Cytogenetic analysis of women with ovarian defects revealed that the chromosome abnormalities are associated with 14% of the analyzed cases. Interestingly, among the majority of the abnormalities, approximately 70% of the defects involved the X chromosome in the form of 45,XO or variant. Mechanisms underlying the chromosome defects have been reported earlier [7
]. Loss of X chromosome (Turner's syndrome) is a result of either anaphase lag or mitotic nondisjunction in the early embryonic stage [14
]. The typical phenotypic changes observed were short stature, webbing of neck, shield chest, cubitus valgi, and absence of secondary sexual characters. Ultrasonographic examination of majority of cases revealed that the uterus is not visualized, and a few showed hypoplastic uterus. Other types of defects observed include testicular feminization (primary amenorrhea) with 46,XY karyotype in 12 individuals. The X-Y interchange hypothesis states that at meiosis in males, interchanges between pairing areas of the X and Y chromosomes could produce X chromosome that contains some Y material or a Y chromosome that contains some X material [17
]. These XY females display gonadal dysgenesis. It has also been found that different portions of the chromosome could overlap thereby causing the variation in the severity of the sexual disorders [18
]. X-chromosome mosaicism with 45,XO/46,XX karyotype may be the consequence of elimination of one of the X chromosomes during the subsequent divisions of zygote that is initially with a normal female chromosome complement [19
]. Mos,46,XX/46,XY karyotype is a product of double fertilization by X-and Y-bearing sperms [20
]. Although there are several reports on the occurrence of mosaicism [9
], this is the first report of two unique structural abnormalities, involving X chromosome in association with ovarian failure.
An interesting karyotype associated with ovarian failure was 46,XX,del(Xq21-22) and q28. In addition to secondary amenorrhea, the proband was also found to have b
tosis and e
picanthus inversus s
yndrome (BPES). Earlier studies suggested that the BPES was associated with the autosomal abnormality, involving 3q23 and 7p13 [22
]. By linkage analysis, critical region for BPES has been mapped at 3q22-q23 [25
]. However, this is the first report of BPES phenotype associated with X chromosome abnormality. The explanation could be either that BPES phenotype is a multifactorial, or the sequence presents between 3q22-q23 has homology with sequence at Xq21-q22 and/or Xq28. However, so far, six putative genes for ovarian function have been identified. Of these, DIAPH2 and FMR1 genes were localized on Xq22 and Xq28, respectively [26
]. As the abnormality observed in this study involved both the regions (Xq22 and 28) suggesting that the ovarian defect in this case might be due to this deletion. There is evidence that the sex chromosomes (X and Y) have homologous sequence on autosomes [27
]. Molecular mechanisms of the X-chromosome deletions in familial cases are well documented [29
]. Deletion between Xq21-q22 in this case may be due to recombination between homologous chromosomes during the meiosis, most probably in mother. During the recombination, one of the X chromosomes might have gained the additional copy of Xq21-q22. When the egg carrying the X chromosome with the deletion of Xq21-q22 is fertilized with the normal sperm, it would have led to this abnormality.
Another abnormality associated with primary amenorrhea was mos,45,XO/46,X+ringX that had both structural and numerical abnormality (Figures and . Mosaicism of 45,XO and 46,X+ringX was found in 1
1 ratio. The structural abnormality of ring formation of one of the X chromosome was found only in metaphase possessing 46,Xr(X) chromosome complement (). This unique abnormality may be due to the occurrence of the deletion during gametogenesis in one of the parents followed by nondisjunction in the early stage of the embryonic development. Ring X chromosomes have been recognized in girls with Turner syndrome, often with mosaicism for a 45,XO cell line. In some instances, they are associated with mental retardation and a distinct phenotype of short stature, facial dysmorphism characterized by long palpebral fissures, a relatively broad nasal root and tip, anteverted nares, a wide mouth with a thin upper lip, soft tissue syndactyly, and mental handicap. Careful cytogenetic characterization of the ring X chromosomes has suggested that the smaller the size of the ring X, the more likely are the findings of mental handicap and dysmorphic features in the patient. This has been attributed to failure of dosage compensation, by X chromosome inactivation, for the genes on the ring chromosome [31
A region of the proximal long arm of the X chromosome is required in cis for inactivation of the chromosome [34
] and contains the XIST gene, which is expressed exclusively from the inactive X chromosome [36
] and is necessary for X inactivation in mice [37
]. Smaller ring chromosomes may lack the XIST locus, rendering them functionally disomic for the genes present on the ring [38
]. The phenotype of individuals with small ring X chromosomes presumably results from the continued expression of genes in the pericentromeric region of the X chromosome due to failure of inactivation [8
Patients with Turner syndrome present with a variety of phenotypes. However, in most X-chromosome abnormalities, a preferential inactivation of the abnormal X occurs, and this results in a mild phenotype [40
]. Small ring X chromosomes lacking the XIST locus (Candidate Gene for X-inactivation Center) may not be subject to X inactivation and therefore present with a greatly affected phenotype [40
]. Our patient presented with primary amenorrhea showed Turner phenotype, probably due to the equal presence of 45,XO cells along with the mosaic pattern. However, we did not investigate the presence of XIST in the cells that showed.46, Xr(X) karyotype.
Very few cases with X chromosome and autosome translocations have been reported [41
]. Chromosome 3, 9 and 15 are the frequent partners of X-autosome translocations [42
]. Here in our study, we report autosome defects at a very low frequency that include chromosomes 2, 3, 4, 7, 9, 15, 17, and 19 involved in translocations, inversions and deletions that are associated abnormal ovarian development and function.
To summarize, our study showed novel X-chromosome abnormalities associated with ovarian defects, and these observations would be helpful for genetic counseling. Besides, infertility clinics could use them to decide suitable strategies to help patients. The sequence analysis of the breakpoints of both autosomes and X chromosomes involved could help in understanding the molecular basis of ovarian defects and to map the genes involved.