eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Genetics

Klinefelter Syndrome: Differential Diagnoses & Workup

Author: Harold Chen, MD, MS, FAAP, FACMG, Professor, Departments of Pediatrics, Obstetrics and Gynecology, and Pathology, Director of Genetic Laboratory Services, Louisiana State University Medical Center
Contributor Information and Disclosures

Updated: Jun 10, 2009

Differential Diagnoses

Fragile X Syndrome
Hypogonadism
Marfan Syndrome

Other Problems to Be Considered

Kallmann syndrome
46,XX karyotype (in males)
Infertility

Workup

Laboratory Studies

  • Cytogenetic studies
    • Klinefelter syndrome may be diagnosed prenatally based on cytogenetic analysis of a fetus. 
    • If Klinefelter syndrome is not diagnosed prenatally, the 47,XXY karyotype may manifest as various subtle age-related clinical signs that may prompt chromosomal evaluation.
      • Infants - Hypospadias, small phallus, cryptorchidism, or developmental delay
      • Kindergarten-aged boys and elementary school–aged boys - Language delay, learning disabilities, or behavioral problems
      • Older boys and adolescent males - Eunuchoid body habitus, gynecomastia, or small testes
    • The 47,XXY variant is found in 80-90% of patients.
    • About 10% of patients have mosaicism; karyotypes include 46,XY/47,XXY; 46,XY/48,XXXY; and 47,XXY/48,XXXY.
    • Remaining cases include variants such as the 48,XXYY; 48,XXXY; 49,XXXYY; and 49,XXXXY karyotypes.
    • About 1% of cases are due to a structurally abnormal X in addition to a normal X and Y, such as 47,X,i(Xq)Y and 47,X,del(X)Y.
  • Androgen receptor gene quantitative real-time PCR (AR-qPCR) technique: A simple and reliable screening method for diagnosis of patients with Klinefelter syndrome or other chromosomal disorders involving an aberrant number of X-chromosomes.
  • Gonadal function15
    • During childhood and early puberty: Relatively normal pituitary-gonadal function is observed in 47,XXY individuals.
    • After midpuberty: Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels increase to hypergonadotropic levels, inhibin B decreases to undetectable levels, and testosterone levels return to low or low-normal levels after an initial increase. Hence, most adult males with Klinefelter syndrome display a clear hypergonadotropism with a varying degree of androgen deficiency.
  • Hormone testing
    • A full hormonal evaluation should include FSH, LH, testosterone, estradiol, prolactin, and insulinlike growth factor (IGF)-1 levels.6
    • Cortisol levels should be routinely measured because growing evidence suggests that adrenal steroidogenic deficiency may be seen in 47% of men with Klinefelter syndrome.16
    • Patients aged 12-14 years have high plasma FSH, LH, and estradiol levels and low plasma testosterone levels.
    • In response to administration of human chorionic gonadotropin (hCG), the increase in testosterone levels in patients with Klinefelter syndrome is diminished compared with the general population.
    • Urinary gonadotropin levels are increased because of abnormal Leydig cell function.
    • Serum osteocalcin levels are decreased and the hydroxyl-proline–to-creatinine ratio is increased, reflecting decreased bone formation and increased bone resorption.
  • Routine bone density screening: This is recommended because decreased testosterone significantly increases the risk of osteopenia and osteoporosis.
  • Hypercoagulability screening: Men with Klinefelter syndrome have an increased risk of deep vein thrombosis and pulmonary embolism. Whether screening for mutations that lead to hypercoagulability is indicated in all men with Klinefelter syndrome is unclear.6

Imaging Studies

  • Echocardiography is performed to assess for mitral valve prolapse.
  • Radiography is performed to assess for lower bone mineral density, radioulnar synostosis, and taurodontism.

Histologic Findings

  • Testicular biopsies of a prepubertal Klinefelter syndrome boy may reveal preservation of seminiferous tubules with reduced numbers of germ cells; Sertoli and Leydig cells appear normal.15  
  • The testes in the adult male with Klinefelter syndrome are characterized by extensive fibrosis and hyalinization of the seminiferous tubules and hyperplasia of the interstitium; however, the tubules may show residual foci of spermatogenesis.15
  • Histologic findings may include small, firm testes with seminiferous tubular hyalinization; sclerosis; and atrophy with focal hyperplasia of mostly degenerated Leydig cells. Germ cells are markedly deficient or absent. Spermatogenesis is rare.
  • In patients with mosaicism, progressive degeneration and hyalinization of seminiferous tubules take place after puberty despite the presence of normal-sized testes and spermatogenesis at puberty.
  • Histology of gynecomastic breasts reveals hyperplasia of interductal tissue.

More on Klinefelter Syndrome

Overview: Klinefelter Syndrome
Differential Diagnoses & Workup: Klinefelter Syndrome
Treatment & Medication: Klinefelter Syndrome
Follow-up: Klinefelter Syndrome
Multimedia: Klinefelter Syndrome
References
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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. Jan 2007;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. Sep 2007;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. Jan 2007;99(1):141-6. [Medline].

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

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

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

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

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

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

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

  12. 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. Nov 2001;69(5):1046-54. [Medline]. [Full Text].

  13. 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. Dec 2004;89(12):6208-17. [Medline].

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

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

  16. 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. Feb 2002;10(2):137-40. [Medline].

  17. 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. Nov 2005;90(11):6263-7. [Medline].

  18. 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. Nov 2001;76(5):1054-6. [Medline].

  19. 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). Jul 2006;65(1):92-7. [Medline].

  20. 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. Feb 2003;18(2):271-5. [Medline]. [Full Text].

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

  22. 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].

  23. 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. Aug 2001;76(2):249-53. [Medline].

  24. 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. Apr 1997;12(4):682-6. [Medline]. [Full Text].

  25. 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].

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

  27. 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. Jan 1998;13(1):124-7. [Medline]. [Full Text].

  28. 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. Jul 1998;13(7):1887-92. [Medline]. [Full Text].

  29. 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. Mar 2002;19(3):149-51. [Medline].

  30. 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. Oct 1997;68(4):718-20. [Medline].

  31. 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. Feb 26 1998;338(9):588-90. [Medline].

  32. 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. Oct 2000;74(4):832-3. [Medline].

  33. 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. Sep 2001;16(9):1909-11. [Medline]. [Full Text].

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

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

  36. 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].

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

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

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

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

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

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

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

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

  45. 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. Dec 2001;16(12):2616-20. [Medline]. [Full Text].

  46. 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. Apr 2008;89(4):991.e5-7. [Medline].

  47. 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].

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

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

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

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

  52. 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].

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

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

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

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

  57. 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].

  58. 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. Aug 2000;15(8):1804-6. [Medline]. [Full Text].

  59. 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].

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

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

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

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

  64. 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. Aug 17 2005;97(16):1204-10. [Medline].

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

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

  67. Yoshida A, Miura K, Nagao K, et al. Sexual function and clinical features of patients with Klinefelter's syndrome with the chief complaint of male infertility. Int J Androl. Apr 1997;20(2):80-5. [Medline].

  68. 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. May 28 1966;94(22):1143-54. [Medline].

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Further Reading

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Contributor Information and Disclosures

Author

Harold Chen, MD, MS, FAAP, FACMG, Professor, Departments of Pediatrics, Obstetrics and Gynecology, and Pathology, Director of Genetic Laboratory Services, Louisiana State University Medical Center
Harold Chen, MD, MS, FAAP, FACMG is a member of the following medical societies: American Academy of Pediatrics, American Medical Association, American Society of Human Genetics, and Teratology Society
Disclosure: Nothing to disclose.

Medical Editor

Ian Krantz, MD, Department of Pediatrics, Assistant Professor, University of Pennsylvania and Children's Hospital of Philadelphia
Ian Krantz, MD is a member of the following medical societies: American Society of Human Genetics
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Margaret M McGovern, MD, PhD, Professor and Chair of Pediatrics, Stony Brook University, New York
Margaret M McGovern, MD, PhD is a member of the following medical societies: American Academy of Pediatrics and American Society of Human Genetics
Disclosure: Genzyme Grant/research funds PI

CME Editor

Paul D Petry, DO, FACOP, FAAP, Consulting Staff, Freeman Pediatric Care, Freeman Health System
Paul D Petry, DO, FACOP, FAAP is a member of the following medical societies: American Academy of Osteopathy, American Academy of Pediatrics, American College of Osteopathic Pediatricians, and American Osteopathic Association
Disclosure: Nothing to disclose.

Chief Editor

Bruce Buehler, MD, Professor, Department of Pediatrics and Genetics, Director RSA, University of Nebraska Medical Center
Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association
Disclosure: Nothing to disclose.

 
 
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