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Congenital Causes of Hypergonadotropic Hypogonadism: Anorchia and Klinefelter Syndrome

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Pediatric and Adolescent Andrology

Part of the book series: Trends in Andrology and Sexual Medicine ((TASM))

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Abstract

Congenital hypergonadotropic (primary) hypogonadism in males is most commonly due to anorchia or to Klinefelter syndrome (KS, 47, XXY).

Anorchia is defined as the absence of testes in a 46,XY individual with a male phenotype. Male infants with anorchia typically present with normal penile size, although the presence of micropenis has been reported. The presence of fully developed male genital tract suggests that functional testes were present but disappeared in utero. The incidence is 1 out of 20,000, and the reports of some familial cases suggest a genetic origin, at least in these cases.

KS is the most frequent sex chromosome disorder in the male affecting 1 in 660 newborn boys. KS is characterized by primary testicular failure with small testes, hypergonadotropic hypogonadism, and infertility in almost all patients. Furthermore, patients are at increased risk of having tall stature, eunuchoidism, gynaecomastia, osteoporosis, and metabolic syndrome. However, the phenotypic spectrum is very wide, and the symptoms vary with age and sexual development.

In the majority of patients with hypogonadism regardless of etiology, testosterone replacement is needed in adolescence and adulthood. Testosterone replacement already during the transient hypothalamic-pituitary-gonadal (HPG) hormone axis activation in minipuberty appears to be a biologically sound principle but remains experimental.

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References

  1. Aynsley-Green A, Zachmann M, Illig R, Rampini S, Prader A. Congenital bilateral anorchia in childhood: a clinical, endocrine and therapeutic evaluation of twenty-one cases. Clin Endocrinol. 1976;5(4):381–91.

    Article  CAS  Google Scholar 

  2. Smith NM, Byard RW, Bourne AJ. Testicular regression syndrome--a pathological study of 77 cases. Histopathology. 1991;19(3):269–72.

    Article  CAS  PubMed  Google Scholar 

  3. Philibert P, Zenaty D, Lin L, Soskin S, Audran F, Leger J, et al. Mutational analysis of steroidogenic factor 1 (NR5a1) in 24 boys with bilateral anorchia: a French collaborative study. Hum Reprod. 2007;22(12):3255–61.

    Article  CAS  PubMed  Google Scholar 

  4. Brauner R, Neve M, Allali S, Trivin C, Lottmann H, Bashamboo A, et al. Clinical, biological and genetic analysis of anorchia in 26 boys. PLoS One. 2011;6(8):e23292.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Zenaty D, Dijoud F, Morel Y, Cabrol S, Mouriquand P, Nicolino M, et al. Bilateral anorchia in infancy: occurence of micropenis and the effect of testosterone treatment. J Pediatr. 2006;149(5):687–91.

    Article  CAS  PubMed  Google Scholar 

  6. Lee MM, Donahoe PK, Silverman BL, Hasegawa T, Hasegawa Y, Gustafson ML, et al. Measurements of serum mullerian inhibiting substance in the evaluation of children with nonpalpable gonads. N Engl J Med. 1997;336(21):1480–6.

    Article  CAS  PubMed  Google Scholar 

  7. McEachern R, Houle AM, Garel L, Van VG. Lost and found testes: the importance of the hCG stimulation test and other testicular markers to confirm a surgical declaration of anorchia. Horm Res. 2004;62(3):124–8.

    CAS  PubMed  Google Scholar 

  8. De RM, Lupoli G, Mennitti M, Zarrilli S, Mirone V, Lombardi G. Congenital bilateral anorchia: clinical, hormonal and imaging study in 12 cases. Andrologia. 1996;28(5):281–5.

    Google Scholar 

  9. Jacobs PA, Strong JA. A case of human intersexuality having a possible XXY sex-determining mechanism. Nature. 1959;183(4657):302–3.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  11. Swerdlow AJ, Higgins CD, Schoemaker MJ, Wright AF, Jacobs PA. Mortality in patients with Klinefelter syndrome in Britain: a cohort study. J Clin Endocrinol Metab. 2005;90(12):6516–22.

    Article  CAS  PubMed  Google Scholar 

  12. Lanfranco F, Kamischke A, Zitzmann M, Nieschlag E. Klinefelter’s syndrome. Lancet. 2004;364(9430):273–83.

    Article  CAS  PubMed  Google Scholar 

  13. 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(4):209–23.

    CAS  PubMed  Google Scholar 

  14. Van Assche E, Bonduelle M, Tournaye H, Joris H, Verheyen G, Devroey P, et al. Cytogenetics of infertile men. Hum Reprod. 1996;11(Suppl 4):1–24.

    Article  PubMed  Google Scholar 

  15. Aksglaede L, Skakkebaek NE, Almstrup K, Juul A. Clinical and biological parameters in 166 boys, adolescents and adults with nonmosaic Klinefelter syndrome: a Copenhagen experience. Acta Paediatr. 2011;100(6):793–806.

    Article  PubMed  Google Scholar 

  16. Bianchi DW, Wilkins-Haug L. Integration of noninvasive DNA testing for aneuploidy into prenatal care: what has happened since the rubber met the road? Clin Chem. 2014;60(1):78–87.

    Article  CAS  PubMed  Google Scholar 

  17. Maiburg M, Repping S, Giltay J. The genetic origin of Klinefelter syndrome and its effect on spermatogenesis. Fertil Steril. 2012;98(2):253–60.

    Article  PubMed  Google Scholar 

  18. Gravholt CH, Chang S, Wallentin M, Fedder J, Moore P, Skakkebaek A. Klinefelter syndrome: integrating genetics, neuropsychology, and endocrinology. Endocr Rev. 2018;39(4):389–423.

    Article  PubMed  Google Scholar 

  19. Zinn AR, Ramos P, Elder FF, Kowal K, Samango-Sprouse C, Ross JL. Androgen receptor CAGn repeat length influences phenotype of 47,XXY (Klinefelter) syndrome. J Clin Endocrinol Metab. 2005;14

    Google Scholar 

  20. 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(12):6208–17.

    Article  CAS  PubMed  Google Scholar 

  21. Bojesen A, Hertz JM, Gravholt CH. Genotype and phenotype in Klinefelter syndrome - impact of androgen receptor polymorphism and skewed X inactivation. Int J Androl. 2011;34(6 Pt 2):e642–8.

    Article  CAS  PubMed  Google Scholar 

  22. Ferlin A, Schipilliti M, Vinanzi C, Garolla A, Di Mambro A, Selice R, 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):739–45.

    Article  CAS  Google Scholar 

  23. 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. 2006;65(1):92–7.

    Article  CAS  Google Scholar 

  24. Ross JL, Roeltgen DP, Stefanatos G, Benecke R, Zeger MP, Kushner H, et al. Cognitive and motor development during childhood in boys with Klinefelter syndrome. Am J Med Genet A. 2008;146A(6):708–19.

    Article  PubMed  Google Scholar 

  25. Chang S, Skakkebaek A, Trolle C, Bojesen A, Hertz JM, Cohen A, 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):E508–17.

    Article  CAS  PubMed  Google Scholar 

  26. Ross NL, Wadekar R, Lopes A, Dagnall A, Close J, Delisi LE, et al. Methylation of two Homo sapiens-specific X-Y homologous genes in Klinefelter’s syndrome (XXY). Am J Med Genet B Neuropsychiatr Genet. 2006;141B(5):544–8.

    Article  CAS  PubMed  Google Scholar 

  27. Zeger MP, Zinn AR, Lahlou N, Ramos P, Kowal K, Samango-Sprouse C, et al. Effect of ascertainment and genetic features on the phenotype of Klinefelter syndrome. J Pediatr. 2008;152(5):716–22.

    Article  PubMed  Google Scholar 

  28. Stemkens D, Roza T, Verrij L, Swaab H, van Werkhoven M, Alizadeh B, et al. Is there an influence of X-chromosomal imprinting on the phenotype in Klinefelter syndrome? A clinical and molecular genetic study of 61 cases. Clin Genet. 2006;70(1):43–8.

    Article  CAS  PubMed  Google Scholar 

  29. Ottesen AM, Aksglaede L, Garn I, Tartaglia N, Tassone F, Gravholt CH, et al. Increased number of sex chromosomes affects height in a nonlinear fashion: a study of 305 patients with sex chromosome aneuploidy. Am J Med Genet A. 2010;152A(5):1206–12.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Skakkebaek A, Nielsen MM, Trolle C, Vang S, Hornshoj H, Hedegaard J, et al. DNA hypermethylation and differential gene expression associated with Klinefelter syndrome. Sci Rep. 2018;8(1):13,740.

    Article  CAS  Google Scholar 

  31. Belling K, Russo F, Jensen AB, Dalgaard MD, Westergaard D, Rajpert-De ME, et al. Klinefelter syndrome comorbidities linked to increased X chromosome gene dosage and altered protein interactome activity. Hum Mol Genet. 2017;26(7):1219–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Liu X, Tang D, Zheng F, Xu Y, Guo H, Zhou J, et al. Single-cell sequencing reveals the relationship between phenotypes and genotypes of Klinefelter syndrome. Cytogenet Genome Res. 2019;159:55–65.

    Article  CAS  PubMed  Google Scholar 

  33. Winge SB, Dalgaard MD, Belling KG, Jensen JM, Nielsen JE, Aksglaede L, et al. Transcriptome analysis of the adult human Klinefelter testis and cellularity-matched controls reveals disturbed differentiation of Sertoli- and Leydig cells. Cell Death Dis. 2018;9(6):586.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Winge SB, Dalgaard MD, Jensen JM, Graem N, Schierup MH, Juul A, et al. Transcriptome profiling of fetal Klinefelter testis tissue reveals a possible involvement of long non-coding RNAs in gonocyte maturation. Hum Mol Genet. 2018;27(3):430–9.

    Article  CAS  PubMed  Google Scholar 

  35. Huang J, Zhang L, Deng H, Chang L, Liu Q, Liu P. Global transcriptome analysis of peripheral blood identifies the most significantly down-regulated genes associated with metabolism regulation in Klinefelter syndrome. Mol Reprod Dev. 2015;82(1):17–25.

    Article  CAS  PubMed  Google Scholar 

  36. Laurentino S, Heckmann L, Di PS, Li X, Meyer Zu HG, Wistuba J, et al. High-resolution analysis of germ cells from men with sex chromosomal aneuploidies reveals normal transcriptome but impaired imprinting. Clin Epigenetics. 2019;11(1):127.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. 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(1):39–45.

    CAS  PubMed  Google Scholar 

  38. Bojesen A, Juul S, Birkebaek NH, Gravholt CH. Morbidity in Klinefelter syndrome: a Danish register study based on hospital discharge diagnoses. J Clin Endocrinol Metab. 2006;91(4):1254–60.

    Article  CAS  PubMed  Google Scholar 

  39. Aksglaede L, Petersen JH, Main KM, Skakkebaek NE, Juul A. High normal testosterone levels in infants with non-mosaic Klinefelter’s syndrome. Eur J Endocrinol. 2007;157(3):345–50.

    Article  CAS  PubMed  Google Scholar 

  40. Cabrol S, Ross JL, Fennoy I, Bouvattier C, Roger M, Lahlou N. Assessment of Leydig and Sertoli cell functions in infants with nonmosaic Klinefelter syndrome: insulin-like peptide 3 levels are normal and positively correlated with LH levels. J Clin Endocrinol Metab. 2011;96(4):E746–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Lahlou N, Fennoy I, Carel JC, Roger M. Inhibin B and anti-Mullerian hormone, but not testosterone levels, are normal in infants with nonmosaic Klinefelter syndrome. J Clin Endocrinol Metab. 2004;89(4):1864–8.

    Article  CAS  PubMed  Google Scholar 

  42. Aksglaede L, Christiansen P, Sorensen K, Boas M, Linneberg A, Main KM, et al. Serum concentrations of anti-Mullerian hormone (AMH) in 95 patients with Klinefelter syndrome with or without cryptorchidism. Acta Paediatr. 2011;100(6):839–45.

    Article  CAS  PubMed  Google Scholar 

  43. Fennoy I. Testosterone and the child (0-12 years) with Klinefelter syndrome (47XXY): a review. Acta Paediatr. 2011;100(6):846–50.

    Article  CAS  PubMed  Google Scholar 

  44. Ratcliffe SG, Butler GE, Jones M. Edinburgh study of growth and development of children with sex chromosome abnormalities. IV Birth defects. Orig Artic Ser. 1990;26(4):1–44.

    CAS  Google Scholar 

  45. 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(1):169–76.

    Article  CAS  PubMed  Google Scholar 

  46. Bardsley MZ, Falkner B, Kowal K, Ross JL. Insulin resistance and metabolic syndrome in prepubertal boys with Klinefelter syndrome. Acta Paediatr. 2011;100(6):866–70.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Close S, Fennoy I, Smaldone A, Reame N. Phenotype and adverse quality of life in boys with Klinefelter syndrome. J Pediatr. 2015;167(3):650–7.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Davis S, Lahlou N, Bardsley M, Temple MC, Kowal K, Pyle L, et al. Gonadal function is associated with cardiometabolic health in pre-pubertal boys with Klinefelter syndrome. Andrology. 2016;4(6):1169–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Wikstrom 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. Pediatr Res. 2006;59(6):854–9.

    Article  PubMed  Google Scholar 

  50. 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(1):8–12.

    Article  CAS  PubMed  Google Scholar 

  51. 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):888–91.

    Article  CAS  PubMed  Google Scholar 

  52. 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(1):82–6.

    Article  CAS  PubMed  Google Scholar 

  53. Bastida MG, Rey RA, Bergada I, Bedecarras P, Andreone L, del Rey G, et al. Establishment of testicular endocrine function impairment during childhood and puberty in boys with Klinefelter syndrome. Clin Endocrinol. 2007;67(6):863–70.

    Article  CAS  Google Scholar 

  54. Wikstrom AM, Bay K, Hero M, Andersson AM, Dunkel L. Serum insulin-like factor 3 levels during puberty in healthy boys and boys with Klinefelter syndrome. J Clin Endocrinol Metab. 2006;91(11):4705–8.

    Article  CAS  PubMed  Google Scholar 

  55. Ratcliffe SG, Murray L, Teague P. Edinburgh study of growth and development of children with sex chromosome abnormalities. III. Birth defects. Orig Artic Ser. 1986;22(3):73–118.

    CAS  Google Scholar 

  56. Robinson A, Bender BG, Borelli JB, Puck MH, Salbenblatt JA, Winter JS. Sex chromosomal aneuploidy: prospective and longitudinal studies. Birth Defects Orig Artic Ser. 1986;22(3):23–71.

    CAS  PubMed  Google Scholar 

  57. Wikstrom AM, Raivio T, Hadziselimovic F, Wikstrom 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(5):2263–70.

    Article  PubMed  CAS  Google Scholar 

  58. Mieritz MG, Raket LL, Hagen CP, Nielsen JE, Talman ML, Petersen JH, et al. A longitudinal study of growth, sex steroids, and IGF-1 in boys with physiological gynecomastia. J Clin Endocrinol Metab. 2015;100(10):3752–9.

    Article  CAS  PubMed  Google Scholar 

  59. Ratcliffe SG, Bancroft J, Axworthy D, McLaren W. Klinefelter’s syndrome in adolescence. Arch Dis Child. 1982;57(1):6–12.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Girardin CM, Lemyre E, Alos N, Deal C, Huot C, Van VG. Comparison of adolescents with Klinefelter syndrome according to the circumstances of diagnosis: amniocentesis versus clinical signs. Horm Res. 2009;72(2):98–105.

    CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  62. Rohayem J, Nieschlag E, Zitzmann M, Kliesch S. Testicular function during puberty and young adulthood in patients with Klinefelter’s syndrome with and without spermatozoa in seminal fluid. Andrology. 2016;4(6):1178–86.

    Article  CAS  PubMed  Google Scholar 

  63. Foresta C, Bettella A, Vinanzi C, Dabrilli P, Meriggiola MC, Garolla A, et al. A novel circulating hormone of testis origin in humans. J Clin Endocrinol Metab. 2004;89(12):5952–8.

    Article  CAS  PubMed  Google Scholar 

  64. Skakkebaek NE. Two types of tubules containing only Sertoli cells in adults with Klinefelter’s syndrome. Nature. 1969;223(206):643–5.

    Article  CAS  PubMed  Google Scholar 

  65. Aksglaede L, Wikstrom AM, Rajpert-De ME, Dunkel L, Skakkebaek NE, Juul A. Natural history of seminiferous tubule degeneration in Klinefelter syndrome. Hum Reprod Update. 2006;12(1):39–48.

    Article  PubMed  Google Scholar 

  66. Foresta C, Galeazzi C, Bettella A, Marin P, Rossato M, Garolla A, et al. Analysis of meiosis in intratesticular germ cells from subjects affected by classic Klinefelter’s syndrome. J Clin Endocrinol Metab. 1999;84(10):3807–10.

    CAS  PubMed  Google Scholar 

  67. Van SD, Vloeberghs V, Gies I, Mateizel I, Sermon K, De SJ, et al. When does germ cell loss and fibrosis occur in patients with Klinefelter syndrome? Hum Reprod. 2018;33(6):1009–22.

    Article  CAS  Google Scholar 

  68. Oates RD. The natural history of endocrine function and spermatogenesis in Klinefelter syndrome: what the data show. Fertil Steril. 2012;98(2):266–73.

    Article  CAS  PubMed  Google Scholar 

  69. Kitamura M, Matsumiya K, Koga M, Nishimura K, Miura H, Tsuji T, et al. Ejaculated spermatozoa in patients with non-mosaic Klinefelter’s syndrome. Int J Urol. 2000;7(3):88–92.

    CAS  PubMed  Google Scholar 

  70. Aksglaede L, Jorgensen N, Skakkebaek NE, Juul A. Low semen volume in 47 adolescents and adults with 47,XXY Klinefelter or 46,XX male syndrome. Int J Androl. 2009;32(4):376–84.

    Article  CAS  PubMed  Google Scholar 

  71. Corona G, Pizzocaro A, Lanfranco F, Garolla A, Pelliccione F, Vignozzi L, et al. Sperm recovery and ICSI outcomes in Klinefelter syndrome: a systematic review and meta-analysis. Hum Reprod Update. 2017;23(3):265–75.

    Article  CAS  PubMed  Google Scholar 

  72. Vloeberghs V, Verheyen G, Santos-Ribeiro S, Staessen C, Verpoest W, Gies I, et al. Is genetic fatherhood within reach for all azoospermic Klinefelter men? PLoS One. 2018;13(7):e0200300.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Garolla A, Selice R, Menegazzo M, Valente U, Zattoni F, Iafrate M, et al. Novel insights on testicular volume and testosterone replacement therapy in Klinefelter patients undergoing testicular sperm extraction. A retrospective clinical study. Clin Endocrinol. 2018;88(5):711–8.

    Article  CAS  Google Scholar 

  74. Westlander G, Ekerhovd E, Bergh C. Low levels of serum inhibin B do not exclude successful sperm recovery in men with nonmosaic Klinefelter syndrome. Fertil Steril. 2003;79(Suppl 3):1680–2.

    Article  PubMed  Google Scholar 

  75. 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(5):1135–9.

    Article  CAS  PubMed  Google Scholar 

  76. Okada H, Goda K, Yamamoto Y, Sofikitis N, Miyagawa I, Mio Y, et al. Age as a limiting factor for successful sperm retrieval in patients with nonmosaic Klinefelter’s syndrome. Fertil Steril. 2005;84(6):1662–4.

    Article  PubMed  Google Scholar 

  77. Ferhi K, Avakian R, Griveau JF, Guille F. Age as only predictive factor for successful sperm recovery in patients with Klinefelter’s syndrome. Andrologia. 2009;41(2):84–7.

    Article  CAS  PubMed  Google Scholar 

  78. 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(11):6263–7.

    Article  CAS  PubMed  Google Scholar 

  79. Koga M, Tsujimura A, Takeyama M, Kiuchi H, Takao T, Miyagawa Y, et al. Clinical comparison of successful and failed microdissection testicular sperm extraction in patients with nonmosaic Klinefelter syndrome. Urology. 2007;70(2):341–5.

    Article  PubMed  Google Scholar 

  80. Plotton I, Giscard ES, Cuzin B, Brosse A, Benchaib M, Lornage J, et al. Preliminary results of a prospective study of testicular sperm extraction in young versus adult patients with nonmosaic 47,XXY Klinefelter syndrome. J Clin Endocrinol Metab. 2015;100(3):961–7.

    Article  CAS  PubMed  Google Scholar 

  81. Emre BM, Erden HF, Kaplancan T, Ciray N, Bener F, Bahceci M. Aging may adversely affect testicular sperm recovery in patients with Klinefelter syndrome. Urology. 2006;68(5):1082–6.

    Article  Google Scholar 

  82. Ramasamy R, Ricci JA, Palermo GD, Gosden LV, Rosenwaks Z, Schlegel PN. Successful fertility treatment for Klinefelter’s syndrome. J Urol. 2009;182(3):1108–13.

    Article  CAS  PubMed  Google Scholar 

  83. Fullerton G, Hamilton M, Maheshwari A. Should non-mosaic Klinefelter syndrome men be labelled as infertile in 2009? Hum Reprod. 2010;25(3):588–97.

    Article  CAS  PubMed  Google Scholar 

  84. Van SD, Gies I, De SJ, Tournaye H, Goossens E. Can pubertal boys with Klinefelter syndrome benefit from spermatogonial stem cell banking? Hum Reprod. 2012;27(2):323–30.

    Article  CAS  Google Scholar 

  85. Nahata L, Yu RN, Paltiel HJ, Chow JS, Logvinenko T, Rosoklija I, et al. Sperm retrieval in adolescents and young adults with Klinefelter syndrome: a prospective, pilot study. J Pediatr. 2016;170:260–5.

    Article  PubMed  Google Scholar 

  86. Franik S, Hoeijmakers Y, D’Hauwers K, Braat DD, Nelen WL, Smeets D, et al. Klinefelter syndrome and fertility: sperm preservation should not be offered to children with Klinefelter syndrome. Hum Reprod. 2016;31(9):1952–9.

    Article  CAS  PubMed  Google Scholar 

  87. Gies I, De SJ, Van SD, Anckaert E, Goossens E, Tournaye H. Failure of a combined clinical- and hormonal-based strategy to detect early spermatogenesis and retrieve spermatogonial stem cells in 47,XXY boys by single testicular biopsy. Hum Reprod. 2012;27:998–1004.

    Article  CAS  PubMed  Google Scholar 

  88. Mehta A, Paduch DA, Schlegel PN. Successful testicular sperm retrieval in adolescents with Klinefelter syndrome treated with at least 1 year of topical testosterone and aromatase inhibitor. Fertil Steril. 2013;100(4):e27.

    Article  PubMed  Google Scholar 

  89. Zganjar A, Nangia A, Sokol R, Ryabets A, Samplaski MK. Fertility in adolescents with Klinefelter syndrome: a survey of current clinical practice. J Clin Endocrinol Metab. 2019;14

    Google Scholar 

  90. Robinson A, Bender BG, Linden MG. Summary of clinical findings in children and young adults with sex chromosome anomalies. Birth Defects Orig Artic Ser. 1990;26(4):225–8.

    CAS  PubMed  Google Scholar 

  91. Pennington BF, Bender B, Puck M, Salbenblatt J, Robinson A. Learning disabilities in children with sex chromosome anomalies. Child Dev. 1982;53(5):1182–92.

    Article  CAS  PubMed  Google Scholar 

  92. Lee NR, Wallace GL, Clasen LS, Lenroot RK, Blumenthal JD, White SL, et al. Executive function in young males with Klinefelter (XXY) syndrome with and without comorbid attention-deficit/hyperactivity disorder. J Int Neuropsychol Soc. 2011;22:1–9.

    Google Scholar 

  93. Tartaglia NR, Ayari N, Hutaff-Lee C, Boada R. Attention-deficit hyperactivity disorder symptoms in children and adolescents with sex chromosome aneuploidy: XXY, XXX, XYY, and XXYY. J Dev Behav Pediatr. 2012;33(4):309–18.

    Article  PubMed  PubMed Central  Google Scholar 

  94. Van RS, Swaab H. Executive dysfunction and the relation with behavioral problems in children with 47,XXY and 47,XXX. Genes Brain Behav. 2015;14(2):200–8.

    Article  Google Scholar 

  95. Ross JL, Roeltgen DP, Kushner H, Zinn AR, Reiss A, Bardsley MZ, et al. Behavioral and social phenotypes in boys with 47,XYY syndrome or 47, XXY Klinefelter syndrome. Pediatrics. 2012;129(4):769–78.

    Article  PubMed  PubMed Central  Google Scholar 

  96. Wilson AC, King J, Bishop DVM. Autism and social anxiety in children with sex chromosome trisomies: an observational study. Wellcome Open Res. 2019;4:32.

    Article  PubMed  PubMed Central  Google Scholar 

  97. Corona G, Petrone L, Paggi F, Lotti F, Boddi V, Fisher A, et al. Sexual dysfunction in subjects with Klinefelter’s syndrome. Int J Androl. 2010;33(4):574–80.

    CAS  PubMed  Google Scholar 

  98. El BH, Majzoub A, Al SS, Alnawasra H, Dabbous Z, Arafa M. Sexual dysfunction in Klinefelter’s syndrome patients. Andrologia. 2017:49(6).

    Google Scholar 

  99. Skakkebaek A, Moore PJ, Chang S, Fedder J, Gravholt CH. Quality of life in men with Klinefelter syndrome: the impact of genotype, health, socioeconomics, and sexual function. Genet Med. 2018;20(2):214–22.

    Article  PubMed  Google Scholar 

  100. Ferlin A, Selice R, Angelini S, Di GM, Caretta N, Cavalieri F, et al. Endocrine and psychological aspects of sexual dysfunction in Klinefelter patients. Andrology. 2018;6(3):414–9.

    Article  CAS  PubMed  Google Scholar 

  101. Fisher AD, Castellini G, Casale H, Fanni E, Bandini E, Campone B, et al. Hypersexuality, paraphilic behaviors, and gender dysphoria in individuals with Klinefelter’s syndrome. J Sex Med. 2015;12(12):2413–24.

    Article  PubMed  Google Scholar 

  102. Davies GW, Parkinson J. Gender dysphoria in Klinefelter’s syndrome: three cases. Australas Psychiatry. 2018;26(3):313–4.

    Article  PubMed  Google Scholar 

  103. Fernandez R, Guillamon A, Gomez-Gil E, Esteva I, Almaraz MC, Cortes-Cortes J, et al. Analyses of karyotype by G-banding and high-resolution microarrays in a gender dysphoria population. Genes Genomics. 2018;40(5):465–73.

    Article  CAS  PubMed  Google Scholar 

  104. Kreukels BPC, Cohen-Kettenis PT, Roehle R, van de Grift TC, Slowikowska-Hilczer J, Claahsen-van der Grinten H, et al. Sexuality in adults with differences/disorders of sex development (DSD): findings from the dsd-LIFE study. J Sex Marital Ther. 2019;45(8):688–705.

    Article  PubMed  Google Scholar 

  105. 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(1):30–4.

    Article  CAS  PubMed  Google Scholar 

  106. Baughman FA Jr. Klinefelter’s syndrome and essential tremor. Lancet. 1969;2(7619):545.

    Article  PubMed  Google Scholar 

  107. Tartaglia N, Borodyanskya M, Hall DA. Tremor in 48,XXYY syndrome. Mov Disord. 2009;24:2001–7.

    Article  PubMed  PubMed Central  Google Scholar 

  108. Tatum WO, Passaro EA, Elia M, Guerrini R, Gieron M, Genton P. Seizures in Klinefelter’s syndrome. Pediatr Neurol. 1998;19(4):275–8.

    Article  PubMed  Google Scholar 

  109. Bojesen A, Gravholt CH. Morbidity and mortality in Klinefelter syndrome (47,XXY). Acta Paediatr. 2011;100(6):807–13.

    Article  PubMed  Google Scholar 

  110. Gravholt CH, Jensen AS, Host C, Bojesen A. Body composition, metabolic syndrome and type 2 diabetes in Klinefelter syndrome. Acta Paediatr. 2011;100(6):871–7.

    Article  PubMed  Google Scholar 

  111. Jiang-Feng M, Hong-Li X, Xue-Yan W, Min N, Shuang-Yu L, Hong-Ding X, et al. Prevalence and risk factors of diabetes in patients with Klinefelter syndrome: a longitudinal observational study. Fertil Steril. 2012;98(5):1331–5.

    Article  PubMed  Google Scholar 

  112. Andersen NH, Bojesen A, Kristensen K, Birkebaek NH, Fedder J, Bennett P, et al. Left ventricular dysfunction in Klinefelter syndrome is associated to insulin resistance, abdominal adiposity and hypogonadism. Clin Endocrinol. 2008;69(5):785–91.

    Article  CAS  Google Scholar 

  113. Salzano A, Arcopinto M, Marra AM, Bobbio E, Esposito D, Accardo G, et al. Klinefelter syndrome, cardiovascular system, and thromboembolic disease: review of literature and clinical perspectives. Eur J Endocrinol. 2016;175(1):R27–40.

    Article  CAS  PubMed  Google Scholar 

  114. Seminog OO, Seminog AB, Yeates D, Goldacre MJ. Associations between Klinefelter’s syndrome and autoimmune diseases: English national record linkage studies. Autoimmunity. 2015;48(2):125–8.

    Article  CAS  PubMed  Google Scholar 

  115. Sawalha AH, Harley JB, Scofield RH. Autoimmunity and Klinefelter’s syndrome: when men have two X chromosomes. J Autoimmun. 2009;33(1):31–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. 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;97(16):1204–10.

    Article  PubMed  Google Scholar 

  117. Volkl 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;140(5):471–81.

    Article  PubMed  Google Scholar 

  118. Williams LA, Pankratz N, Lane J, Krailo M, Roesler M, Richardson M, et al. Klinefelter syndrome in males with germ cell tumors: a report from the Children’s Oncology Group. Cancer. 2018;124(19):3900–8.

    Article  PubMed  Google Scholar 

  119. Keung YK, Buss D, Chauvenet A, Pettenati M. Hematologic malignancies and Klinefelter syndrome. A chance association? Cancer Genet Cytogenet. 2002;139(1):9–13.

    Article  PubMed  Google Scholar 

  120. Rogol AD, Swerdloff RS, Reiter EO, Ross JL, Zumbrunnen TL, Pratt GA, et al. A multicenter, open-label, observational study of testosterone gel (1%) in the treatment of adolescent boys with Klinefelter syndrome or Anorchia. J Adolesc Health. 2014;54:20–5.

    Article  PubMed  Google Scholar 

  121. Moorthy B, Papadopolou M, Shaw DG, Grant DB. Depot testosterone in boys with anorchia or gonadotrophin deficiency: effect on growth rate and adult height. Arch Dis Child. 1991;66(2):197–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Fouatih K, Belin F, Lambert AS, Bouligand J, Bouvattier C. Pubertal growth spurt in patients with bilateral anorchia after testosterone replacement therapy. Arch Pediatr. 2019;26(6):320–3.

    Article  CAS  PubMed  Google Scholar 

  123. Wong SC, Scott D, Lim A, Tandon S, Ebeling PR, Zacharin M. Mild deficits of cortical bone in young adults with Klinefelter syndrome or Anorchia treated with testosterone. J Clin Endocrinol Metab. 2015;100(9):3581–9.

    Article  CAS  PubMed  Google Scholar 

  124. Samango-Sprouse CA, Sadeghin T, Mitchell FL, Dixon T, Stapleton E, Kingery M, et al. Positive effects of short course androgen therapy on the neurodevelopmental outcome in boys with 47,XXY syndrome at 36 and 72 months of age. Am J Med Genet A. 2013;161A(3):501–8.

    Article  PubMed  CAS  Google Scholar 

  125. Davis SM, Reynolds RM, Dabelea DM, Zeitler PS, Tartaglia NR. Testosterone treatment in infants with 47,XXY: effects on body composition. J Endocr Soc. 2019;3(12):2276–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Davis SM, Cox-Martin MG, Bardsley MZ, Kowal K, Zeitler PS, Ross JL. Effects of oxandrolone on cardiometabolic health in boys with Klinefelter syndrome: a randomized controlled trial. J Clin Endocrinol Metab. 2017;102(1):176–84.

    PubMed  Google Scholar 

  127. Davis SM, Lahlou N, Cox-Martin M, Kowal K, Zeitler PS, Ross JL. Oxandrolone treatment results in an increased risk of gonadarche in prepubertal boys with Klinefelter syndrome. J Clin Endocrinol Metab. 2018;103(9):3449–55.

    Article  PubMed  PubMed Central  Google Scholar 

  128. Ross JL, Kushner H, Kowal K, Bardsley M, Davis S, Reiss AL, et al. Androgen treatment effects on motor function, cognition, and behavior in boys with Klinefelter syndrome. J Pediatr. 2017;185:193–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Samango-Sprouse C, Lasutschinkow P, Powell S, Sadeghin T, Gropman A. The incidence of anxiety symptoms in boys with 47,XXY (Klinefelter syndrome) and the possible impact of timing of diagnosis and hormonal replacement therapy. Am J Med Genet A. 2019;179(3):423–8.

    Article  CAS  PubMed  Google Scholar 

  130. Host C, Bojesen A, Erlandsen M, Groth K, Kritstensen K, Jurik AG, et al. A placebo-controlled randomized study with testosterone in Klinefelter syndrome—beneficial effects on body composition. Endocr Connect. 2019;8:1250–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Growth and Reproduction, GR, 5064, Rigshospitalet, Copenhagen, Denmark

    Lise Aksglaede & Anders Juul

  2. Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA

    Shanlee Davis

  3. Section of Pediatric Endocrinology, Children’s Hospital Colorado, Aurora, CO, USA

    Shanlee Davis

  4. Department of Pediatrics, Thomas Jefferson University, Philadelphia, PA, USA

    Judith L. Ross

  5. Nemours DuPont Hospital for Children, Wilmington, DE, USA

    Judith L. Ross

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  1. Lise Aksglaede
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  2. Shanlee Davis
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  3. Judith L. Ross
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  4. Anders Juul
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Correspondence to Lise Aksglaede .

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Editors and Affiliations

  1. Department of Medicine, Unit of Andrology and Reproductive Medicine, University of Padua, Padova, Italy

    Carlo Foresta

  2. Department of Experimental Medicine, Section of Pathophysiology, Food Science and Endocrinology, Sapienza University of Rome, Roma, Italy

    Daniele Gianfrilli

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Aksglaede, L., Davis, S., Ross, J.L., Juul, A. (2021). Congenital Causes of Hypergonadotropic Hypogonadism: Anorchia and Klinefelter Syndrome. In: Foresta, C., Gianfrilli, D. (eds) Pediatric and Adolescent Andrology. Trends in Andrology and Sexual Medicine. Springer, Cham. https://doi.org/10.1007/978-3-030-80015-4_8

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