Skip to main content

Macroorchidisme et spermatogenèse dans le syndrome de l’X fragile

Macroorchidism and spermatogenesis in fragile X syndrome

Résumé

Le syndrome de l’X fragile est lié à l’expansion d’une séquence répétitive de triplets CGG dans la région 5’ du gène FMR1. II en résulte l’absence de production de la protéine FMRP par blocage de la transcription du gène FMR1. Nous rapportons une étude hormonale, histologique et immunohistochimique d’un cas, centrée sur les fonctions testiculaires et l’origine du macroorchidisme.

Le syndrome de l’X fragile ’saccompagne d’une spermatogenèse normale ou incomplète ou encore présentant des lésions aux stades tardifs. Ces lésions tardives associées à l’œdème interstitiel s’apparentent aux lésions observées chez les vasectomisés ce qui a fait soulever l’hypothèse du rôle d’une hyperpression péritubulaire et/ou d’anticorps anti-spermatozoïdes. Dans notre observation, la négativité des anticorps anti-spermatozoïdes et la discrétion de l’œdème ne sont pas en faveur de cette hypothèse. L’histologie retrouve l’existence d’une hyperplasie du tissu interstitiel, d’un épaississement de la membrane basale péritubulaire et d’une augmentation du diamètre externe des tubes séminifères sans anomalie morphologique des cellules de Leydig ou des cellules de Sertoli.

Les immunomarquages réalisés montrent la présence de la protéine FMRp dans les cellules germinales ce qui indique que ces cellules ne sont pas porteuse de la mutation complète. Cette expression de la protéine FMRp dans le testicule peut permettre d’expliquer la conservation de la spermatogenèse alors même qu’il a été suggéré que la protéine FMRp soit nécessaire la survie des cellules germinales. Nos résultats sont compatible avec l’hypothèse que les atteintes différentes de la spermatogenèse selon les patients attients du syndrome puissent être liées au nombre de cellules germinales touchées par la mutation complète. Des travaux complémentaires sont toutefois nécessaires pour comprendre la variabilité des atteintes de la spermatogenèse et la physiopathologie du macroorchidisme dans le syndrome de l’X fragile.

Abstract

Fragile X syndrome is associated with expansion of a repeated triple CGG sequence in the 5’ region of the FMR-1 gene, resulting in absence of production of FMRp protein due to blocking of the FMR1 transcription gene. The authors report a hormonal, histological, and immunohistochemical study of one case, focusing on the origin of macroorchidism and the variability of testicular functions in these patients.

Our observations confirm the existence of interstitial tissue hyperplasia, thickening of the peritubular basal membrane and an increased external diameter of the seminiferous tubes with no morphological anomalies in the Leydig or Sertoli cells.

Spermatogenesis in fragile X Syndrome patients has been extensively studied: it may be normal, incomplete or patients may present impaired spermatogenesis in the late stages. These later lesions, which are associated with interstitial oedema, resemble the lesions observed after vasectomy, suggesting the role of raised peritubular pressure and anti-sperm antibodies. In our study, no antibodies were detected in the serum and oedema was minimal, which tends to discredit this theory.

The role of the FRMp protein in spermatogenesis remains controversial. Immunolabelling on slides prepared from testicular biopsies confirms that a complete form of mutation is not seen in the germ cells. Although the FMRp protein might be necessary for survival of germ cells, its persistent expression in the testis could explain preservation of spermatogenesis in some patients. Our results are consistent with the hypothesis that the varying degrees of impaired spermatogenes is could be related to the number of germ cells not affected by the complet mutation. However, additional data are necessary to fully understand the variability of spermatogenesis and the pathophysiology of macroorchidism observed in patients with fragile X syndrome.

Références

  1. 1.

    BACHNER D., MANCA A., STEINBACH P., WOHRLE D., JUST W., VOGEL W., HAMEISTER H., POUSTKA A.: Enhanced expression of the murine FMR1 gene during germ cell proliferation suggests a special function in both the male and the female gonad. Hum. Mol. Genet., 1993, 2: 2043–2050.

    PubMed  Article  CAS  Google Scholar 

  2. 2.

    BAKKER C.E., VERHEIJ C., WILLEMSEN R., VAN DER HELM R., OERLEMANS R.: Fmr-1 Knockout Mice: a model to study fragile X mental retardation. Cell, 1994, 78: 23–33.

    Google Scholar 

  3. 3.

    BERKOVITZ G.D., WILSON D.P., CARPENTER N.J., BROWN T.R., MIGEON C.J.: Gonadal function in men with the Martin-Bell (fragile-X) syndrome. Am. J. Med. Genet., 1986, 23: 227–239.

    PubMed  Article  CAS  Google Scholar 

  4. 4.

    BOWEN P., BIEDERMAN B., SWALLOW K.A.: The X linked syndrome of macroorchidism and mental retardation: further observations. Am. J. Med. Genet. 1978; 2: 409–414.

    PubMed  Article  CAS  Google Scholar 

  5. 5.

    CARMI R., MERYASH D.L., WOOD J., GERALD P.S.: Fragile-X syndrome asceratined by the presence of macro-orchidism in a 5-month-old infant. Pediatrics, 1984, 74: 883–886.

    PubMed  CAS  Google Scholar 

  6. 6.

    DE GRAAFF E., WILLEMSEN R., ZHONG N., DE DIESMULDERS C.E., BROWN W.T., FRELING G., OOSTRA B.: Instability of the CGG repeat and expression of the FMR1 protein in a male fragile X patient with a lung tumor. Am. J. Hum. Genet., 1995, 57: 609–618.

    PubMed  Google Scholar 

  7. 7.

    DEVYS D., LUTZ Y., ROUYER N., BELLOCQ J.P., MANDEL J.L.: The FMR-1 protein is cytoplasmic, most abundant in neurons and appears normal in carriers of a fragile X premutation. Nature Genet., 1993, 4: 335–340.

    PubMed  Article  CAS  Google Scholar 

  8. 8.

    HINDS H.L., ASHLEY C.T., SUTCLIFFE J.S., NELSON D.L., WARREN S.T., HOUSMAN D.E., SCHALLING M.: Tissue specific expression of FMR-1 provides evidence for a functional role in fragile X syndrome. Nature Genet., 1993, 3: 36–43.

    PubMed  Article  CAS  Google Scholar 

  9. 9.

    HUTTON L., RANKIN R.N., POSZONYI J.: High resolution ultrasound of macro-orchidism in mental retardation. J. Clin. Ultrasound., 1985, 13: 19–22.

    PubMed  Article  CAS  Google Scholar 

  10. 10.

    ITO M., SUGIE H.: Age dependent and tissue specific FMR-1 gene expression in human organs. Nippon Rinsho, 1999, 57: 950–954.

    PubMed  CAS  Google Scholar 

  11. 11.

    JOHANNISSON R., REHDER H., WENDT V., SCHWINGER E.: Spermatogenesis in two patients with the fragile X syndrome. I. Histology: light and electron microscopy. Hum. Genet., 1987, 76: 141–147.

    PubMed  Article  CAS  Google Scholar 

  12. 12.

    SLEGTENHORST-EEGDEMAN K.E., DE ROOIJ D.G., VERHOEF-POST M., VAN DE H.J., BAKKER CE., OOSTRA B.A., GROOTEGOED J.A., THEMMEN A.P.: Macroorchidism in FMR1 knockout mice is caused by increased Sertoli cell proliferation during testicular development. Endocrinology, 1998, 139: 156–162.

    PubMed  Article  CAS  Google Scholar 

  13. 13.

    LACHIEWICZ A.M., DAWSON D.V.: Do young boys with fragile X syndrome have macroorchidism? Pediatrics, 1994, 93: 992–995.

    PubMed  CAS  Google Scholar 

  14. 14.

    LINDSAY S., SPLITT M., EDNEY S., BERNEY T.P., KNIGHT S.J., DAVIES K.E., O’BRIEN O., GALE M., BURN J.: PPM-X: a new X-linked mental retardation syndrome with psychosis, pyramidal signs, and macroorchidism maps to Xq28. Am. J. Hum. Genet., 1996, 58: 1120–1126.

    PubMed  CAS  Google Scholar 

  15. 15.

    LUBS H.A.: A marker X chromosome. Am. J. Hum. Genet., 1969, 21: 231.

    PubMed  CAS  Google Scholar 

  16. 16.

    MALTER H.E., IBER J.C., WILLEMSEN R., DE GRAAF E., TARLETON J.C., LEISTI J., WARREN S.T., OOSTRA B.A.: Characterization of the full fragile X syndrome mutation in fetal gametes. Nature Genet., 1997, 15: 165–169.

    PubMed  Article  CAS  Google Scholar 

  17. 17.

    MARTINEZ-GARCIA F., REGADERA J., COBO P., MARTIN-CORDOVA C., PANIAGUA R., NISTAL M.: Macro-orchidism: new pathogenic and histopathologic aspects. Arch. Esp. Urol., 1994, 47: 59–65.

    PubMed  CAS  Google Scholar 

  18. 18.

    MASON D.Y., SAMMONS R.E.: The labeled antigen method of immunoenzymatic staining. J. Histochem. Cytochem., 1979, 14: 291–302.

    Google Scholar 

  19. 19.

    MEIJER H., DE GRAAF E., MERCKX D.M., JONGBLOED R.J., DE DIE-SMULDERS C.E., EENGELEN J.J., FRYNS J.P., CURFS P.M., OOSTRA B.A.: A deletion of 1.6 kb proximal to the CGG repeat of the FMR1 gene causes the clinical phenotype of the fragile X syndrome. Hum. Mol. Genet., 1994, 3: 615–620.

    PubMed  Article  CAS  Google Scholar 

  20. 20.

    NISTAL M., MARTINEZ-GARCIA F., REGADERA J., COBO P., PANIAGUA R.: Macro-orchidism: light and electron microscopic study of four cases. Hum. Pathol., 1992, 23: 1011–1018.

    PubMed  Article  CAS  Google Scholar 

  21. 21.

    OOSTRA B.A.: A fragile gene. Bioessays, 1995, 17: 941–947.

    PubMed  Article  CAS  Google Scholar 

  22. 22.

    PIERETTI M.: Abscence of expression of the Fmr-1 gene in fragile X syndrome. Cell, 1991, 66 817–822.

    PubMed  Article  CAS  Google Scholar 

  23. 23.

    REYNIERS E., VITS L., DE BOULLE K., VAN ROY B.: The full mutation in the Fmr-1 gene of male fragile X patients is absent in their sperm. Nature Genet., 1993, 4 143–146.

    PubMed  Article  CAS  Google Scholar 

  24. 24.

    TAMANINI F., WILLEMSEN R., VAN UNEN L., BONTEKOE C., GALJAARD H., OOSTRA B.A., HOOGEVEN A.T.: Differential expression of FMR1, FXR1 and FXR2 proteins in human brain and testis. Hum. Mol. Genet., 1997, 6: 1315–1322.

    PubMed  Article  CAS  Google Scholar 

  25. 25.

    THOMAS C.: Fragile X Syndrome. Improving understanding and diagnosis. J.A.M.A., 1994, 19: 7–21.

    Google Scholar 

  26. 26.

    TURNER G., EASTMAN C., CASEY J.: X-linked mental retardation associated with macroorchidism. Journal of medecine genetics. 1975, 12: 367–371.

    Article  CAS  Google Scholar 

  27. 27.

    VALETTE J., GRIMAUD J.A., LANSAC J.: Essai d’interpretation standardisée histopathologique testiculaire dans le cadre de la fértilité masculine. Gynécologie, 1976, 27: 219–223.

    PubMed  CAS  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to A. Pages.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Pages, A., Gentil-Perret, A., Levy, R. et al. Macroorchidisme et spermatogenèse dans le syndrome de l’X fragile. Androl. 11, 226–230 (2001). https://doi.org/10.1007/BF03034635

Download citation

Mots clés

  • Fertilité
  • Macroorchidisme
  • Spermatogenèse
  • Syndrome de l’X Fragile

Keywords

  • Fertility
  • Fragile X syndrome
  • Macroorchidism
  • Spermatogenesis
\