Klinefelter syndrome (KS): genetics, clinical phenotype and hypogonadism

Klinefelter HFRE, Albright F (1942) Syndrome characterized by gynecomastia, aspermatogenesis without A-Leydigism, and increased excretion of follicle stimulating hormone. J Clin Endocrinol 2(11):615–627

Forti G, Corona G, Vignozzi L, Krausz C, Maggi M (2010) Klinefelter’s syndrome: a clinical and therapeutical update. Sex Dev Gene Mol Biol Evol Endocrinol Embryol Pathol Sex Determ Differ 4(4–5):249–258. doi: 10.1159/000316604

Bojesen A, Juul S, Gravholt CH (2003) Prenatal and postnatal prevalence of Klinefelter syndrome: a national registry study. J Clin Endocrinol Metab 88(2):622–626. doi: 10.1210/jc.2002-021491

Morris JK, Alberman E, Scott C, Jacobs P (2008) Is the prevalence of Klinefelter syndrome increasing? Eur J Hum Genet EJHG 16(2):163–170. doi: 10.1038/sj.ejhg.5201956

Lanfranco F, Kamischke A, Zitzmann M, Nieschlag E (2004) Klinefelter’s syndrome. Lancet 364(9430):273–283. doi: 10.1016/s0140-6736(04)16678-6 (London, England)

Groth KA, Skakkebaek A, Host C, Gravholt CH, Bojesen A (2013) Clinical review: Klinefelter syndrome—a clinical update. J Clin Endocrinol Metab 98(1):20–30. doi: 10.1210/jc.2012-2382

Visootsak J, Graham JM Jr (2006) Klinefelter syndrome and other sex chromosomal aneuploidies. Orphanet J Rare Dis 1:42. doi: 10.1186/1750-1172-1-42

Abramsky L, Chapple J (1997) 47, XXY (Klinefelter syndrome) and 47, XYY: estimated rates of and indication for postnatal diagnosis with implications for prenatal counselling. Prenat Diagn 17(4):363–368

Simpson JL, de la Cruz F, Swerdloff RS, Samango-Sprouse C, Skakkebaek NE, Graham JM Jr, Hassold T, Aylstock M, Meyer-Bahlburg HF, Willard HF, Hall JG, Salameh W, Boone K, Staessen C, Geschwind D, Giedd J, Dobs AS, Rogol A, Brinton B, Paulsen CA (2003) Klinefelter syndrome: expanding the phenotype and identifying new research directions. Genet Med Off J Am College Med Genet 5(6):460–468

Bojesen A, Gravholt CH (2007) Klinefelter syndrome in clinical practice. Nat Clin Pract Urol 4(4):192–204. doi: 10.1038/ncpuro0775

Meschede DHJ (2002) Klinefelter Syndrome. In: Wass JHSS (ed) Oxford textbook of endocrinology and diabetes, vol 11, 1st edn. Oxford University Press, Oxford, pp 1292–1294

Zitzmann M, Depenbusch M, Gromoll J, Nieschlag E (2004) 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 89(12):6208–6217. doi: 10.1210/jc.2004-1424

Bojesen A, Hertz JM, Gravholt CH (2011) Genotype and phenotype in Klinefelter syndrome—impact of androgen receptor polymorphism and skewed X inactivation. Int J Androl 34(6 Pt 2):e642–e648. doi: 10.1111/j.1365-2605.2011.01223.x

Samplaski MK, Lo KC, Grober ED, Millar A, Dimitromanolakis A, Jarvi KA (2014) Phenotypic differences in mosaic Klinefelter patients as compared with non-mosaic Klinefelter patients. Fertil Steril 101(4):950–955. doi: 10.1016/j.fertnstert.2013.12.051

Linden MG, Bender BG, Robinson A (1995) Sex chromosome tetrasomy and pentasomy. Pediatrics 96(4 Pt 1):672–682

Bojesen A, Kristensen K, Birkebaek NH, Fedder J, Mosekilde L, Bennett P, Laurberg P, Frystyk J, Flyvbjerg A, Christiansen JS, Gravholt CH (2006) The metabolic syndrome is frequent in Klinefelter’s syndrome and is associated with abdominal obesity and hypogonadism. Diabetes Care 29(7):1591–1598. doi: 10.2337/dc06-0145

Chang S, Skakkebaek A, Trolle C, Bojesen A, Hertz JM, Cohen A, Hougaard DM, Wallentin M, Pedersen AD, Ostergaard JR, Gravholt CH (2015) Anthropometry in Klinefelter syndrome—multifactorial influences due to CAG length, testosterone treatment and possibly intrauterine hypogonadism. J Clin Endocrinol Metab 100(3):E508–E517. doi: 10.1210/jc.2014-2834

Wattendorf DJ, Muenke M (2005) Klinefelter syndrome. Am Fam Phys 72(11):2259–2262

Temple CM, Sanfilippo PM (2003) Executive skills in Klinefelter’s syndrome. Neuropsychologia 41(11):1547–1559

Geschwind DH, Boone KB, Miller BL, Swerdloff RS (2000) Neurobehavioral phenotype of Klinefelter syndrome. Ment Retard Dev Disabil Res Rev 6(2):107–116. doi: 10.1002/1098-2779(2000)6:2<107:aid-mrdd4>3.0.co;2-2

Lee YS, Cheng AW, Ahmed SF, Shaw NJ, Hughes IA (2007) Genital anomalies in Klinefelter’s syndrome. Horm Res 68(3):150–155. doi: 10.1159/000106375

Wikstrom AM, Dunkel L (2011) Klinefelter syndrome. Best Pract Res Clin Endocrinol Metab 25(2):239–250. doi: 10.1016/j.beem.2010.09.006

Bojesen A, Host C, Gravholt CH (2010) Klinefelter’s syndrome, type 2 diabetes and the metabolic syndrome: the impact of body composition. Mol Hum Reprod 16(6):396–401. doi: 10.1093/molehr/gaq016

Host C, Skakkebaek A, Groth KA, Bojesen A (2014) The role of hypogonadism in Klinefelter syndrome. Asian J Androl 16(2):185–191. doi: 10.4103/1008-682x.122201

Thomas NS, Hassold TJ (2003) Aberrant recombination and the origin of Klinefelter syndrome. Hum Reprod Update 9(4):309–317

Wikstrom AM, Painter JN, Raivio T, Aittomaki K, Dunkel L (2006) Genetic features of the X chromosome affect pubertal development and testicular degeneration in adolescent boys with Klinefelter syndrome. Clin Endocrinol 65(1):92–97. doi: 10.1111/j.1365-2265.2006.02554.x

Jacobs PA, Hassold TJ, Whittington E, Butler G, Collyer S, Keston M, Lee M (1988) Klinefelter’s syndrome: an analysis of the origin of the additional sex chromosome using molecular probes. Ann Hum Genet 52(Pt 2):93–109

Lorda-Sanchez I, Binkert F, Maechler M, Robinson WP, Schinzel AA (1992) Reduced recombination and paternal age effect in Klinefelter syndrome. Hum Genet 89(5):524–530

Zinn AR, Ramos P, Elder FF, Kowal K, Samango-Sprouse C, Ross JL (2005) Androgen receptor CAGn repeat length influences phenotype of 47, XXY (Klinefelter) syndrome. J Clin Endocrinol Metab 90(9):5041–5046. doi: 10.1210/jc.2005-0432

Fonseka KG, Griffin DK (2011) Is there a paternal age effect for aneuploidy? Cytogenet Genome Res 133(2–4):280–291. doi: 10.1159/000322816

Barr ML, Bertram EG (1949) A morphological distinction between neurones of the male and female, and the behaviour of the nucleolar satellite during accelerated nucleoprotein synthesis. Nature 163(4148):676

Brown CJ, Ballabio A, Rupert JL, Lafreniere RG, Grompe M, Tonlorenzi R, Willard HF (1991) A gene from the region of the human X inactivation centre is expressed exclusively from the inactive X chromosome. Nature 349(6304):38–44. doi: 10.1038/349038a0

Plath K, Mlynarczyk-Evans S, Nusinow DA, Panning B (2002) Xist RNA and the mechanism of X chromosome inactivation. Annu Rev Genet 36:233–278. doi: 10.1146/annurev.genet.36.042902.092433

Penny GD, Kay GF, Sheardown SA, Rastan S, Brockdorff N (1996) Requirement for Xist in X chromosome inactivation. Nature 379(6561):131–137. doi: 10.1038/379131a0

Wistuba J, Luetjens CM, Stukenborg JB, Poplinski A, Werler S, Dittmann M, Damm OS, Hamalainen T, Simoni M, Gromoll J (2010) Male 41, XXY* mice as a model for klinefelter syndrome: hyperactivation of leydig cells. Endocrinology 151(6):2898–2910. doi: 10.1210/en.2009-1396

Poplinski A, Wieacker P, Kliesch S, Gromoll J (2010) Severe XIST hypomethylation clearly distinguishes (SRY+) 46, XX-maleness from Klinefelter syndrome. Eur J Endocrinol/Eur Fed Endocr Soc 162(1):169–175. doi: 10.1530/eje-09-0768

Wistuba J (2010) Animal models for Klinefelter’s syndrome and their relevance for the clinic. Mol Hum Reprod 16(6):375–385. doi: 10.1093/molehr/gaq024

Kleinheinz A, Schulze W (1994) Klinefelter’s syndrome: new and rapid diagnosis by PCR analysis of XIST gene expression. Andrologia 26(3):127–129

Froland A, Skakkebaek NE (1971) Dimorphism in sex chromatin pattern of Sertoli cells in adults with Klinefelter’s syndrome: correlation with 2 types of “Sertoli-cell-only” tubules. J Clin Endocrinol Metab 33(4):683–687. doi: 10.1210/jcem-33-4-683

Shamsuddin AK, Tang CK (1980) Barr bodies in testis with Klinefelter syndrome. Urology 15(1):74–76

Tuttelmann F, Gromoll J (2010) Novel genetic aspects of Klinefelter’s syndrome. Mol Hum Reprod 16(6):386–395. doi: 10.1093/molehr/gaq019

Yang F, Babak T, Shendure J, Disteche CM (2010) Global survey of escape from X inactivation by RNA-sequencing in mouse. Genome Res 20(5):614–622. doi: 10.1101/gr.103200.109

Berletch JB, Yang F, Disteche CM (2010) Escape from X inactivation in mice and humans. Genome Biol 11(6):213. doi: 10.1186/gb-2010-11-6-213

Carrel L, Willard HF (1999) Heterogeneous gene expression from the inactive X chromosome: an X-linked gene that escapes X inactivation in some human cell lines but is inactivated in others. Proc Natl Acad Sci USA 96(13):7364–7369

Carrel L, Willard HF (2005) X-inactivation profile reveals extensive variability in X-linked gene expression in females. Nature 434(7031):400–404. doi: 10.1038/nature03479

Carrel L, Cottle AA, Goglin KC, Willard HF (1999) A first-generation X-inactivation profile of the human X chromosome. Proc Natl Acad Sci USA 96(25):14440–14444

Werler S, Poplinski A, Gromoll J, Wistuba J (2011) Expression of selected genes escaping from X inactivation in the 41, XX(Y)* mouse model for Klinefelter’s syndrome. Acta Paediatr 100(6):885–891. doi: 10.1111/j.1651-2227.2010.02112.x (Oslo, Norway: 1992)

Armstrong SJ, Hulten MA, Keohane AM, Turner BM (1997) Different strategies of X-inactivation in germinal and somatic cells: histone H4 underacetylation does not mark the inactive X chromosome in the mouse male germline. Exp Cell Res 230(2):399–402. doi: 10.1006/excr.1996.3394

Fernandez-Capetillo O, Mahadevaiah SK, Celeste A, Romanienko PJ, Camerini-Otero RD, Bonner WM, Manova K, Burgoyne P, Nussenzweig A (2003) H2AX is required for chromatin remodeling and inactivation of sex chromosomes in male mouse meiosis. Dev Cell 4(4):497–508

Salido EC, Yen PH, Mohandas TK, Shapiro LJ (1992) Expression of the X-inactivation-associated gene XIST during spermatogenesis. Nat Genet 2(3):196–199. doi: 10.1038/ng1192-196

Wang PJ, McCarrey JR, Yang F, Page DC (2001) An abundance of X-linked genes expressed in spermatogonia. Nat Genet 27(4):422–426. doi: 10.1038/86927

Ross MT, Grafham DV, Coffey AJ, Scherer S, McLay K, Muzny D, Platzer M, Howell GR, Burrows C, Bird CP, Frankish A, Lovell FL, Howe KL, Ashurst JL, Fulton RS, Sudbrak R, Wen G, Jones MC, Hurles ME, Andrews TD, Scott CE, Searle S, Ramser J, Whittaker A, Deadman R, Carter NP, Hunt SE, Chen R, Cree A, Gunaratne P, Havlak P, Hodgson A, Metzker ML, Richards S, Scott G, Steffen D, Sodergren E, Wheeler DA, Worley KC, Ainscough R, Ambrose KD, Ansari-Lari MA, Aradhya S, Ashwell RI, Babbage AK, Bagguley CL, Ballabio A, Banerjee R, Barker GE, Barlow KF, Barrett IP, Bates KN, Beare DM, Beasley H, Beasley O, Beck A, Bethel G, Blechschmidt K, Brady N, Bray-Allen S, Bridgeman AM, Brown AJ, Brown MJ, Bonnin D, Bruford EA, Buhay C, Burch P, Burford D, Burgess J, Burrill W, Burton J, Bye JM, Carder C, Carrel L, Chako J, Chapman JC, Chavez D, Chen E, Chen G, Chen Y, Chen Z, Chinault C, Ciccodicola A, Clark SY, Clarke G, Clee CM, Clegg S, Clerc-Blankenburg K, Clifford K, Cobley V, Cole CG, Conquer JS, Corby N, Connor RE, David R, Davies J, Davis C, Davis J, Delgado O, Deshazo D, Dhami P, Ding Y, Dinh H, Dodsworth S, Draper H, Dugan-Rocha S, Dunham A, Dunn M, Durbin KJ, Dutta I, Eades T, Ellwood M, Emery-Cohen A, Errington H, Evans KL, Faulkner L, Francis F, Frankland J, Fraser AE, Galgoczy P, Gilbert J, Gill R, Glockner G, Gregory SG, Gribble S, Griffiths C, Grocock R, Gu Y, Gwilliam R, Hamilton C, Hart EA, Hawes A, Heath PD, Heitmann K, Hennig S, Hernandez J, Hinzmann B, Ho S, Hoffs M, Howden PJ, Huckle EJ, Hume J, Hunt PJ, Hunt AR, Isherwood J, Jacob L, Johnson D, Jones S, de Jong PJ, Joseph SS, Keenan S, Kelly S, Kershaw JK, Khan Z, Kioschis P, Klages S, Knights AJ, Kosiura A, Kovar-Smith C, Laird GK, Langford C, Lawlor S, Leversha M, Lewis L, Liu W, Lloyd C, Lloyd DM, Loulseged H, Loveland JE, Lovell JD, Lozado R, Lu J, Lyne R, Ma J, Maheshwari M, Matthews LH, McDowall J, McLaren S, McMurray A, Meidl P, Meitinger T, Milne S, Miner G, Mistry SL, Morgan M, Morris S, Muller I, Mullikin JC, Nguyen N, Nordsiek G, Nyakatura G, O’Dell CN, Okwuonu G, Palmer S, Pandian R, Parker D, Parrish J, Pasternak S, Patel D, Pearce AV, Pearson DM, Pelan SE, Perez L, Porter KM, Ramsey Y, Reichwald K, Rhodes S, Ridler KA, Schlessinger D, Schueler MG, Sehra HK, Shaw-Smith C, Shen H, Sheridan EM, Shownkeen R, Skuce CD, Smith ML, Sotheran EC, Steingruber HE, Steward CA, Storey R, Swann RM, Swarbreck D, Tabor PE, Taudien S, Taylor T, Teague B, Thomas K, Thorpe A, Timms K, Tracey A, Trevanion S, Tromans AC, d’Urso M, Verduzco D, Villasana D, Waldron L, Wall M, Wang Q, Warren J, Warry GL, Wei X, West A, Whitehead SL, Whiteley MN, Wilkinson JE, Willey DL, Williams G, Williams L, Williamson A, Williamson H, Wilming L, Woodmansey RL, Wray PW, Yen J, Zhang J, Zhou J, Zoghbi H, Zorilla S, Buck D, Reinhardt R, Poustka A, Rosenthal A, Lehrach H, Meindl A, Minx PJ, Hillier LW, Willard HF, Wilson RK, Waterston RH, Rice CM, Vaudin M, Coulson A, Nelson DL, Weinstock G, Sulston JE, Durbin R, Hubbard T, Gibbs RA, Beck S, Rogers J, Bentley DR (2005) The DNA sequence of the human X chromosome. Nature 434(7031):325–337. doi: 10.1038/nature03440

Mroz K, Carrel L, Hunt PA (1999) Germ cell development in the XXY mouse: evidence that X chromosome reactivation is independent of sexual differentiation. Dev Biol 207(1):229–238. doi: 10.1006/dbio.1998.9160

Spatz A, Borg C, Feunteun J (2004) X-chromosome genetics and human cancer. Nat Rev Cancer 4(8):617–629. doi: 10.1038/nrc1413

Fan G, Tran J (2011) X chromosome inactivation in human and mouse pluripotent stem cells. Hum Genet 130(2):217–222. doi: 10.1007/s00439-011-1038-1

Berletch JB, Yang F, Xu J, Carrel L, Disteche CM (2011) Genes that escape from X inactivation. Hum Genet 130(2):237–245. doi: 10.1007/s00439-011-1011-z

Pessia E, Makino T, Bailly-Bechet M, McLysaght A, Marais GA (2012) Mammalian X chromosome inactivation evolved as a dosage-compensation mechanism for dosage-sensitive genes on the X chromosome. Proc Natl Acad Sci USA 109(14):5346–5351. doi: 10.1073/pnas.1116763109

Yu YH, Siao FP, Hsu LC, Yen PH (2012) TEX11 modulates germ cell proliferation by competing with estrogen receptor beta for the binding to HPIP. Mol Endocrinol 26(4):630–642. doi: 10.1210/me.2011-1263 (Baltimore, Md)

Zitzmann M, Nieschlag E (2003) The CAG repeat polymorphism within the androgen receptor gene and maleness. Int J Androl 26(2):76–83

Iitsuka Y, Bock A, Nguyen DD, Samango-Sprouse CA, Simpson JL, Bischoff FZ (2001) Evidence of skewed X-chromosome inactivation in 47, XXY and 48, XXYY Klinefelter patients. Am J Med Genet 98(1):25–31

Suzuki Y, Sasagawa I, Tateno T, Ashida J, Nakada T, Muroya K, Ogata T (2001) Mutation screening and CAG repeat length analysis of the androgen receptor gene in Klinefelter’s syndrome patients with and without spermatogenesis. Hum Reprod 16(8):1653–1656 (Oxford, England)

Ferlin A, Schipilliti M, Vinanzi C, Garolla A, Di Mambro A, Selice R, Lenzi A, Foresta C (2011) Bone mass in subjects with Klinefelter syndrome: role of testosterone levels and androgen receptor gene CAG polymorphism. J Clin Endocrinol Metab 96(4):E739–E745. doi: 10.1210/jc.2010-1878

Foresta C, Caretta N, Palego P, Ferlin A, Zuccarello D, Lenzi A, Selice R (2012) Reduced artery diameters in Klinefelter syndrome. Int J Androl 35(5):720–725. doi: 10.1111/j.1365-2605.2012.01269.x

Helena Mangs A, Morris BJ (2007) The human pseudoautosomal region (PAR): origin, function and future. Curr Genomics 8(2):129–136

Mohandas TK, Speed RM, Passage MB, Yen PH, Chandley AC, Shapiro LJ (1992) Role of the pseudoautosomal region in sex-chromosome pairing during male meiosis: meiotic studies in a man with a deletion of distal Xp. Am J Hum Genet 51(3):526–533

Burgoyne PS, Mahadevaiah SK, Sutcliffe MJ, Palmer SJ (1992) Fertility in mice requires X-Y pairing and a Y-chromosomal “spermiogenesis” gene mapping to the long arm. Cell 71(3):391–398

Matsuda Y, Moens PB, Chapman VM (1992) Deficiency of X and Y chromosomal pairing at meiotic prophase in spermatocytes of sterile interspecific hybrids between laboratory mice (Mus domesticus) and Mus spretus. Chromosoma 101(8):483–492

Ottesen AM, Aksglaede L, Garn I, Tartaglia N, Tassone F, Gravholt CH, Bojesen A, Sorensen K, Jorgensen N, Rajpert-De Meyts E, Gerdes T, Lind AM, Kjaergaard S, Juul A (2010) Increased number of sex chromosomes affects height in a nonlinear fashion: a study of 305 patients with sex chromosome aneuploidy. Am J Med Genet Part A 152A(5):1206–1212. doi: 10.1002/ajmg.a.33334

Marchini A, Hacker B, Marttila T, Hesse V, Emons J, Weiss B, Karperien M, Rappold G (2007) BNP is a transcriptional target of the short stature homeobox gene SHOX. Hum Mol Genet 16(24):3081–3087. doi: 10.1093/hmg/ddm266

Decker E, Durand C, Bender S, Rodelsperger C, Glaser A, Hecht J, Schneider KU, Rappold G (2011) FGFR3 is a target of the homeobox transcription factor SHOX in limb development. Hum Mol Genet 20(8):1524–1535. doi: 10.1093/hmg/ddr030

Rocca MS, Pecile V, Cleva L, Speltra E, Selice R, Di Mambro A, Foresta C, Ferlin A (2016) The Klinefelter syndrome is associated with high recurrence of copy number variations on the X chromosome with a potential role in the clinical phenotype. Andrology 4(2):328–334. doi: 10.1111/andr.12146

Ratcliffe S (1999) Long-term outcome in children of sex chromosome abnormalities. Arch Dis Child 80(2):192–195

Topper E, Dickerman Z, Prager-Lewin R, Kaufman H, Maimon Z, Laron Z (1982) Puberty in 24 patients with Klinefelter syndrome. Eur J Pediatr 139(1):8–12

Salbenblatt JA, Bender BG, Puck MH, Robinson A, Faiman C, Winter JS (1985) Pituitary-gonadal function in Klinefelter syndrome before and during puberty. Pediatr Res 19(1):82–86. doi: 10.1203/00006450-198501000-00022

Wikstrom AM, Dunkel L, Wickman S, Norjavaara E, Ankarberg-Lindgren C, Raivio T (2006) Are adolescent boys with Klinefelter syndrome androgen deficient? A longitudinal study of Finnish 47,XXY boys. Pediatric Res 59(6):854–859. doi: 10.1203/01.pdr.0000219386.31398.c3

Wikstrom AM, Bay K, Hero M, Andersson AM, Dunkel L (2006) Serum insulin-like factor 3 levels during puberty in healthy boys and boys with Klinefelter syndrome. J Clin Endocrinol Metab 91(11):4705–4708. doi: 10.1210/jc.2006-0669

Smyth CM, Bremner WJ (1998) Klinefelter syndrome. Arch Intern Med 158(12):1309–1314

Kamischke A, Baumgardt A, Horst J, Nieschlag E (2003) Clinical and diagnostic features of patients with suspected Klinefelter syndrome. J Androl 24(1):41–48

Bhasin S, Cunningham GR, Hayes FJ, Matsumoto AM, Snyder PJ, Swerdloff RS, Montori VM (2010) Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 95(6):2536–2559. doi: 10.1210/jc.2009-2354

Wang C, Nieschlag E, Swerdloff R, Behre HM, Hellstrom WJ, Gooren LJ, Kaufman JM, Legros JJ, Lunenfeld B, Morales A, Morley JE, Schulman C, Thompson IM, Weidner W, Wu FC (2008) Investigation, treatment and monitoring of late-onset hypogonadism in males: ISA, ISSAM, EAU, EAA and ASA recommendations. Eur J Endocrinol/Eur Fed Endocr Soc 159(5):507–514. doi: 10.1530/eje-08-0601

Daniele Santi SS, Rochira V (2015) Is serum estradiol really increased in patients with Klinefeler syndrome? Results from a meta-analysis study. Endocr Abstr 37:EP182. doi: 10.1530/endoabs.37.EP182

Maseroli E, Rastrelli G, Corona G, Boddi V, Amato AM, Mannucci E, Forti G, Maggi M (2014) Gynecomastia in subjects with sexual dysfunction. J Endocrinol Invest 37(6):525–532. doi: 10.1007/s40618-014-0055-z

Christiansen P, Andersson AM, Skakkebaek NE (2003) Longitudinal studies of inhibin B levels in boys and young adults with Klinefelter syndrome. J Clin Endocrinol Metab 88(2):888–891. doi: 10.1210/jc.2002-021379

Anawalt BD, Bebb RA, Matsumoto AM, Groome NP, Illingworth PJ, McNeilly AS, Bremner WJ (1996) Serum inhibin B levels reflect Sertoli cell function in normal men and men with testicular dysfunction. J Clin Endocrinol Metab 81(9):3341–3345. doi: 10.1210/jcem.81.9.8784094

Aksglaede L, Christiansen P, Sorensen K, Boas M, Linneberg A, Main KM, Andersson AM, Skakkebaek NE, Juul A (2011) Serum concentrations of Anti-Mullerian Hormone (AMH) in 95 patients with Klinefelter syndrome with or without cryptorchidism. Acta Paediatr 100(6):839–845. doi: 10.1111/j.1651-2227.2011.02148.x (Oslo, Norway: 1992)

Rohayem J, Fricke R, Czeloth K, Mallidis C, Wistuba J, Krallmann C, Zitzmann M, Kliesch S (2015) Age and markers of Leydig cell function, but not of Sertoli cell function predict the success of sperm retrieval in adolescents and adults with Klinefelter’s syndrome. Andrology 3(5):868–875. doi: 10.1111/andr.12067

Ferlin A, Zuccarello D, Zuccarello B, Chirico MR, Zanon GF, Foresta C (2008) Genetic alterations associated with cryptorchidism. JAMA 300(19):2271–2276. doi: 10.1001/jama.2008.668

Overvad S, Bay K, Bojesen A, Gravholt CH (2014) Low INSL3 in Klinefelter syndrome is related to osteocalcin, testosterone treatment and body composition, as well as measures of the hypothalamic-pituitary-gonadal axis. Andrology 2(3):421–427. doi: 10.1111/j.2047-2927.2014.00204.x

Bojesen A, Gravholt CH (2011) Morbidity and mortality in Klinefelter syndrome (47, XXY). Acta Paediatr 100(6):807–813. doi: 10.1111/j.1651-2227.2011.02274.x (Oslo, Norway: 1992)

Bojesen A, Birkebaek N, Kristensen K, Heickendorff L, Mosekilde L, Christiansen JS, Gravholt CH (2011) Bone mineral density in Klinefelter syndrome is reduced and primarily determined by muscle strength and resorptive markers, but not directly by testosterone. Osteoporos Int J Estab Result Coop Between Eur Found Osteoporos Natl Osteoporos Found USA 22(5):1441–1450. doi: 10.1007/s00198-010-1354-7

Boone KB, Swerdloff RS, Miller BL, Geschwind DH, Razani J, Lee A, Gonzalo IG, Haddal A, Rankin K, Lu P, Paul L (2001) Neuropsychological profiles of adults with Klinefelter syndrome. J Int Neuropsy Chol Soc JINS 7(4):446–456

Boada R, Janusz J, Hutaff-Lee C, Tartaglia N (2009) The cognitive phenotype in Klinefelter syndrome: a review of the literature including genetic and hormonal factors. Dev Disabil Res Rev 15(4):284–294. doi: 10.1002/ddrr.83

Hong DS, Reiss AL (2014) Cognitive and neurological aspects of sex chromosome aneuploidies. Lancet Neurol 13(3):306–318. doi: 10.1016/s1474-4422(13)70302-8

Fisher AD, Castellini G, Casale H, Fanni E, Bandini E, Campone B, Ferruccio N, Maseroli E, Boddi V, Dettore D, Pizzocaro A, Balercia G, Oppo A, Ricca V, Maggi M (2015) Hypersexuality, paraphilic behaviors, and gender dysphoria in individuals with Klinefelter’s Syndrome. J Sex Med 12(12):2413–2424. doi: 10.1111/jsm.13048

Balestrieri A, Zirilli L, Madeo B, Pignatti E, Rossi G, Carani C, Rochira V (2008) 21-hydroxylase deficiency and klinefelter syndrome in an adult man: striking a balance between androgen excess and insufficiency. J Androl 29(6):605–609. doi: 10.2164/jandrol.107.004648