Sindrome di Klinefelter

Eziologia e patogenesi

In realtà, nella definizione attuale, la Sindrome di Klinefelter (SK) descrive un gruppo di patologie cromosomiche caratterizzate dalla presenza di almeno un extra-cromosoma X rispetto al cariotipo maschile normale 46,XY. In tal senso il cariotipo più frequente è 47,XXY, ma possiamo avere anche 48,XXXY, 49,XXXXY e 49,XXXYY oltre a mosaicismi 46,XY/47,XXY, 47,XXY/48,XXXY o più complessi. Il mosaicismo è un’alterazione genetica che consiste nella presenza, in uno stesso soggetto di cellule con corredo genetico diverso le une dalle altre. Questo aspetto è importante perché normalmente le manifestazioni cliniche della sindrome sono tanto più gravi quanto maggiore è il numero dei cromosomi X sopranumerari. I dati della letteratura riportano un decremento medio del quoziente intellettivo (QI) di circa 15 punti per ogni X “in più” (Linden et al, 1995).

La causa dell’aneuploidia è un difetto nella separazione dei cromosomi in una fase della riproduzione cellulare definita meiosi. La meiosi consiste nella formazione di quattro cellule con “mezzo” corredo cromosomico (detto aploide) a partire da un’unica cellula eucariotica, vale a dire con corredo cromosomico diploide. La meiosi è caratteristica dei gameti: lo spermatozoo e la cellula uovo (ovocita). Una mancata separazione dei cromosomi che si sono replicati nella meiosi, che avvenga durante la formazione dei gameti nella madre o nel padre, determina rispettivamente circa il 50% dei casi di cariotipo classico della Sindrome di Klinefelter: 47,XXY (Iitsuka et al, 2001; Bojesen et al, 2007); l'età avanzata della madre e probabilmente del padre sarebbero correlate con l’aumento del rischio. Nei mosaicismi la non-disgiunzione si realizza durante le prime divisioni delle cellule dell’embrione ed avviene in circa il 10% dei casi.

In questa sezione troverete le seguenti schede relative alla Sindrome di Klinefelter

• Aspetti endocrini della Sindrome di Klinefelter
• Clinica della Sindrome di Klinefelter
• Terapia della Sindrome di Klinefelter

Bibliografia

• Abramsky L, Chapple J. 47, XXY (Klinefelter syndrome) and 47,XYY: estimated rates of and indication for postnatal diagnosis with implications for prenatal counseling. Prenat Diagn 1997, 17: 363-68.
• Aksglaede L, Petersen JH, Main KM, Skakkebæk NE, Juul A (2007) High normal testosterone levels in infants with non-mosaic Klinefelter’s syndrome. Europ J Endocrinol 157: 345–350.
• Aksglaede L, Molgaard C, Skakkebaek NE, Juul A. Normal bone mineral content but unfavourable muscle/fat ratio in Klinefelter syndrome. Arch Dis Child 2008, 93: 30.
• 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.
• Anawalt BD, Bebb RA, Matsumoto AM, et al. Serum inhibin B levels reflect Sertoli cell function in normal men and men with testicular dysfunction. J Clin Endocrinol Metab 1996, 81 (9): 3341-45.
• Andersson AM, Müller J, Skakkebaek NE. Different roles of prepubertal and postpubertal germ cells and Sertoli cells in the regulation of serum inhibin B levels. J Clin Endocrinol Metab. 1998, 83 (12): 4451-58.
• Bojesen A, Juul S, Højbjerg Gravholt CH. Prenatal and postnatal prevalence of Klinefelter syndrome: a national registry study. J Clin Endocrinol Metab 2003, 88: 622–26.
• Bancroft J, Axworthy D, Ratcliffe S. The personality and psychosexual development of boys with 47, XXY chromosome constitution. J Child Psychol Psychiatry. 1982, 23 (2): 169-80.
• Bender BG, Harmon RJ, Linden MG, Robinson A. Psychosocial adaptation of 39 adolescents with sex chromosome abnormalities. Pediatrics 1995, 96 (2 Pt 1): 302-308.
• Bojesen A, Gravholt CH. Klinefelter syndrome in clinical practice. Nat Clin Pract Urol 2007, 4 (4): 192-204.
• Bojesen A, Juul S, Birkebaek N, Gravholt CH. Increased mortality in Klinefelter syndrome. J Clin Endocrinol Metab 2004, 89 (8): 3830-34.
• Bojesen A, Kristensen K, Birkebaek NH, et al. CH. The metabolic syndrome is frequent in Klinefelter's syndrome and is associated with abdominal obesity and hypogonadism. Diabetes Care 2006, 29 (7): 1591-98.
• Cherrier MM, Asthana S, Plymate S, et al. Testosterone supplementation improves spatial and verbal memory in healthy older men. Neurology 2001, 57: 80-88.
• 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.
• DeLisi LE, Maurizio AM, Svetina C, et al. Klinefelter's syndrome (XXY) as a genetic model for psychotic disorders. Am J Med Genet B Neuropsychiatr Genet 2005, 135B (1):15-23.
• Girardin CM, Lemyere E, Alos N, Deal C, Huot C, Van Vliet G. Comparison of Adolescents with Klinefelter Syndrome according to the circumstances of diagnosis: amniocentesis versus clinical signs. Horm Res 2009, 72: 98-105.
• Horowitz M, Mordin BEC, Aaron JE. Klinefelter’s Syndrome. Berlin: Springer-Verlag, 1984: 51-61.
• Iitsuka Y, Bock A, Nguyen DD, Samango-Sprouse CA, Simpson JL, Bischoff FZ. Evidence of Skewed X-Chromosome Inactivation in 47, XXY and 48,XXYY Klinefelter patients. Am J Med Genet 2001, 98 (1): 25-31.
• Jacobs PA, Strong JA. A case of Human intersexuality having a possible XXY sex-determining mechanism. Nature 1959, 183: 302-303.
• Kamischke A, Baumgardt A, Horst J, Nieschlag E. Clinical and diagnostic features of patients with suspected Klinefelter syndrome. J Androl 2003, 24: 41-48.
• Klinefelter HF, Refenstein EC, Albright F. Syndrome characterized by gynecomastia, aspermatogenesis without a leydigism and increased excretion of follicle stimulating hormone. J Clin Endocrinol Metab 1942, 2: 615-27.
• Klingmüller D, Haidl G. Inhibin B in men with normal and disturbed spermatogenesis. Hum Reprod 1997, 12: 2376-78.
• 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 (2004) J Clin Endocrinol Metab, April, 89(4):1864–1868.
• Lanfranco F, Kamischke A, Zitzmann M, Nieschlag E. Klinefelter’s syndrome. Lancet 2004, 364: 273-83.
• Lanfranco F, Zitzmann M, Simoni M, Nieschlag E. Serum adiponectin levels in hypogonadal males: influence of testosterone replacement therapy. Clin Endocrinol 2004, 60 (4): 500-507.
• Lee YS, Cheng AW, Ahmed SF, Shaw NJ, Hughes IA. Genital anomalies in Klinefelter's syndrome. Hormone Research 2007, 68: 150-55.
• Linden MG, Bender BG, Robinson A.. Sex chromosome tetrasomy and pentasomy. Pediatrics 1995, 96: 672-682.
• Nielsen J, Wohlert M. Sex chromosome abnormalities found among 34,910 newborn children: results from a 13-year incidence study in Arhus, Denmark. Birth Defects Orig Artic Ser 1990, 26: 209–23.
• NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis and Therapy. Osteoporosis prevention, diagnosis and therapy. JAMA 2001, 285: 785.
• Pugh PJ et al. Testosterone improves functional capacity and symptoms in men with hearth failure. Heart 2004, 90:446-447
• Radicioni AF, Anzuini A, De Marco E, Nofroni I, Castracane VD, Lenzi A. Changes in serum inhibin B during normal male puberty. Eur J Endocrinol. 2005,152 (3): 403-9.
• Ratcliffe SG, Jenkins J, Teague P. Cognitive and behavioural development of the 47, XYY child. In Berch, DB, Bender BG (eds) Boulder (CO) 1990, Westview Press, pp. 161-184.
• Ratcliffe S. Long-term outcome in children of sex chromosome abnormalities. Arch Dis Child 1999; 80: 192–195
• Ravaglia G, Forti P, Maioli F, et al. Metabolic Syndrome: prevalence and prediction of mortality in elderly individuals. Diabetes Care 2006; 29:2471-6
• Salbenblatt JA, Bender BG, Puck MH, Robinson A, Faiman C, Winter JS. Pituitary-gonadal function in Klinefelter syndrome before and during puberty. Pediatr Res 1985; 19:82-86.
• Sasco AJ. Rewiev articles: epidemiology of male breast cancer. A mate-analysis of published case-control studies and discussion of selected aetiological factors. Int J Cancer, 1993; 53: 538-49
• Scheithauer BW, Moschopulos M, Kovacs K, Jhaveri BS, Percek T, Lloyd RV. The pituitary in klinefelter syndrome. Endocr Pathol. 2005 Summer;16(2):133-8
• Schneider DT, Schuster AE, Fritsch MK, et al. Genetic analysis of mediastinal nonseminomatous germ cell tumors in children and adolescents. Genes Chromosomes Cancer 2002;34:115- 25.
• Simm PJ et al. The psychosocial impact of Klinefelter syndrome--a 10 year review. J Pediatr Endocrinol Metab 2006; 19: 499-505.
• Smyth CM and Bremner WJ (1998) Klinefelter syndrome. Arch Intern Med 158:1309–1314
• Swerdlow AJ, Higgins CD, Schoemaker MJ, et al., Mortality in patients with Klinefelter syndrome in Britain: a cohort study. J Clin Endocrinol Metab. 2005a;90:6516-22.
• Swerdlow Aj, Schoemaker MJ, Higgins CD, et al.,. Cancer Incidence and Mortality in Men with Klinefelter Syndrome: A Cohort Study. J Natl Cancer Ins. 2005; 97:1204-10.
• Topper E et al. Puberty in 24 patients with Klinefelter syndrome. Eur J Pediatr 1982; 139:8-12.
• Van den Bergh JP, Hermus AR, Spruyt AI, Sweep CG, Corstens FH, Smals AG Bone mineral density and quantitative ultrasound parameters in patients with Klinefelter's syndrome after long-term testosterone substitution. Osteoporos Int. 2001;12(1):55-62.
• Wang C et al. Transdermal testosterone gel improves sexual function, mood, muscle strength, and
• Visootsak J, Aylstock M and Graham JM Jr Kilnefelter Syndrome and Its Variants: An Update and Review for the Primary Pediatrician Clin Pediatr (Phila) 2001; 40; 639
• Wikstrom AM et al. Are adolescent boys with Klinefelter syndrome androgen deficient? A longitudinal study of Finnish 47, XXY boys. Pediatric Res 2006; 59:854-859.
• Zeger MP, Zinn AR, Lahlou N, Ramos P, Kowal K, Samango-Sprouse C, Ross JL. Effect of ascertainment and genetic features on the phenotype of Klinefelter syndrome. J Pediatr. 2008; 152:716-22.
• Zitzman M et al. X-Chromosome Inactivation Patterns and Androgen Receptor Functionality Influence Phenotype and Social Characteristics as Well as Pharmacogenetics of Testosterone Therapy in Klinefelter Patients. JCEM 2004; 89:6208-6217.