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Klinefelter Syndrome Differential Diagnoses

  • Author: Harold Chen, MD, MS, FAAP, FACMG; Chief Editor: Luis O Rohena, MD  more...
 
Updated: Jun 08, 2016
 
 

Diagnostic Considerations

These include the following:

  • Kallmann syndrome
  • 46,XX karyotype (in males)
  • Infertility

Differential Diagnoses

 
 
Contributor Information and Disclosures
Author

Harold Chen, MD, MS, FAAP, FACMG Professor, Department of Pediatrics, Louisiana State University Medical Center

Harold Chen, MD, MS, FAAP, FACMG is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics and Genomics, American Medical Association, American Society of Human Genetics

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Lois J Starr, MD, FAAP Assistant Professor of Pediatrics, Clinical Geneticist, Munroe Meyer Institute for Genetics and Rehabilitation, University of Nebraska Medical Center

Lois J Starr, MD, FAAP is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics and Genomics

Disclosure: Nothing to disclose.

Chief Editor

Luis O Rohena, MD Chief, Medical Genetics, San Antonio Military Medical Center; Assistant Professor of Pediatrics, Uniformed Services University of the Health Sciences, F Edward Hebert School of Medicine; Assistant Professor of Pediatrics, University of Texas Health Science Center at San Antonio

Luis O Rohena, MD is a member of the following medical societies: American Academy of Pediatrics, American Chemical Society, American College of Medical Genetics and Genomics, American Society of Human Genetics

Disclosure: Nothing to disclose.

References
  1. Klinefelter HF Jr, Reifenstein EC Jr, Albright F. Syndrome characterized by gynecomastia aspermatogenesis without a-Leydigism and increased excretion of follicle-stimulating hormone. J Clin Endocr Metabl. 1942. 2:615-624.

  2. Giedd JN, Clasen LS, Wallace GL, et al. XXY (Klinefelter syndrome): a pediatric quantitative brain magnetic resonance imaging case-control study. Pediatrics. 2007 Jan. 119(1):e232-40. [Medline]. [Full Text].

  3. Vorona E, Zitzmann M, Gromoll J, Schuring AN, Nieschlag E. Clinical, endocrinological, and epigenetic features of the 46,XX male syndrome, compared with 47,XXY Klinefelter patients. J Clin Endocrinol Metab. 2007 Sep. 92(9):3458-65. [Medline]. [Full Text].

  4. Seo JT, Lee JS, Oh TH, Joo KJ. The clinical significance of bone mineral density and testosterone levels in Korean men with non-mosaic Klinefelter's syndrome. BJU Int. 2007 Jan. 99(1):141-6. [Medline].

  5. Rovenský J. Rheumatic diseases and Klinefelter's syndrome. Autoimmun Rev. 2006 Nov. 6(1):33-6. [Medline].

  6. Paduch DA, Fine RG, Bolyakov A, Kiper J. New concepts in Klinefelter syndrome. Curr Opin Urol. 2008 Nov. 18(6):621-7. [Medline].

  7. Close S, Fennoy I, Smaldone A, Reame N. Phenotype and Adverse Quality of Life in Boys with Klinefelter Syndrome. J Pediatr. 2015 Sep. 167 (3):650-7. [Medline].

  8. Paduch DA, Bolyakov A, Cohen P, Travis A. Reproduction in men with Klinefelter syndrome: the past, the present, and the future. Semin Reprod Med. 2009 Mar. 27(2):137-48. [Medline].

  9. Sokol RZ. It's not all about the testes: medical issues in Klinefelter patients. Fertil Steril. 2012 Aug. 98(2):261-5. [Medline].

  10. Robinson A, Bender BG, Linden MG, Salbenblatt JA. Sex chromosome aneuploidy: the Denver Prospective Study. Birth Defects Orig Artic Ser. 1990. 26(4):59-115. [Medline].

  11. Visootsak J, Aylstock M, Graham JM Jr. Klinefelter syndrome and its variants: an update and review for the primary pediatrician. Clin Pediatr (Phila). 2001 Dec. 40(12):639-51. [Medline].

  12. Boks MP, de Vette MH, Sommer IE, et al. Psychiatric morbidity and X-chromosomal origin in a Klinefelter sample. Schizophr Res. 2007 Jul. 93(1-3):399-402. [Medline].

  13. Völkl TM, Langer T, Aigner T, Greess H, Beck JD, Rauch AM, et al. Klinefelter syndrome and mediastinal germ cell tumors. Am J Med Genet A. 2006 Mar 1. 140(5):471-81. [Medline].

  14. Boada R, Janusz J, Hutaff-Lee C, Tartaglia N. The cognitive phenotype in Klinefelter syndrome: a review of the literature including genetic and hormonal factors. Dev Disabil Res Rev. 2009. 15(4):284-94. [Medline].

  15. Hong DS, Reiss AL. Cognitive and neurological aspects of sex chromosome aneuploidies. Lancet Neurol. 2014 Mar. 13(3):306-18. [Medline].

  16. [Guideline] Centre for Women's and Children's Health. Fertility: assessment and treatment for people with fertility problems. 2004 Feb. 216. [Full Text].

  17. Lee YS, Cheng AW, Ahmed SF, Shaw NJ, Hughes IA. Genital anomalies in Klinefelter's syndrome. Horm Res. 2007. 68(3):150-5. [Medline].

  18. Salzano A, Arcopinto M, Marra AM, et al. Klinefelter syndrome, cardiovascular system, and thromboembolic disease: review of literature and clinical perspectives. Eur J Endocrinol. 2016 Jul. 175 (1):R27-40. [Medline]. [Full Text].

  19. Zoller B, Ji J, Sundquist J, Sundquist K. High Risk of Venous Thromboembolism in Klinefelter Syndrome. J Am Heart Assoc. 2016 May 20. 5 (5):[Medline].

  20. Tartaglia N, Ayari N, Howell S, D'Epagnier C, Zeitler P. 48,XXYY, 48,XXXY and 49,XXXXY syndromes: not just variants of Klinefelter syndrome. Acta Paediatr. 2011 Jun. 100(6):851-60. [Medline]. [Full Text].

  21. Jacobs PA, Strong JA. A case of human intersexuality having a possible XXY sex-determining mechanism. Nature. 1959 Jan 31. 183(4657):302-3. [Medline].

  22. Thomas NS, Hassold TJ. Aberrant recombination and the origin of Klinefelter syndrome. Hum Reprod Update. 2003 Jul-Aug. 9(4):309-17. [Medline]. [Full Text].

  23. Lowe X, Eskenazi B, Nelson DO, Kidd S, Alme A, Wyrobek AJ. Frequency of XY sperm increases with age in fathers of boys with Klinefelter syndrome. Am J Hum Genet. 2001 Nov. 69(5):1046-54. [Medline]. [Full Text].

  24. 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 Dec. 89(12):6208-17. [Medline].

  25. Bojesen A, Gravholt CH. Klinefelter syndrome in clinical practice. Nat Clin Pract Urol. 2007 Apr. 4(4):192-204. [Medline].

  26. Wikstrom AM, Dunkel L. Testicular function in Klinefelter syndrome. Horm Res. 2008. 69(6):317-26. [Medline].

  27. Mantovani V, Dondi E, Larizza D, et al. Do reduced levels of steroid 21-hydroxylase confer a survival advantage in fetuses affected by sex chromosome aberrations?. Eur J Hum Genet. 2002 Feb. 10(2):137-40. [Medline].

  28. Samango-Sprouse C, Stapleton EJ, Lawson P, et al. Positive effects of early androgen therapy on the behavioral phenotype of boys with 47,XXY. Am J Med Genet C Semin Med Genet. 2015 Jun. 169 (2):150-7. [Medline].

  29. Schiff JD, Palermo GD, Veeck LL, et al. Success of testicular sperm injection and intracytoplasmic sperm injection in men with Klinefelter syndrome. J Clin Endocrinol Metab. 2005 Nov. 90(11):6263-7. [Medline].

  30. 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 Nov. 76(5):1054-6. [Medline].

  31. Wikstrom AM, Painter JN, Raivio T, Aittomaki K, Dunkel L. Genetic features of the X chromosome affect pubertal development and testicular degeneration in adolescent boys with Klinefelter syndrome. Clin Endocrinol (Oxf). 2006 Jul. 65(1):92-7. [Medline].

  32. Ramasamy R, Ricci JA, Palermo GD, Gosden LV, Rosenwaks Z, Schlegel PN. Successful fertility treatment for Klinefelter's syndrome. J Urol. 2009 Sep. 182(3):1108-13. [Medline].

  33. Tournaye H, Staessen C, Liebaers I, et al. Testicular sperm recovery in nine 47,XXY Klinefelter patients. Hum Reprod. 1996 Aug. 11(8):1644-9. [Medline]. [Full Text].

  34. Westlander G, Ekerhovd E, Granberg S, Hanson L, Hanson C, Bergh C. Testicular ultrasonography and extended chromosome analysis in men with non mosaic Klinefelter syndrome: a prospective study of possible predictive factors for successful sperm recovery. Fertil Steril. 2001. 75:1102-1105. [Medline].

  35. Aboulghar H, Aboulghar M, Mansour R, Serour G, Amin Y, Al-Inany H. A prospective controlled study of karyotyping for 430 consecutive babies conceived through intracytoplasmic sperm injection. Fertil Steril. 2001 Aug. 76(2):249-53. [Medline].

  36. Van Opstal D, Los FJ, Ramlakhan S, et al. Determination of the parent of origin in nine cases of prenatally detected chromosome aberrations found after intracytoplasmic sperm injection. Hum Reprod. 1997 Apr. 12(4):682-6. [Medline]. [Full Text].

  37. Bonduelle M, Aytoz A, Van Assche E, Devroey P, Liebars I, VanSteirteghem A. Incidence of chromosomal aberrations in childrenborn after assisted reproduction through intracytoplasmic sperm injection. Hum Reprod. 1998. 13:781-782. [Medline]. [Full Text].

  38. Staessen C, Coonen E, Van Assche E, et al. Preimplantation diagnosis for X and Y normality in embryos from three Klinefelter patients. Hum Reprod. 1996 Aug. 11(8):1650-3. [Medline]. [Full Text].

  39. Estop AM, Munne S, Cieply KM, Vandermark KK, Lamb AN, Fisch H. Meiotic products of a Klinefelter 47,XXY male as determined by sperm fluorescence in-situ hybridization analysis. Hum Reprod. 1998 Jan. 13(1):124-7. [Medline]. [Full Text].

  40. Reubinoff BE, Abeliovich D, Werner M, Schenker JG, Safran A, Lewin A. A birth in non-mosaic Klinefelter's syndrome after testicular fine needle aspiration, intracytoplasmic sperm injection and preimplantation genetic diagnosis. Hum Reprod. 1998 Jul. 13(7):1887-92. [Medline]. [Full Text].

  41. Rosenlund B, Hreinsson JG, Hovatta O. Birth of a healthy male after frozen thawed blastocyst transfer following intracytoplasmic injection of frozen thawed testicular spermatozoa from a man with nonmosaic Klinefelter's syndrome. J Assist Reprod Genet. 2002 Mar. 19(3):149-51. [Medline].

  42. Hinney B, Guttenbach M, Schmid M, Engel W, Michelmann HW. Pregnancy after intracytoplasmic sperm injection with sperm from a man with a 47,XXY Klinefelter's karyotype. Fertil Steril. 1997 Oct. 68(4):718-20. [Medline].

  43. Palermo GD, Schlegel PN, Sills ES, et al. Births after intracytoplasmic injection of sperm obtained by testicular extraction from men with nonmosaic Klinefelter's syndrome. N Engl J Med. 1998 Feb 26. 338(9):588-90. [Medline].

  44. Ron-El R, Raziel A, Strassburger D, Schachter M, Bern O, Friedler S. Birth of healthy male twins after intracytoplasmic sperm injection of frozen-thawed testicular spermatozoa from a patient with nonmosaic Klinefelter syndrome. Fertil Steril. 2000 Oct. 74(4):832-3. [Medline].

  45. Crüger D, Toft B, Agerholm I, Fedder J, Hald F, Bruun-Petersen G. Birth of a healthy girl after ICSI with ejaculated spermatozoa from a man with non-mosaic Klinefelter's syndrome. Hum Reprod. 2001 Sep. 16(9):1909-11. [Medline]. [Full Text].

  46. Tachdjian G, Frydman N, Morichon-Delvallez N, et al. Reproductive genetic counselling in non-mosaic 47,XXY patients: implications for preimplantation or prenatal diagnosis: Case report and review. Hum Reprod. 2003 Feb. 18(2):271-5. [Medline]. [Full Text].

  47. Close S, Sadler L, Grey M. In the Dark: Challenges of Caring for Sons with Klinefelter Syndrome. J Pediatr Nurs. 2015 May 30. [Medline].

  48. Aguirre D, Nieto K, Lazos M, et al. Extragonadal germ cell tumors are often associated with Klinefelter syndrome. Hum Pathol. 2006 Apr. 37(4):477-80. [Medline].

  49. van Rijn S, Swaab H. Vulnerability for psychopathology in Klinefelter syndrome: age-specific and cognitive-specific risk profiles. Acta Paediatr. 2011 Jun. 100(6):908-16. [Medline].

  50. Campbell WA, Price WH. Venous thromboembolic disease in Klinefelter's syndrome. Clin Genet. 1981 Apr. 19(4):275-80. [Medline].

  51. Bardsley MZ, Falkner B, Kowal K, Ross JL. Insulin resistance and metabolic syndrome in prepubertal boys with Klinefelter syndrome. Acta Paediatr. 2011 Jun. 100(6):866-70. [Medline].

  52. Lahlou N, Fennoy I, Ross JL, Bouvattier C, Roger M. Clinical and hormonal status of infants with nonmosaic XXY karyotype. Acta Paediatr. 2011 Jun. 100(6):824-829. [Medline].

  53. Herlihy AS, McLachlan RI, Gillam L, Cock ML, Collins V, Halliday JL. The psychosocial impact of Klinefelter syndrome and factors influencing quality of life. Genet Med. 2011 Jul. 13(7):632-642. [Medline].

  54. 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. Sep 1996. 81(9):3341-5. [Medline].

  55. Bagatell CJ, Bremner WJ. Androgens in men--uses and abuses. N Engl J Med. 1996 Mar 14. 334(11):707-14. [Medline].

  56. Bender BG, Harmon RJ, Linden MG, Robinson A. Psychosocial adaptation of 39 adolescents with sex chromosome abnormalities. Pediatrics. 1995 Aug. 96(2 Pt 1):302-8. [Medline].

  57. Bhasin S, Ma K, Sinha I, et al. The genetic basis of male infertility. Endocrinol Metab Clin North Am. 1998 Dec. 27(4):783-805, viii. [Medline].

  58. Bojesen A, Juul S, Gravholt CH. Prenatal and postnatal prevalence of Klinefelter syndrome: a national registry study. J Clin Endocrinol Metab. 2003 Feb. 88(2):622-6. [Medline].

  59. Chen H. Klinefelter syndrome. Atlas of Genetic Diagnosis and Counseling. Totowa, New Jersey: Humana Press; 2006. 570-574.

  60. De la Chapelle A. Sex Chromosome Abnormalities. Emery AEH, Rimoin DL, eds. Principles and Practice of Medical Genetics. Edinburgh, England: Churchill Livingstone; 1990. Vol 1: 273-299.

  61. Denschlag D, Tempfer C, Kunze M, Wolff G, Keck C. Assisted reproductive techniques in patients with Klinefelter syndrome: a critical review. Fertil Steril. 2004 Oct. 82(4):775-9. [Medline].

  62. Ferrier PE, Ferrier SA, Pescia G. The XXXY Klinefelter syndrome in childhood. Am J Dis Child. 1974 Jan. 127(1):104-5. [Medline].

  63. 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 Dec. 16(12):2616-20. [Medline]. [Full Text].

  64. Greco E, Iacobelli M, Rienzi L, Fabris GF, Tesorio N, Tesarik J. Birth of a healthy boy after fertilization of cryopreserved oocytes with cryopreserved testicular spermatozoa from a man with nonmosaic Klinefelter syndrome. Fertil Steril. 2008 Apr. 89(4):991.e5-7. [Medline].

  65. Kamischke A, Baumgardt A, Horst J, Nieschlag E. Clinical and diagnostic features of patients with suspected klinefelter syndrome. J Androl. Jan-Feb 2003. 24(1):41-8. [Medline]. [Full Text].

  66. Kleczkowska A, Fryns JP, Van den Berghe H. X-chromosome polysomy in the male. The Leuven experience 1966-1987. Hum Genet. 1988 Sep. 80(1):16-22. [Medline].

  67. Krausz C, Forti G. Sperm cryopreservation in male infertility due to genetic disorders. Cell Tissue Bank. 2006. 7(2):105-12. [Medline].

  68. Linden MG, Bender BG, Robinson A. Sex chromosome tetrasomy and pentasomy. Pediatrics. 1995 Oct. 96(4 Pt 1):672-82. [Medline].

  69. Mandoki MW, Sumner GS, Hoffman RP, Riconda DL. A review of Klinefelter's syndrome in children and adolescents. J Am Acad Child Adolesc Psychiatry. 1991 Mar. 30(2):167-72. [Medline].

  70. Meschede D, Louwen F, Nippert I. Low rates of pregnancy termination for prenatally diagnosed Klinefelter syndrome and other sex chromosome polysomies. Am J Med Genet. Dec 4 1998. 80(4):330-4. [Medline].

  71. Nielsen J, Pelsen B, Sorensen K. Follow-up of 30 Klinefelter males treated with testosterone. Clin Genet. 1988 Apr. 33(4):262-9. [Medline].

  72. Peet J, Weaver DD, Vance GH. 49,XXXXY: a distinct phenotype. Three new cases and review. J Med Genet. 1998 May. 35(5):420-4. [Medline].

  73. Ratcliffe SG, Bancroft J, Axworthy D, McLaren W. Klinefelter's syndrome in adolescence. Arch Dis Child. 1982 Jan. 57(1):6-12. [Medline].

  74. Robinson A, Bender BG, Linden MG. Prognosis of prenatally diagnosed children with sex chromosome aneuploidy. Am J Med Genet. 1992 Oct 1. 44(3):365-8. [Medline].

  75. Robinson A, Lubs HA, Nielsen J, Sorensen K. Summary of clinical findings: profiles of children with 47,XXY, 47,XXX and 47,XYY karyotypes. Birth Defects Orig Artic Ser. 1979. 15(1):261-6. [Medline].

  76. Ron-El R, Strassburger D, Gelman-Kohan S, Friedler S, Raziel A, Appelman Z. A 47,XXY fetus conceived after ICSI of spermatozoa from a patient with non-mosaic Klinefelter's syndrome: case report. Hum Reprod. 2000 Aug. 15(8):1804-6. [Medline]. [Full Text].

  77. Schulte-Beerbuhl M, Nieschlag E. Comparison of testosterone, dihydrotestosterone, luteinizing hormone, and follicle-stimulating hormone in serum after injection of testosterone enanthate of testosterone cypionate. Fertil Steril. Feb 1980. 33(2):201-3. [Medline].

  78. Schwartz ID, Root AW. The Klinefelter syndrome of testicular dysgenesis. Endocrinol Metab Clin North Am. 1991 Mar. 20(1):153-63. [Medline].

  79. Smith S. Index of suspicion. Case 1. Diagnosis: Klinefelter syndrome. Pediatr Rev. 1992 Nov. 13(11):435-6. [Medline].

  80. Smyth CM, Bremner WJ. Klinefelter syndrome. Arch Intern Med. 1998 Jun 22. 158(12):1309-14. [Medline].

  81. Swerdlow AJ, Higgins CD, Schoemaker MJ, et al. Mortality in patients with Klinefelter syndrome in Britain: a cohort study. J Clin Endocrinol Metab. 2005 Dec. 90(12):6516-22. [Medline].

  82. Swerdlow AJ, Schoemaker MJ, Higgins CD, Wright AF, Jacobs PA,. Cancer incidence and mortality in men with Klinefelter syndrome: a cohort study. J Natl Cancer Inst. 2005 Aug 17. 97(16):1204-10. [Medline].

  83. Visootsak J, Graham JM Jr. Klinefelter syndrome and other sex chromosomal aneuploidies. Orphanet J Rare Dis. 2006. 1:42. [Medline].

  84. Wattendorf DJ, Muenke M. Klinefelter syndrome. Am Fam Physician. 2005 Dec 1. 72(11):2259-62. [Medline].

  85. 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 Apr. 20(2):80-5. [Medline].

  86. Zaleski WA, Houston CS, Pozsonyi J, Ying KL. The XXXXY chromosome anomaly: report of three new cases and review of 30 cases from the literature. Can Med Assoc J. 1966 May 28. 94(22):1143-54. [Medline].

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Adolescent male with gynecomastia and Klinefelter syndrome.
Child with Klinefelter syndrome. Other than a thin build and disproportionately long arms and legs, the phenotype is normal.
G-banded 47,XXY karyotype.
Adolescent male with Klinefelter syndrome who has female-type distribution of pubic hair and testicular dysgenesis.
 
 
 
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