MONOSOMY X MOSAICISM (MOSAIC TURNER SYNDROME)
45,X is a common cause of early pregnancy loss accounting for about 7% of spontaneous abortions. Based on the liveborn frequency of 45,X (also called Turner syndrome) of 1-2/10,000, it is estimated that less than 1% of 45,X conceptuses will survive to term. About 30% of Turners syndrome patients are mosaic with both a 45,X cell line and either a 46,XX cell line or one containing a rearranged X chromosome (Hook and Warburton 1983). The phenotype in a liveborn infant is relatively mild considering the high embryonic lethality and it has been hypothesized that possibly all liveborn females with Turner syndrome carry a cell line containing two sex chromosomes, but it may be confined to a specific tissue (e.g. the placenta) or too low frequency to detect. In fact studies using molecular means to detect low level mosaicism suggest that most Turner's individuals have some diploid cells. Individuals with detectable mosaicism (i.e. observed in amniotic fluid or blood will on average have a milder phenotype than those with 100% 45,X in amniotic fluid or blood. Molecular studies show than the single X chromosome is maternally derived in about 80% of 45,X cases. This is probably a consequence of greater pairing problems between the X and Y chromosome during male meiosis, as well as perhaps a greater tendency to somatic loss of a Y as compared to an X chromosome.
45,X mosaicism is also a common and probably harmless finding in blood cultures from normal women. It appears that as a consequence of aging and errors occurring in cell divisions that the inactivated X-chromosome tends to be lost (Surralles et al. 1999). Although, in the past it was suggested that 45,X mosaicism in a phenotypically normal woman might be associated with increased miscarriage rates, that does not appear to be true. The frequency of blood mosaicism for 45,X is similar among women with recurrent miscarriage as those without -- when age is taken into account (Horsman et al.1987).
45,X cells are also seen in the blood of normal males though at a lower rate than females. In one study (Bukvic et al. 2001, Mut Res 498:159-167), about 2% of lymphocytes in 30 year old males were missing a Y chromosome, whereas an average of 10% of cells showed sex chromosome loss in 5 centenarian males.
There are numerous sources for information on Turner syndrome and mosaic Turner syndrome including differences between 45,X/ 46, XX and 45,X/46,XY mosaicism and we will not attempt to address them here. It is important to emphasize that most patients have been identified after birth because of presence of abnormalities and it is therefore difficult to assess how often such mosaicism is present but not associated with any adverse effects.
Most cases of 45,X mosaicism identified at CVS are not confirmed in follow-up amniocetesis or in fetal tissues. This is one of the most common mosaicisms found and generally results from a post-conception loss of one sex chromosome in early embryo or placental development.
Sachs et. al. (1990) reported on 7 cases of monosomy X mosaicism detected by CVS. Six cases involved 45,X and 46,XX cells, while one case was mosaic for normal male cells and monosomy X cells. In these cases the percentage of abnormal cells measured on CVS direct studies ranged from 2% to 50%. In six cases the pregnancies resulted in a normal outcomes. One pregnancy was terminated due to a lack of growth.
Vejerslev and Mikkelsen (1989) report 19 cases of 46,XX/45,X mosaicism detected on CVS. Of these 12 cases resulted in birth of a normal-looking female with 46,XX cells (it was not clear what the outcome of the other 7 cases were--i.e. whether they ended in a livebirth or not). Two cases of 45,X detected in direct CVS but 46,XY in cultured CVS were detected , but all follow-up studies in palcenta and fetus showed only 46,XY cells.
Schuring-Blom et al. 1993 report one case of 45,X being found in all of 12 cells analyzed from CVS but follow-up amniocentesis revealed a normal male karyotype. A healthy boy was born at term.
Several cases of 45,X mosaicism in CVS are reported by a collaborative group working in the UK ( Prental Diag 14:363-379 (1994)). Of three cases of 45,X directed in direct preparations only in which outcome is known, two resulted in normal 46,XX females and one resulted in a normal 46,XY male. Of those cases where the 45,X cells were detected in cultured CVS, and where outcome was known, 4 resulted in a normal 46,XX female , one in a normal 46,XY male. In one case pregnancy was terminated after amniocentesis also showed 45,X/46,XX mosaicism.
van den Berg et al. (2000) report of 45,X identified in all of 31 cells analyzed by direct CVS and 46,XY in all of 24 cultured cells. X/XY mosaicism was observed on both cultured and uncultured amniocytes. Ultrasound showed a normally developed male fetus. Pregnancy was terminated and no significant abnormalities were detected on autopsy, specifically there was no sign of any female differentiation.
Lazebnik et al. (1996) identified six cases that were 45,X/46,XY mosaics on CVS. Amniocentesis indicated normal 46,XY karyotypes for three of these fetuses-- all of which showed normal male genitalia on detailed ultrasound. As was the case for one case in which amniocentesis was refused. 45,X/46,XY mosaicism was obsevered in amniocentesis for two others, in one of which ultrasound analysis showed ambiguous genitalia.
Amniocentesis and Postnatal Outcomes
The phenotype of 45,X/46,XX msoaicsim varies considerably from individual to individual and, as for other types of mosaicism, it is not clear that the level of 45,X cells on amniocentesis is predictive of the exact level found in newborn blood or phenotypic outcomes. It has been reported that 86% of prentally detected 45,X/46,XX will result in a phenotypically normal liveborn female; However, it should be considered that some of the manifestations of Turner syndrome (e.g. premature ovarian failure) may only be identified later in life ( Hsu 1998).
Huang et al. (2002) identified 17 cases of prentally detected 45,X/46,XX mosaicism. 1 of these cases demonstrated growth restriction on prenatal ultrasound and resulted in a stillbirth. The remaining 16 cases were normal on ultrasound examination. Five pregnancies were terminated and three were lost to follow-up. Of the 8 livebirths with follow-up, two showed features of Turner Syndrome and 6 were apparently normal at birth.
Confirmation of 45,X/46,XY mosaicism on CVS by aminocentesis is low. Also, studies which are published using postnatally diagnosed individuals who are 45,X/46,XY mosaics often have an ascertainment bias. The individuals in the studies usually have phenotypic features which allowed for postnatal diagnosis and exclude the majority of 45,X/46,XY mosaics who are phenotypically normal.
The study by Lazebnik et al. (1996) stresses the importance of having follow-up by ultrasound. They looked at all cases over the period of five years where 45,X/46,XY was found on CVS and/or amniocentesis. True 45,X/46,XY mosaicism was indicated for two detected initially on CVS. There were another two cases,where 45,X/46,XY mosaicism was detected on amniocentesis (with no previous CVS). Ultrasound analysis of three of these fetuses showed normal male genitalia and one fetus with ambiguous genitalia. This pregnancy was then terminated. This study recognizes that outcomes differ greatly when comparing postnatal and prenatal studies: prenatal studies have consistently showed that about 5% of fetuses prenatally diagnosed as 45,X/46,XY mosaics have phenotypic abnormalities (ie. ambiguous genitalia). Thus, about 95% of these fetuses are found to be phenotypically normal at birth. One of these studies also recognizes that about 27% of 45,X/46,XY mosaic fetuses with normal phenotype have abnormal gonadal histology which could give rise to gonadoblastoma (cancer) if not treated. Because there is no obvious correlation between amniocentesis results and phenotypic outcome, other types of testing and screening such as ultrasound is suggested to be considered by the researchers.
Huang et al. (2002) looked at 105 pregnancies where a 45,X cell line was found. Seven of these cases showed 45,X/46,XY mosaicism. Ultrasound examination was normal for all. Out of the seven cases, one was terminated through ultrasound findings showed a normal male, one was lost to follow up, and one was mosaic yet phenotypically normal at birth. The other four males were also phenotypically normal at birth.
Roland et al. (1990) showed it is possible to obtain a karyotype of 45,X though the postnatal follow-up shows a mosaic genotype of 45,X/46,X,dic(Y)(q11) [meaning there is a part of the Y chromosome present] in 50% of blood cells. The male infant showed no abnormal phenotypic features postnatally.
A review by Telvi et al. (1999) reviewed postnatally ascertained 45,X/46,XY cases. Some males (proportion unknown since these were ascertained on such features postnatally) who appeared normal at birth can develop late-onset “Turner syndrome-like” abnormalities such as dysmorphic features, mild mental retardation, infertility, and Ulrich-Turner stigmata (drooping of upper eyelid, extra “webbing” on the neck). Gonadal dysgenesis, infertility, low testosterone levels, and azoospermia has also been reported in postnatally ascertianed cases. They also found that there was no correlation between severity of phenotype and ratio of 45,X and 46,XY cell lines in the blood.
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