To the Editor:
That so-called 45,X infertile or sterile males are seldom ascertained is well illustrated by a recent case report in Fertility and Sterility (1) in which the authors only refer to three other infertile males (2-4). Yet, it seems pertinent to point out that at least six further 45,X infertile males have been described in full (5-10); moreover, another patient was found among 84 infertile men (11).
In all these 11 patients, the 45,X karyotype turned out to include an unbalanced Y;autosome translocation with variable breakpoints; remarkably, the involved autosome was always an acrocentric: 13, three times; 14, twice; 15, twice; 21, once, and 22, twice (in one patient the autosome was not identified). Such a defective spermatogenesis contrasts with the normal fertility of 45,X males carrying a comparable translocation, namely a tdic(Y;15) in two families (12, 13) or a tdic(Y,22) also in two families (14,15).
Horacio Rivera, M.D., Ph.D.
Instituto Mexicano del Seguro Social and Universidad de Guadalajara
1. Mancini A, Zollino M, Leone E, Grande G, Festa R, Lecce R, et al. A case of 45,X male: genetic reevaluation and hormonal and metabolic follow-up in adult age. Fertil Steril 2008;90:2011.e17-21.
2. Arnemann J, Schnittger S, Hinkel GK, Tolkendorf E, Schmitke J, Hansmann I. A sterile male with 45,X0 and a Y;22 translocation. Hum Genet 1991;87:134-8.
3. Buonadonna AL, Cariola F, Caroppo E, Di Carlo A, Fiorente P, Valenzano MC, et al. Molecular and cytogenetic characterization of
an azoospermic male with a de-novo Y;14 translocation and alternate centromere inactivation. Hum Reprod 2002;17:564-9.
4. Brisset S, Izard V, Misrahi M, Aboura A, Madoux S, Ferlicot S, et al. Cytogenetic, molecular and testicular tissue studies in an infertile 45,X male carrying an unbalanced Y;22 translocation: case report. Hum Reprod 2005;20:2168-72.
5. Turleau C, Chavin-Colin F, de Grouchy J. A 45,X male with translocation of euchromatic Y chromosome material. Hum Genet 1980;53:299-302.
6. Copelli S, Castiñeyra G, Levalle O, Aszpis S, Mormandi E, Targovnik H. PCR analysis of Y-chromosome sequences in a 45,X male patient and review of the literature. Arch Androl 2000;44:137-45.
7. Siffroi JP, Benzacken B, Angelopoulou R, Le Bourhis C, Berthaut I, Kanafani S, et al. Alternative centromeric inactivation in a pseudodicentric t(Y;13)(q12;p11.2) translocation chromosome associated with extreme oligozoospermia. J Med Genet 2001;38:802-6.
8. Alves C, Carvalho F, Cremades N, Sousa M, Barros A. Unique (Y;13) translocation in a male with oligozoospermia: cytogenetic and molecular studies. Eur J Hum Genet 2002;10:467-74.
9. Dávalos IP, Rivera H, Vásquez AI, Gutiérrez-Angulo M, Hernández-Vázquez MC, Cortina-Lunas FA, et al. A 45,X sterile male with Yp disguised as 21p. Am J Med Genet 2002;111:202-4.
10. Cui YX, Xia XY, Pan LJ, Wang YH, Yao B, Huang YF. An infertile male with apparent 45,X turned out to have 45,X,der(Y)t(Y:13)(q11.2;q12),– 13: clinicopathologic and cytogenomic studies. Fertil Steril 2007;88:1676.e7-11.
11. Penna Videaú S, Araujo H, Ballesta F, Ballescá JL, Vanrell JA. Chromosomal abnormalities and polymoprhisms in infertile men. Arch Androl 2001;46:205-10.
12. Andersson M, Page DC, Pettay D, Subrt I, Turleau C, de Grouchy J, et al. Y;autosome translocation and mosaicism in the aetiology of 45,X maleness: assignment of fertility factor to distal Yq11. Hum Genet 1988;79:2-7.
13. White LM, Treat K, Leff A, Styers D, Mitchell M, Knoll JH. Exclusion of uniparental inheritance of chromosome 15 in a fetus with a familial dicentric (Y;15) translocation. Prenat Diag 1998;18:111-6.
14. Callen DF, Sutherland GR, Carter RF. A fertile man with tdic(Y;22): how a stable neo-X1X2Y sex-determining mechanisms could evolve in man. Am J Med Genet 1987;3(Suppl):151-5.
15. Morales C, Soler A, Bruguera J, Madrigal I, Alsius M, Obon M, et al. Pseudodicentric 22;Y translocation transmitted through four generations of a large family without phenotypic repercussion. Cytogenet Genome Res 2007;116:319-23.
Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2009.07.1009
The Authors Respond:
The letter by Dr. Rivera gives us the opportunity specify some important points in genotype-phenotype correlations of 45, X males carrying an Y;autosomal translocation (1).
Infertility due to oligo-azoospermia can be a consequence of either a disruption/deletion of the AZFs (azoospermic factors), which is critical for spermatogenesis, or inactivation of a fully preserved AZF due to gene silencing (2,3). Dr. Rivera does not consider this different outcome in discussing about fertility of 45,X males with Y;acrocentric translocations. They are not a homogeneous genetic category. Confirming this point, Morales et al. (4) recently reported a pseudodicentric 22;Y translocation transmitted through four generations without impaired spermatogenesis, in which the AZF genes were preserved. As a matter of fact, fertility is possible only if AZF is preserved.
The Yq breakpoint in our patient falls within the spermatogenesis region, which is disrupted, and azoospermia in our patient is consistent with this genotype. More importantly, the main message of our report was not to make a revision of all the previous published cases. On the contrary our paper deals with the follow-up in adult age and with metabolic consequences of hypotestosteronemia. Hypogonadism, likely pathogenically related to the genetic constitution, could be involved in the development of the metabolic syndrome in our patient.
Antonio Mancini, M.D.
Erika Leone, M.D.
Alfredo Pontecorvi, M.D.
Chair of Endocrinology
Catholic University of the Sacred Heart
Roberto Festa, M.D.
Institute of Clinical Pathology
University “Politecnica delle Marche”
Marcella Zollino, M.D.
Giovanni Neri, M.D.
Institute of Genetics
Catholic University of the Sacred Heart
1. Mancini A, Zollino M, Leone E, Grande G, Festa R, Lecce R, Pontecorvi A, Neri G. A case of 45,X male: genetic reevaluation and hormonal and metabolic follow-up in adult age. Fertil Steril 2008;90:2011.e17-21.
2. Hsu LYF: Phenotype/karyotype correlations of Y chromosome aneuploidy with emphasis on structural aberrations in postnatally diagnosed cases. Am J Med Genet 1994; 53: 108 – 140.
3. Alves C, Carvalho F, Cremades N, Sousa M, Barros A. Unique (Y;13) translocation in a male with oligozoospermia: cytogenetic and molecular studies. Eur J Hum Genet 2002;10:467-74.
4. Morales C, Soler A, Bruguera J, Madrigal I, Alsius M, Obon M, Margarit E, Sanchez A. Pseudodicentric 22;Y translocation transmitted through four generations of a large family without phenotypic repercussion. Cytogenet Genome Res 2007; 116:319-23.
Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2009.07.1010