

    PubMed  Google Scholar 

  92. Lue Y, Jentsch JD, Wang C, et al. XXY mice exhibit gonadal and behavioral phenotypes similar to Klinefelter syndrome. Endocrinology 2005, 146: 4148–54.

    PubMed  CAS  Google Scholar 

  93. Lewejohann L, Damm OS, Luetjens CM, et al. Impaired recognition memory in male mice with a supernumerary X chromosome. Physiol Behav 2009, 96: 23–9.

    PubMed  CAS  Google Scholar 

  94. Bender BG, Harmon RJ, Linden MG, Robinson A. Psychosocial adaptation of 39 adolescents with sex chromosome abnormalities. Pediatrics 1995, 96 (2 Pt 1): 302–308.

    PubMed  CAS  Google Scholar 

  95. DeLisi LE, Friedrich U, Wahlstrom J, et al. Schizophrenia and sex chromosome anomalies. Schizophr Bull 1994, 20: 495–505.

    PubMed  CAS  Google Scholar 

  96. Price WH, Clayton JF, Wilson J, Collyer S, De Mey R. Causes of death in X chromatin positive males (Klinefelter’s syndrome). J Epidemiol Community Health 1985, 39: 330–6.

    PubMed Central  PubMed  CAS  Google Scholar 

  97. Swerdlow AJ, Hermon C, Jacobs PA, et al. Mortality and cancer incidence in persons with numerical sex chromosome abnormalities: a cohort study. Ann Hum Genet 2001, 65: 177–88.

    PubMed  CAS  Google Scholar 

  98. Bojesen A, Juul S, Birkebaek N, Gravholt CH. Increased mortality in Klinefelter syndrome. J Clin Endocrinol Metab 2004, 89: 3830–4.

    PubMed  CAS  Google Scholar 

  99. Harnden DG, Maclean N, Langlands AO. Carcinoma of the breast and Klinefelter’s syndrome. J Med Genet 1971, 8: 460–1.

    PubMed Central  PubMed  CAS  Google Scholar 

  100. Scheike O, Visfeldt J, Petersen B. Male breast cancer. 3. Breast carcinoma in association with the Klinefelter syndrome. Acta Pathol Microbiol Scand A 1973, 81: 352–8.

    PubMed  CAS  Google Scholar 

  101. Hultborn R, Hanson C, Köpf I, Verbiené I, Warnhammar E, Weimarck A. Prevalence of Klinefelter’s syndrome in male breast cancer patients. Anticancer Res 1997, 17: 4293–7.

    PubMed  CAS  Google Scholar 

  102. Sasco AJ, Lowenfels AB, Pasker-de Jong P. Review articles: epidemiology of male breast cancer. A mate-analysis of published case-control studies and discussion of selected aetiological factors. Int J Cancer 1993, 53: 538–49.

    PubMed  CAS  Google Scholar 

  103. Swerdlow AJ, Schoemaker MJ, Higgins CD, Wright AF, Jacobs PA; UK Clinical Cytogenetics Group. Cancer incidence and mortality in men with Klinefelter syndrome: a cohort study. J Natl Cancer lnst 2005, 97: 1204–10.

    Google Scholar 

  104. Wang C, Baker HW, Burger HG, De Kretser DM, Hudson B. Hormonal studies in Klinefelter’s syndrome. Clin Endocrinol 1975, 4: 399–411.

    CAS  Google Scholar 

  105. Lynch HT, Kaplan AR, Lynch JF. Klinefelter syndrome and cancer: a family study. JAMA 1974, 229: 809–11.

    PubMed  CAS  Google Scholar 

  106. Schneider DT, Schuster AE, Fritsch MK, et al. Genetic analysis of mediastinal nonseminomatous germ cell tumors in children and adolescents. Genes Primary mediastinal germ cell tumors in children and adolescents: results of the German cooperative protocols MAKEI 83/86, 89, and 96. J Clin Oncol 2000, 18: 832–9.

    PubMed  CAS  Google Scholar 

  107. Hasle H, Jacobsen BB, Asschenfeldt P, Andersen K. Mediastinal germ cell tumour associated with Klinefelter syndrome. A report of case and review of the literature. Eur J Pediatr 1992, 151: 735–9.

    CAS  Google Scholar 

  108. Nichols CR, Heerema NA, Palmer C, Loehrer PJ Sr, Williams SD, Einhorn LH. Klinefelter’s syndrome associated with mediastinal germ cell neoplasms. J Clin Oncol 1987, 5: 1290–4.

    PubMed  CAS  Google Scholar 

  109. Hachimi-ldrissi S, Desmyttere S, Goossens A, Desprechins B, Otten J. Retroperitoneal teratoma as first sign of Klinefelter’s syndrome. Arch Dis Child 1995, 72: 163–4.

    Google Scholar 

  110. Sato K, Takeuchi H, Kubota T. Pathology of intracranial germ cell tumors. Prog Neurol Surg 2009, 23: 59–75.

    PubMed  Google Scholar 

  111. Hasle H, Mellemgaard A, Nielsen J, Hansen J. Cancer incidence in men with Klinefelter syndrome. Br J Cancer 1995, 71: 416–20.

    PubMed Central  PubMed  CAS  Google Scholar 

  112. Müller J, Skakkebaek NE. Gonadal malignancy in individuals with sex chromosome anomalies. In: Evans JA, Hamertonai JL, Robinson A (eds). Children and young adults with sex chromosome aneuploidy: follow-up, clinical, and molecular Studies. Proceedings of the 5th International Workshop on Sex Chromosome anomalies. Minaki, Ontario, Canada, June 7–10, 1989.

  113. Gordon DL, Krmpotic E, Thomas W, Gandy HM, Paulsen CA. Pathologic testicular findings in Klinefelter’s syndrome. 47, XXY vs 47, XY-47, XXY. Arch Intern Med 1972, 130: 726–9.

    PubMed  CAS  Google Scholar 

  114. Skakkebaek NE. Two types of tubules containing only Sertoli cells in adults with Klinefelter’s syndrome. Nature 1969, 223: 643–5.

    PubMed  CAS  Google Scholar 

  115. Laron Z, Dickerman Z, Zamir R, Galatzer A. Paternity in Klinefelter’s syndrome — a case report. Arch Androl 1982, 8: 149–51.

    PubMed  CAS  Google Scholar 

  116. Lin YM, Huang WJ, Lin JS, Kuo PL. Progressive depletion of germ cells in a man with nonmosaic Klinefelter’s syndrome: optimal time for sperm recovery. Urology 2004, 63: 380–1.

    PubMed  Google Scholar 

  117. Foresta C, Galeazzi C, Bettella A, Stella M, Scandellari C. High incidence of sperm sex chromosomes aneuploidies in two patients with Klinefelter’s syndrome. J Clin Endocrinol Metab 1998, 83: 203–5.

    PubMed  CAS  Google Scholar 

  118. Terzoli G, Lalatta F, Lobbiani A, Simoni G, Colucci G. Fertility in a 47, XXY patient: assessment of biological paternity by deoxyribonucleic acid fingerprinting. Fertil Steril 1992, 58: 821–2.

    PubMed  CAS  Google Scholar 

  119. Foresta C, Galeazzi C, Bettella A, et al. Analysis of meiosis in intratesticular germ cells from subjects affected by classic Klinefelter’s syndrome. J Clin Endocrinol Metab 1999, 84: 3807–10.

    PubMed  CAS  Google Scholar 

  120. Tournaye H, Staessen C, Liebaers I, Van Assche E, Devroey P, Bonduelle M, Van Steirteghem A. Testicular sperm recovery in nine 47, XXY Klinefelter patients. Hum Reprod 1996, 11: 1644–9.

    PubMed  CAS  Google Scholar 

  121. Friedler S, Raziel A, Strassburger D, Schachter M, Bern O, Ron-El R. Outcome of ICSI using fresh and cryopreserved-thawed testicular spermatozoa in patients with non-mosaic Klinefelter’s syndrome. Hum Reprod 2001, 16: 2616–20.

    PubMed  CAS  Google Scholar 

  122. Ulug U, Bener F, Akman MA, Bahceci M. Partners of men with Klinefelter syndrome can benefit from assisted reproductive technologies. Fertil Steril 2003, 80: 903–6.

    PubMed  Google Scholar 

  123. Seo JT, Park YS, Lee JS. Successful testicular sperm extraction in Korean Klinefelter syndrome. Urology 2004, 64: 1208–11.

    PubMed  Google Scholar 

  124. Schiff JD, Palermo GD, Veeck LL, Goldstein M, Rosenwaks Z, Schlegel PN. Success of testicular sperm extraction [corrected] and intracytoplasmic sperm injection in men with Klinefelter syndrome. J Clin Endocrinol Metab 2005, 90: 6263–7.

    PubMed  CAS  Google Scholar 

  125. Vernaeve V, Staessen C, Verheyen G, Van Steirteghem A, Devroey P, Tournaye H. Can biological or clinical parameters predict testicular sperm recovery in 47, XXY Klinefelter’s syndrome patients? Hum Reprod 2004, 19: 1135–9.

    PubMed  CAS  Google Scholar 

  126. Okada H, Goda K, Yamamoto Y, et al. Age as a limiting factor for successful sperm retrieval in patients with nonmosaic Klinefelter’s syndrome. Fertil Steril 2005, 84: 1662–4.

    PubMed  Google Scholar 

  127. Selice R, Di Mambro A, Garolla A, et al. Spermatogenesis in Klinefelter syndrome. J Endocrinol Invest 2010 [Epub ahead of print].

  128. Yarali H, Polat M, Bozdag G, et al. TESE-ICSI in patients with nonmosaic Klinefelter syndrome: a comparative study. Reprod Biomed Online 2009, 18: 756–60.

    PubMed  Google Scholar 

  129. Bielanska M, Tan SL, Ao A. Fluorescence in-situ hybridization of sex chromosomes in spermatozoa and spare preimplantation embryos of a Klinefelter 47, XY/47, XXY male. Hum Reprod 2000, 15: 440–4.

    PubMed  CAS  Google Scholar 

  130. Staessen C, Tournaye H, Van Assche E, et al. PGD in 47, XXY Klinefelter’s syndrome patients. Hum Reprod Update 2003, 9: 319–30.

    PubMed  CAS  Google Scholar 

  131. Paduch DA, Fine RG, Bolyakov A, Kiper J. New concepts in Klinefelter syndrome. Curr Opin Urol 2008, 18: 621–7.

    PubMed  Google Scholar 

  132. Yoshida A, Miura K, Nagao K, Hara H, Ishii N, Shirai M. Sexual function and clinical features of patients with Klinefelter’s syndrome with the chief complaint of male infertility. Int J Androl 1997, 20: 80–5.

    PubMed  CAS  Google Scholar 

  133. Corona G, Petrone L, Paggi F, et al. Sexual dysfunction in subjects with Klinefelter’s syndrome. Int J Androl 2009 Sep 25 (epub ahead of print).

  134. Raboch J, Pietrucha S, Raboch J. Serum testosterone levels and coital activity in men with somatosexual disorders. Neuro Endocrinol Lett 2003, 24: 321–4.

    PubMed  CAS  Google Scholar 

  135. Wu FC, Bancroft J, Davidson DW, Nicol K. The behavioural effects of testosterone undecanoate in adult men with Klinefelter’s syndrome: a controlled study. Clin Endocrinol (Oxf) 1982, 16: 489–97.

    CAS  Google Scholar 

  136. Manning MA, Hoyme HE. Diagnosis and management of the adolescent boy with Klinefelter syndrome. Adolesc Med 2002, 13: 367–74.

    PubMed  Google Scholar 

  137. Wikström AM, Dunkel L. Testicularfunction in Klinefelter syndrome. Horm Res 2008, 69: 317–26.

    PubMed  Google Scholar 

  138. Kamischke A, Jürgens H, Hertle L, Berdel WE, Nieschlag E. Cryopreservation of sperm from adolescents and adults with malignancies. J Androl 2004, 25: 586–92.

    PubMed  Google Scholar 

  139. Damani MN, Mittal R, Oates RD. Testicular tissue extraction in a young male with 47,XXY Klinefelter’s syndrome: potential strategy for preservation of fertility Fertil Steril 2001, 76: 1054–6.

    CAS  Google Scholar 

  140. Sahin FI, Yilmaz Z, Yuregir oo, Bulakbasi T, Ozer O, Zeyneloglu HB. Chromosome heteromorphisms: an impact on infertility. J Assist Reprod Genet 2008, 25: 191–5.

    PubMed Central  PubMed  Google Scholar 

  141. Schor EL; American Academy of Pediatrics Task Force on the Family. Family pediatrics: report of the Task Force on the Family. Pediatrics 2003, 111: 1541–71.

    PubMed  Google Scholar 

  142. Sørensen K. Physical and mental development of adolescent males with Klinefelter syndrome. Hormone Research 1992, 37 (Suppl 3): 55–61.

    PubMed  Google Scholar 

  143. Nielsen J, Pelsen B, Sørensen K. Follow-up of 30 Klinefelter males treated with testosterone. Clin Genet 1988, 33: 262–9.

    PubMed  CAS  Google Scholar 

  144. Simm PJ, Zacharin MR. The psychosocial impact of Klinefelter syndrome-a 10 year review. J Pediatr Endocrinol Metab 2006, 19: 499–505.

    PubMed  CAS  Google Scholar 

  145. Wang C, Swerdloff RS, Iranmanesh A, et al. Transdermal testosterone gel improves sexual function, mood, muscle strength, and body composition parameters in hypogonadal men. J Clin Endocrinol Metab 2000, 85: 2839–53.

    PubMed  CAS  Google Scholar 

  146. Cherrier MM, Asthana S, Plymate S, et al. Testosterone supplementation improves spatial and verbal memory in healthy older men. Neurology 2001, 57: 80–8.

    PubMed  CAS  Google Scholar 

  147. Zitzmann M, Depenbusch M, Gromoll J, Nieschlag E. X-chromosome inactivation patterns and androgen receptor functionality influence phenotype and social characteristics as well as pharmacogenetics of testosterone therapy in Klinefelter patients. J Clin Endocrinol Metab 2004, 89: 6208–17.

    PubMed  CAS  Google Scholar 

  148. Scheithauer BW, Moschopulos M, Kovacs K, Jhaveri BS, Percek T, Lloyd RV. The pituitary in Klinefelter syndrome. Endocr Pathol 2005, 16: 133–8.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Rare Diseases Regional Centre, Department of Medical Pathophysiology, Sapienza University of Rome, Rome

    A. F. Radicioni MD & A. Lenzi

  2. Section of Clinical Pathology and Centre for Male Gamete Cryopreservation, Department of Histology, Microbiology and Medical Biotechnologies, University of Padua, Padua

    A. Ferlin & C. Foresta

  3. Andrology Unit, Endocrinology, Department of Internal Medicine and Applied Biotechnologies, Polytechnic University of Ancona, Ancona

    G. Balercia

  4. Endocrine Unit, Department of Clinical and Experimental Medicine and Surgery, Second University of Naples, Naples

    D. Pasquali

  5. Sexual Medicine and Andrology, University of Florence, Florence, Italy

    L. Vignozzi & M. Maggi

Authors
  1. A. F. Radicioni MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A. Ferlin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. G. Balercia
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. D. Pasquali
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. L. Vignozzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M. Maggi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. C. Foresta
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. A. Lenzi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A. F. Radicioni MD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Radicioni, A.F., Ferlin, A., Balercia, G. et al. Consensus statement on diagnosis and clinical management of Klinefelter syndrome. J Endocrinol Invest 33, 839–850 (2010). https://doi.org/10.1007/BF03350351

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03350351

Key-words

Search

Navigation