1001.e1. a Laboratoire de Cytogenetique, Hôpital Saint Antoine, Paris; b Department of Reproductive Biology, Cytogenetics, Gynaecology and

Transcription

1 Whole-arm translocations between chromosome 1 and acrocentric G chromosomes are associated with a poor prognosis for spermatogenesis: two new cases and review of the literature François Vialard, M.D., a,b,c Marc Nouchy, M.D., a Valérie Malan, M.D., a Jean-Louis Taillemite, M.D., a Jacqueline Selva, M.D., Ph.D., b,c and Marie-France Portnoï, M.D. a a Laboratoire de Cytogenetique, Hôpital Saint Antoine, Paris; b Department of Reproductive Biology, Cytogenetics, Gynaecology and Obstetrics, Centre Hospitalier Intercommunal Poissy-Saint Germain, Poissy; c Institut National de la Santé et de la Recherche Médicale (INSERM U 407), Faculté de Médecine Lyon-Sud, Oullins, France Objective: To analyze unusual translocations involving a chromosome 1 whole arm and an acrocentric G chromosome p arm found in two men with azoospermia. Design: Case report with review of the scientific literature. Setting: Cytogenetics department. Patient(s): Two men with azoospermia and normal hormonal levels. Interventions(s): Peripheral blood lymphocytes were obtained for karyotype, and metaphases were studied by standard GBG, RBG, and CBG banding procedures. Main Outcome Measure(s): Karyotype GBG, RBG, and CBG banding. Result(s): Karyotype revealed balanced translocation involving a chromosome 1 whole arm and an acrocentric G chromosome p arm: 46,XY,t(1;21)(q11;p13) (patient 1) and 46,XY,t(1;22)(q11;p11) (patient 2). Conclusion(s): With regard to published cases of whole-arm translocation of human chromosome 1 with an acrocentric p arm and a maternal origin of these abnormalities, we argue for an impairment of meiosis resulting in a high probability of quadrivalent XY-body interaction. Male factor infertility might be due to two poor prognostic factors, first the involvement of human chromosome 1 (and its heterochromatic region) and second the involvement of an acrocentric chromosome p-arm breakpoint. This probable interaction between the pachytene quadrivalent and XY body might explain azoospermia. (Fertil Steril 2006;86:1001.e by American Society for Reproductive Medicine.) Key Words: Human chromosome 1, infertility, acrocentric p arm, translocation, azoospermia From the first large survey of karyotypes in infertile men, it became evident that compared with newborn infants, infertile men have a higher prevalence of chromosome abnormalities (1). Several chromosome screenings have established the frequency and type of chromosomal abnormalities in either patients affected by severe oligozoospermia or those undergoing IVF/intracytoplasmic sperm injection (ICSI) procedures (2). The frequency increases with the severity of infertility, and especially the raised incidence of chromosome abnormalities was linked to the severity of the alteration in sperm count (1). Various chromosome rearrangements are linked to male factor infertility. Acrocentric chromosomes are known to be frequently involved, especially robertsonian translocations (1). This may be the result of interaction of robertsonian translocation derivate with the XY bivalent (3). Furthermore, in the nucleus, acrocentric chromosomes are known to be Received September 15, 2005; revised and accepted January 9, Reprint requests: Francois Vialard, Department of Reproductive Biology, Cytogenetics, Gynaecology and Obstetrics, CHI Poissy-Saint Germain, 10 rue du Champ Gaillard, Poissy Cedex, France (FAX: ; fvialard@hotmail.com). linked to the nucleolus organizer region (NOR) close to the XY bivalent (4). In contrast with the autosomal chromosomes, most of the X and Y chromatins are not paired during male meiosis at the zygotene and pachytene stage. Additionally, the sex chromosomes undergo transcriptional inactivation, meiotic sex chromosome inactivation. These differences are reflected in remodeling of XY chromatin into heterochromatin, thus forming the XY body, or sex body, or XY bivalent. This mammalian pachytene spermatocytes subnuclear domain differs from the autosomal domain both by lack of RNA synthesis and by sequestration of an array of proteins not found elsewhere in the spermatocyte s nucleus (for review [5]). Recently, rearrangements of human chromosome 1, the largest chromosome, were found to be linked to male factor infertility and especially to azoospermia (6). In this study of infertile males with a balanced autosomal rearrangement, 26.5% had a chromosome 1 breakpoint. This chromosome has been shown to be close to human chromosome Y in mature sperm cells (7) but also to chromosome X (8). Sperm donor studies have found no translocations involving chro /06/$32.00 Fertility and Sterility Vol. 86, No. 4, October 2006 doi: /j.fertnstert Copyright 2006 American Society for Reproductive Medicine, Published by Elsevier Inc e1

2 mosome 1 but have identified robertsonian translocations (9 out of 75) (9, 10). Previous studies have reported a relation between male sterility and chromosome 1 whole-arm translocation and an acrocentric chromosome p arm (6, 11 14). Here we report two new cases of azoospermia associated with reciprocal translocation of chromosome 1 whole arm and acrocentric G chromosome p arm. We discuss the probable failed mechanism in spermatogenesis and argue for the combination of two poor prognostic factors for fertility. CASE REPORTS Patient 1 was a healthy 36-year-old man referred to us for azoospermia discovered after failure to conceive for up to 2 years. Follicle-stimulating hormone, LH, and T levels were normal (3.7 IU/L, 2.9 IU/L, and 5.2 ng/ml, respectively). Clinical phenotype was normal. The testes were normal in size and consistency. Karyotyping was performed for possible testicular sperm retrieval and ICSI. Patient 2 was a healthy 37-year-old man referred to us for azoospermia also discovered after a failure to conceive for up to 10 years. Follicle-stimulating hormone, LH, and T levels were normal (4.2 IU/L, 6.4 IU/L, and 11.3 ng/ml, respectively). The testes were normal in size and consistency, and testicular ultrasound detected no abnormality. Karyotyping was performed for possible ICSI and testicular sperm retrieval. There was no family history of miscarriage or infertility in either patient. MATERIALS AND METHODS Cytogenetic analysis was performed by standard methods with use of cultured lymphocytes from the patients. Spread metaphases were examined by GTG, CBG, and NORs banding techniques. RESULTS In patient 1, a reciprocal translocation was found between chromosomes 1 and 21. The karyotype was 46,XY,t(1;21) (q11;p13). The patient s parents were not available for testing. A testicular biopsy was performed, and no spermatozoa were found for ICSI. In patient 2, a reciprocal translocation was found between chromosomes 1 and 22. The karyotype was 46,XY,t(1;22) (q11;p11). A testicular biopsy was performed, and no spermatozoa were found. Histologic analysis suggested incomplete maturation arrest of spermatogenesis with few spermatids and no spermatozoa. No material had been conserved for meiosis analysis. The couple decided on intrauterine insemination with donor sperm. Parental karyotypes showed that the translocation was of maternal origin, and the proband s sister had a normal karyotype. DISCUSSION We describe here two cases of azoospermia with a reciprocal translocation involving a chromosome 1 whole arm and an acrocentric G chromosome p arm. A similar maternal inherited translocation was previously reported, t(1;22)(q11;p11), in two infertile brothers (14), one of whom had oligospermia and the other azoospermia. Four cases of translocation involving a chromosome 1 whole arm and D acrocentric chromosomes have been described in infertile men: two t(1;15)(q11;p11), one in a man with azoospermia (12) and one in a patient without sperm data (6); one t(1;13)(q11.p13) associated with azoospermia (11); and one t(1;14)(p11;q11) without sperm data (13). Hence, five out of six patients with a translocation involving a chromosome 1 whole arm and a short arm of the acrocentric chromosome had azoospermia (Table 1). These findings strongly suggest that this particular chromosome rearrangement severely affects male fertility. When the carrier status of the parents was available, the translocation was of maternal origin or de novo but never paternally inherited. Although it was not statistically significant, Bache et al.(6) also found that the majority of breakpoints on chromosome 1 were inherited from the mother. TABLE 1 Whole-arm translocation between chromosome 1 and acrocentric chromosome. 46,XY,t(1;13)(q11;p13)? Azoospermia (11) 46,XY,t(1;15)(q11;p11) De novo Azoospermia (12) 46,XY,t(1;15)(q11;p11)? Unknown (6) 46,XY,t(1;14)(p11;q11)? Unknown (13) 46,XY,t(1;22)(q11;p11) Maternal 2 brothers: (14) One with azoospermia One with oligospermia ( /ml) 46,XY,t(1;21)(q11;p13)? Azoospermia Present study 46,XY,t(1;22)(q11;p11) Maternal Azoospermia Present study 1001.e2 Vialard et al. Chromosomes 1 and G whole-arm translocation Vol. 86, No. 4, October 2006

3 These findings support the hypothesis that rearrangements on chromosome 1 lead to normal female meiosis and may affect male meiosis (15). This was confirmed by the predominance of female chromosome rearrangements in couples with recurrent miscarriages where unbalanced translocations are lethal (16). To our knowledge, no translocation involving a chromosome 1 whole arm and a G chromosome has been reported in women with recurrent miscarriages. Our two patients show a discordance between nonobstructive azoospermia, normal hormonal levels, and normal testicular volumes. In our experience, meiotic arrest is the most frequent similar situation, also described by Lorda-Sanchez et al. (14). Further studies are needed to confirm that translocations inducing meiotic arrests do not affect hormonal levels or testicular volumes. Recently, an excess of chromosome 1 breakpoints has been noted in male factor infertility (6), with 123 chromosome 1 breakpoints out of 464 in a population of infertile men with chromosome rearrangement. Five breakpoints were frequently found on 1p32, 1p22, 1q12, 1q21, and 1q24. Genetic screening of the 1q21 region indicated the absence of a single gene defect. Different hypotheses have been proposed to explain the high rate of chromosome 1 breakpoints in infertile men. First, the disruption of male meiosis-specific genes at breakpoints was suggested, but fluorescence in situ hybridization mapping excluded this hypothesis (6). The other hypotheses were the interaction of chromosome 1 with the XY body, synaptonemal disturbances linked to large heterochromatic blocks, and the presence of a large chromosomal domain, the integrity of which must be preserved for normal spermatogenesis (17). The exact mechanism by which chromosomal abnormalities can induce gametogenesis failure is still not clear. Different hypotheses have been put forward to explain the alteration in spermatogenesis. First, interaction at the pachytene stage between the pachytene quadrivalent and the XY body may explain the failed meiosis and the male-female difference in deleterious effects. In a mouse meiosis study, Forejt and Ivanyi (18) suggested that nonrandom associations between the XY body and the quadrivalent might produce interference with the early X chromosome inactivation in the primary spermatocyte, which would be required, according to the Lifschytz hypothesis (19), for normal spermatogenesis. This hypothesis has been confirmed (20), and extension of XY inactivation to the associated quadrivalent autosomes has been demonstrated. The authors related this extended inactivation to male sterility. Another hypothesis was synaptonemal disturbances, because spermatogenic failure was observed in the case of large pericentric inversion of chromosome 1 or translocation (21). A recent study in t(x;16) mice has demonstrated meiotic silencing in unsynapsed chromosome 16 (MSUC) involved in translocation (22). Taking into account this result, Sun et al. (23), in an analysis of a t(y;1) infertile patient, discuss the hypothesis that infertility in this patient might be due to transcriptional repression of the part of chromosome 1 involved in the translocation. This repression finally silenced some genes necessary for the progression of meiosis. Another case of t(y ;1)(q12 ;q12) infertility with loss of the heterochromatic region of chromosome 1 was also reported (24). In this case, the rearrangement caused unpairing of sex chromosomes followed by meiosis I arrest at the zygotene/pachytene stage, apoptotic degeneration of germ cells, and azoospermia. However, although excess chromosome 1 breakpoints in male infertility are clearly demonstrated, this cannot explain the high frequency of azoospermia. In this same study (6), there were 20 cases of azoospermia (46.5%) (azoospermia frequency 35.4% for other chromosomes) among 43 cases for which the sperm count was known. To explain azoospermia in our cases we need to take into account the presence of the acrocentric chromosome. An association with the XY body is frequent in rearrangements involving an acrocentric chromosome (25). Bache et al. (6) also report excess breakpoints on an acrocentric p arm in infertile patients. In this study, the p arm was involved in 27 translocations, in 14 patients with oligospermia and 13 with azoospermia. Therefore, the involvement of the chromosome p arm in translocations could not in itself explain the frequency of azoospermia, as in our cases. The presence of another poor prognostic factor seems to be necessary. TABLE 2 Previous chromosomal abnormalities involving the chromosome 1 (except whole-arm translocation) and acrocentric p arm. 46,XY,t(1;15)(q21;p11)? Unknown (28) 46,XY,t(1;15)(q21;p13) De novo Azoospermia (29) 46,XY,t(1;21)(p13;p13)? Azoospermia (6) 46,XY,t(1;21)(q21;p11)? Azoospermia (6) Fertility and Sterility 1001.e3

4 TABLE 3 Previous chromosomal abnormalities involving the chromosome 9 or 16 and acrocentric p arm. 46,XY,t(9;21)(q11;p13) De novo Unknown (6) 46,XY,t(9;22)(p11;p11)? Unknown (30) 46,XY,t(16;21)(q12;p11)? Azoospermia (6) 46,XY,t(16;22)(p13;q11)? Azoospermia (6) In addition, the interaction of the heterochromatin region and the nucleolus needs to be taken into account. An association has been reported between the heterochromatin region of chromosomes 1 and 9 and the interphase nucleolus (26). Therefore, a disturbance of meiosis, when chromosomes 1, 9, and 16 are involved, cannot be excluded, even though an association with the XY body was not confirmed in pericentric inversion of chromosomes 1 and 9 (27). When chromosome 1, 9, or 16 was involved in a translocation with the acrocentric p arm, azoospermia was noted in 10 of 11 patients (one with oligospermia) (Tables 1 3 [6, 28 30]). 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