A 47,XXY fetus resulting from ICSI in a man with an elevated frequency of 24,XY spermatozoa

Dear Sir, There has been considerable debate and controversy about genetic risks associated with intracytoplasmic sperm injection (ICSI) (Martin, 1996; Persson et al., 1996). As well as concerns about the increased frequency of the cystic fibrosis transmembrane regulator mutations and Y chromosome deletions in infertile males, there is also mounting evidence of increased risks for chromosomal abnormalities following ICSI. Studies of infertile men have repeatedly demonstrated an increased frequency of constitutional chromosomal abnormalities which are mainly sex chromosomal abnormalities and translocations (Montag et al., 1997; Pauer et al., 1997). Reports based on prenatal diagnosis in ICSI pregnancies have indicated an increased risk of sex chromosomal abnormalities (In't Veld et al., 1995; Liebaers et al., 1995). However, the risk does not appear to originate only from men with constitutional chromosomal abnormalities. Infertile men with normal 46,XY somatic karyotypes have been shown to have an increased frequency of chromosomally abnormal spermatozoa. Our laboratory has studied men with oligozoospermia, asthenozoospermia and/or teratozoospermia by both sperm karyotype analysis using the human sperm/hamster oocyte fusion method and by fluorescence in-situ hybridization (FISH) analysis using chromosome-specific DNA probes. (Moosani et al., 1995; Martin, 1996). Sperm karyotyping in five infertile men demonstrated a significant increase in the frequency of numerical chromosomal abnormalities in infertile men compared to control donors. Similarly, FISH analysis showed a significantly increased frequency of disomy 1 and XY disomy in 10 infertile patients. One patient in particular showed a very high frequency of XY disomy of 1.39% compared with a mean of 0.16% in normal males (χ2 = 269.13, P < 0.0001). At the time of analysis this man had not fathered any children. The patient was 28 years of age and had been in an infertile union for 7 years. He had oligoteratozoospermia with 3×106 spermatozoa/ml, 37% motile spermatozoa and 27% normal forms. He had a normal endocrinological profile, with normal concentrations of follicle stimulating hormone, luteinizing hormone and testosterone. Somatic karyotyping of 115 lymphocytes yielded a normal 46,XY karyotype, with no evidence of mosaicism. Prior to ICSI, the couple was told that there was a possible increased risk in the frequency of offspring with sex chromosome abnormalities. The patient underwent ICSI and fathered a pregnancy which was found to have a 47,XXY karyotype after prenatal diagnosis. This is particularly striking as the father had the highest frequency of 24,XY spermatozoa among 10 infertile males studied. It is quite likely that a 24,XY spermatozoon was selected during ICSI and caused the 47,XXY conception. Another possibility is that the spermatozoon was normal 23,Y but fertilized a 24,XX egg. Unfortunately no fetal tissue was saved, so parent of origin studies were not possible. However, Van Opstal et al (1997) demonstrated that in six cases of sex chromosome aneuploidy following ICSI, all had a paternal origin. In some cases, this may occur because the father is a somatic or germinal mosaic with some 47,XXY cells. Since 115 lymphocytes were studied in our patient, this rules out mosaicism of ⩾3% (confidence level = 0.95) in lymphocytes. However, it is certainly possible that mosaicism was present in the testis. Another possibility is that chromosome pairing anomalies in infertile males could lead to meiotic arrest in some cells causing oligozoospermia and aneuploidy in other cells capable of completing spermatogenesis. It is known that a disruption of chromosome pairing causes meiotic arrest in males (Egozcue et al., 1983). The sex chromosome bivalent is particularly susceptible to pairing abnormalities since there is generally only one crossover in the pseudoautosomal region and meioses leading to the 47,XXY karyotype have been shown to have a reduction in recombination in the XY bivalent (Hassold et al., 1991). Therefore, infertile men may have decreased pairing and recombination causing both meiotic arrest (oligozoospermia) and non-disjunction of the sex bivalent (Martin, 1996). The fact that we identified the elevated frequency of sex chromosomal abnormalities in spermatozoa before the abnormal ICSI pregnancy in this case suggests that FISH analysis of spermatozoa may be a valuable clinical test in the infertility clinic.