클라인펠터 증후군 환자에서 착상전 유전진단의 결과

Outcome of Preimplantation Genetic Diagnosis in Patients with Klinefelter Syndrome

  • 김진영 (성균관대학교 의과대학 삼성제일병원 산부인과) ;
  • 임천규 (성균관대학교 의과대학 삼성제일병원 불임연구실) ;
  • 전진현 (성균관대학교 의과대학 삼성제일병원 불임연구실) ;
  • 박소연 (성균관대학교 의과대학 삼성제일병원 유전학 연구실) ;
  • 서주태 (성균관대학교 의과대학 삼성제일병원 비뇨기과) ;
  • 차선화 (성균관대학교 의과대학 삼성제일병원 산부인과) ;
  • 궁미경 (성균관대학교 의과대학 삼성제일병원 산부인과) ;
  • 강인수 (성균관대학교 의과대학 삼성제일병원 산부인과)
  • Kim, Jin-Yeong (Department of Obstetrics and Gynecology, Samsung Cheil Hospital, Sungkyunkwan University School of Medicine) ;
  • Lim, Chun-Kyu (Laboratory of Reproductive Biology and Infertility, Samsung Cheil Hospital, Sungkyunkwan University School of Medicine) ;
  • Jun, Jin-Hyun (Laboratory of Reproductive Biology and Infertility, Samsung Cheil Hospital, Sungkyunkwan University School of Medicine) ;
  • Park, So-Yeon (Laboratory of Genetics, Samsung Cheil Hospital, Sungkyunkwan University School of Medicine) ;
  • Seo, Ju-Tae (Department of Urology, Samsung Cheil Hospital, Sungkyunkwan University School of Medicine) ;
  • Cha, Sun-Hwa (Department of Obstetrics and Gynecology, Samsung Cheil Hospital, Sungkyunkwan University School of Medicine) ;
  • Koong, Mi-Kyoung (Department of Obstetrics and Gynecology, Samsung Cheil Hospital, Sungkyunkwan University School of Medicine) ;
  • Kang, Inn-Soo (Department of Obstetrics and Gynecology, Samsung Cheil Hospital, Sungkyunkwan University School of Medicine)
  • 발행 : 2004.12.30

초록

Objectives: Klinefelter syndrome is the most common genetic cause of male infertility and presents with 47, XXY mainly or 46, XX/47, XXY mosaicism. It is characterized by hypogonadism and azoospermia due to testicular failure, however, sporadic cases of natural pregnancies have been reported. With the development of testicular sperm extraction (TESE) and intracytoplasmic sperm injection (ICSI), sperm can be retrieved successfully and ART is applied in these patients for pregnancy. It has been suggested that the risk of chromosome aneuploidy for both sex chromosome and autosome is increased in the sperms from 47, XXY germ cells. Considering the risk for chromosomal aneuploidy in the offspring, preimplantation genetic diagnosis (PGD) could be applied as a safe and more effective treatment option in Klinefelter syndrome. The aim of this study is to assess the outcome of PGD cycles by using FISH for sex chromosome and autosome in patients with Klinefelter syndrome. Materials and Methods: From Jan. 2001 to Dec. 2003, PGD was attempted in 8 cases of Klinefelter syndrome but TESE was failed to retrieve sperm in the 3 cases, therefore PGD was performed in 8 cycles of 5 cases (four 47, XXY and one 46, XY/47, XXY mosaicism). In one case, ejaculated sperm was used and in 4 cases, TESE sperm was used for ICSI. After fertilization, blastomere biopsy was performed in $6{\sim}7$ cell stage embryo and the chromosome aneuploidy was diagnosed by using FISH with CEP probes for chromosome X, Y and 17 or 18. Results: A total of 127 oocytes were retrieved and ICSI was performed in 113 mature oocytes. The fertilization rate was $65.3{\pm}6.0%$ (mean$\pm$SEM) and 76 embryos were obtained. Blastomere biopsy was performed in 61 developing embryos and FISH analysis was successful in 95.1% of the biopsied blastomeres (58/61). The rate of balanced embryos for chromosome X, Y and 17 or 18 was $39.7{\pm}6.9%$. The rate of aneuploidy for sex chromosome (X and Y) was $45.9{\pm}5.3%$ and $43.2{\pm}5.8%$ for chromosome 17 or 18, respectively. Embryo transfer was performed in all 8 cycles and mean number of transferred embryos was $2.5{\pm}0.5$. In 2 cases, clinical pregnancies were obtained and normal 46, XX and 46, XY karyotypes were confirmed by amniocentesis, respectively. Healthy male and female babies were delivered uneventfully at term. Conclusion: The patients with Klinefelter syndrome can benefit from ART with TESE and ICSI. Considering the risk of aneuploidy for both sex chromosome and autosome in the sperms and embryos of Klinefelter syndrome, PGD could be offered as safe and more effective treatment option.

키워드

참고문헌

  1. Phillip J, Lundsteen C, Owen D, Hirschhom K. The frequency of chromosome aberrations in tall men with special reference to 47,XYY and 47,XXY. Am J Hum Genet 1976; 28: 404-11
  2. Bojesen A, Juul S, Hojbjerg GC. Prenatal and po-stnatal prevalence of Klinefelter syndrome: a nati-onal registry study. J Clin Endocrinol Metab 2003; 88: 622-6 https://doi.org/10.1210/jc.2002-021491
  3. Klinefelter HF, Reifenstein EC, Albright F. Syn-drome characterized by gynecomastia, aspermato-genesis without Leydigism, increased excretion of follicle stimulating hormone. J Clin Endocrinol 1942; 2: 615-27 https://doi.org/10.1210/jcem-2-11-615
  4. Laron Z, Dickerman Z, Zamir R, Galatzer A. Pater-nity in Klinefelter's syndrome-a case report. ArchAndrol 1982; 8(2): 149-51
  5. Bourne H, Stern K, Clark G, Pertile M, Speirs A, Baker HW. Delivery of normal twins following the intracytoplasmic injection of spermatozoa from a patient with 47,XXY Klinefelter syndrome. Hum Reprod 1997; 11: 2447-50
  6. Ron-El R, Friedler S, Strassburger D, Komarovsky D, Schachter M, Raziel A. Birth of a healthy neonate following the intracytoplasmic injection of testicular spermatozoa from a patient with Klinefelter's syn-drome. Hum Reprod 1999; 14: 368-70 https://doi.org/10.1093/humrep/14.2.368
  7. Friedler S, Raziel A, Strassburger D, Schachter M, Bern O, Ron-El R. Outcome of ICSI using fresh and cryopreserved-thawed testicular spermatozoa in pa-tients with non-mosaic Klinefelter's syndrome. Hum Reprod 2001; 16 (12): 2616- 20 https://doi.org/10.1093/humrep/16.12.2616
  8. Ulug U, Bener F, Akman MA, Bahceci M. Partners of men with Klinefelter syndrome can be benefit from assited reproductive technologies. Fertil Steril 2003; 80(4): 903-6 https://doi.org/10.1016/S0015-0282(03)01157-9
  9. Komori S, Horiuchi I, Hamada Y, Hasegawa A, Kasumi H, Kondoh N, et al. Birth of healthy neo-nates after intracytoplasmic injection of ejaculated or testicular spermatozoa from men with nonmosaic Klinefelter's syndrome. J Reprod Med 2004; 49 (2): 126-30
  10. Poulakis V, Witzsch U, Diehl W, de Vries R, Becht E, Trotnow S. Birth of two infants with normal karyotype after intracytoplasmic injection of sperm obtained by testicular extraction from two men with nonmosaic Klinefelter's syndrome. Fertil Steril 2001; 76(5): 1060-2 https://doi.org/10.1016/S0015-0282(01)02830-8
  11. Denschlag D, Tempfer C, Kunze M, Wolff G, Keck C. Assisted reproductive techniques in patients with Klinefelter syndrome: a critical review. Fertil Steril 2004; 82(4): 775-9 https://doi.org/10.1016/j.fertnstert.2003.09.085
  12. Silber S, Escudero T, Lenahan K, Abdelhadi I, KilaniZ, Munne S. Chromosomal abnormalities in embr-yos derived from testicular sperm extraction. Fertil Steril 2003; 79(1): 30-8 https://doi.org/10.1016/S0015-0282(02)04407-2
  13. Staessen C, Coonen E, Van Assche E, Tournaye H, Joris H, Devroey P, et al. Preimplantation diagnosis for X and Y normality in embryos from three Kli-nefelter patients. Hum Reprod 1996; 11(8): 1650-3 https://doi.org/10.1093/oxfordjournals.humrep.a019463
  14. Kahraman S, Findikli N, Berkil H, Bakircioglu E, Donmez E, Sertyel S, et al. Results of preimplan-tation genetic diagnosis in patients with Klinefelter's syndrome. RBM Online 2003; 7(3): 346-52
  15. Staessen C, Tournaye H, Assche EV, Michiels A, Landuyt LV, Devroey P, et al. PGD in 47,XXY Klinefelter's syndrome patients. Hum Reprod Up-date 2003; 9(4): 319-30 https://doi.org/10.1093/humupd/dmg029
  16. Thomas NS, Hassold TJ. Aberrant recombination and the origin of Klinefelter syndrome. Hum Re-prod Update 2003; 9(4): 309-17 https://doi.org/10.1093/humupd/dmg028
  17. Hunt PA, Worthman C, Levinson H, Stallings J, LeMaire R, Mroz K, et al. Germ cell loss in the XXY male mouse: altered X-chromosome dosage affects prenatal development. Mol Reprod Dev 1998; 49: 101-11 https://doi.org/10.1002/(SICI)1098-2795(199802)49:2<101::AID-MRD1>3.0.CO;2-T
  18. Terzoli G, Lattata F, Lobbiani A. Fertility in 47,XXY patient: assessment of biological paternity by deo-xyribonucleic acid fingerprinting. Fertil Steril 1992; 58: 821-2 https://doi.org/10.1016/S0015-0282(16)55334-5
  19. Tournaye H, Staessen C, Liebaers I, Van Assche E, Devroey P, Bonduelle M, et al. Testicular sperm recovery in nine 47,XXY Klinefelter patients. Hum Reprod 1996; 11: 1644-9 https://doi.org/10.1093/oxfordjournals.humrep.a019462
  20. 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 re-covery. Fertil Steril 2001; 75(6): 1102-5 https://doi.org/10.1016/S0015-0282(01)01793-9
  21. Cozzi J, Chevret E, Rousseaux S, Pelletier R, Benitz V, Jalbert H, et al. Achievement of meiosis in XXY germ cells: study of 543 sperm karyotypes from an XY/XXY mosaic patient. Hum Genet 1994; 93(1): 32-4
  22. Foresta C, Galeazzi C, Bettella A, Marin P, Rossato M, Garolla A, et al. Analysis of meiosis in intra-testicular germ cells from subjects affected by classic Klinefelter's syndrome J Clin Endocrinol Metab 1999; 84: 3807-10
  23. Chevret E, Rousseaux S, Monteil M, Usson Y, Cozzi J, Pelletier R, et al. Increased incidence of hyper-ploid 24,XY spermatozoa detected by three-colour FISH in a 46,XY/47,XXY male. Hum Genet 1996; 97: 171-5 https://doi.org/10.1007/BF02265260
  24. Okada H, Fujioka H, Tatsumi N, Kanzaki M, Okuda Y, Fujisawa M, et al. Klinefelter's syndrome in the male infertility clinic. Hum Reprod 1999; 14: 946-52 https://doi.org/10.1093/humrep/14.4.946
  25. Foresta C, Galeazzi C, Bettella A, Stella M, Scan-dellari C. High incidence of sperm sex chromoso-mes aneuploidies in two patients with Klinefelter's syndrome. J Clin Endocrinol Metab 1998; 83: 203-5 https://doi.org/10.1210/jc.83.1.203
  26. Estop AM, Munne S, Cieply KM, Vandermark KK, Lamb AN, Fisch H. Meiotic products of a Kline-felter 47,XXY male as determined by sperm fluore-scence fluorescence in-situ hybridization analysis. Hum Reprod 1998; 13(1): 124-7 https://doi.org/10.1093/humrep/13.1.124
  27. Bergere M, Wainer R, Nataf V, Bailly M, Gombault M, Ville Y, et al. Biopsied testis cells of four 47, XXY patients: fluorescence in-situ hybridization and ICSI results. Hum Reprod 2002; 17(1): 32-7 https://doi.org/10.1093/humrep/17.1.32
  28. Hennebicq S, Pelletier R, Bergues U, Rousseaux S. Risk of trisomy 21 in offspring of patients with Klinefelter's syndrome. Lancet 2001; 357: 2104-5 https://doi.org/10.1016/S0140-6736(00)05201-6
  29. Ron-El R, Strassburger D, Gelman-Kohan S, Friedler S, Raziel A, Appelman Z. A 47,XXY fetus conce-ived after ICSI of spermatozoa from a patient with non-mosaic Klinefelte's syndrome. Hum Reprod 2000; 15(8): 1804-6 https://doi.org/10.1093/humrep/15.8.1804
  30. Gianaroli L, Magli MC, Fiorentio F, Baldi M, Fer-raretti AP. Clinical value of preimplantation genetic diagnosis. Placenta 2003; 24: S77-S83 https://doi.org/10.1016/S0143-4004(03)00169-3
  31. Bielanska M, Tan SL, Ao A. Fluorescence in-situ hy-bridization of sex chromosomes in spermatozoa and spare preimplantation embryos of a Klinefelter 46, XY/47,XXY male. Hum Reprod 2000; 15(2): 440-4 https://doi.org/10.1093/humrep/15.2.440
  32. Sathananthan AH, Ratnam SS, Ng SC, Tarin JJ, Gianaroli L, Trounson A. The sperm centriole: its inheritance, replication and perpetuation in early human embryos. Hum Reprod 1996; 11: 345-56 https://doi.org/10.1093/HUMREP/11.2.345