The Principles of Clinical Cytogenetics - Extra Materials - Springer

Cytogenetics of Spontaneous Abortion 333
the placental chorionic villous tissue, there might be karyotypic differences between the direct preparation
and long-term culture methods. This is a reflection of the different origins of the trophoblast
cells and the extraembryonic mesodermal cells.
Confined placental mosaicism is a potential concern even in the fetus with a normal karyotype.
The presence of confined placental mosaicism has been associated with abnormal mid-trimester hCG
levels (42) and with increased risk for adverse pregnancy outcome, including growth retardation and
fetal demise (43). Confined placental mosaicism could also be a factor leading to spontaneous abortion.
A normal fetal karyotype does not rule out a cytogenetic abnormality in the placenta as a factor
leading to pregnancy failure, suggesting the need for karyotype analysis of both fetal and placental
tissues in unexplained stillbirths (43). Although the incidence of mosaicism in CVS series is often
cited in the 1–2% range, Kalousek and colleagues detected confined placental mosaicism in 11 of 54
spontaneous abortions studied and have suggested that the frequency might be especially high in
growth-disorganized embryos (44). The cytogenetic contribution to human pregnancy failure might
thus be even higher than estimates based on early series, because those cases were often examined
using only a single tissue source, and some morphologically aberrant conceptuses classified as euploid
might actually have been the result of undiagnosed mosaicism.
Recent molecular studies have shown that mosaic autosomal trisomies can arise either from errors
in meiosis, with subsequent loss of one of the chromosomes leading to production of a euploid cell
line, or from the postzygotic duplication of one of the chromosomes in an originally euploid cell line.
The likelihood of one or the other mechanism might vary depending on the particular chromosome
involved. Robinson and colleagues suggest that the mosaic trisomies involving chromosomes 13, 18,
21, and X most often result from somatic loss of a supernumerary chromosome that arose from meiotic
nondisjunction (45). Mosaic trisomy 8, on the other hand, might be more likely to survive when
the aneuploid line is derived later, as a result of a postzygotic error in mitosis in a conceptus that was
originally chromosomally normal.
Mosaicism in the placenta could be a significant determining factor in survival of the trisomic
conceptus. Those cases of trisomies 13 and 18 that survive to term appear to have a diploid cell line
in the cytotrophoblasts, whereas those lost early in gestation are less likely to show a normal cell line
(46,47). Mosaicism does not appear to be necessary for survival in trisomy 21, possible due to a less
deleterious effect of this trisomy on placental function (46).
The presence of a euploid cell line in the fetus does not necessarily imply a genetically normal
fetus. If the mosaicism is the result of “rescue” of a trisomic cell line, the possibility of both remaining
chromosomes of the pair originating from a single parent becomes a concern. This condition,
uniparental disomy, can often have severe consequences in the affected fetus due to the potential loss
of heterozygosity with expression of recessive traits only carried by one parent or because of effects
of inappropriate imprinting (see Chapter 19). Thus, multiple sampling sites should be evaluated in
cases where a cytogenetic abnormality is strongly suspected, even if a normal karyotype is identified
on initial evaluation. Molecular studies could be indicated to rule out uniparental disomy in ongoing
pregnancies that have been identified as mosaic. More study regarding the effects of uniparental
disomy on embryogenesis is clearly needed.
Chimerism
Another possible cause for the presence of more than one cell line in a fetus is chimerism. The
chimera of classical mythology was a creature with the head of a lion, the body of a goat, and the tail
of a serpent. Although the mythical chimera composed of several unrelated species is purely fanciful,
individuals with cells derived from two separate fertilized eggs are known to exist in humans and
other mammals. Postzygotic fusion of dizygotic twin zygotes results in a single chimeric individual.
Chimerism can explain the presence of two cell lines, in a single individual, where neither can be
derived from the other. This is the most likely mechanism underlying 46,XX/46,XY hermaphroditism
and could also explain a 45,X/69,XXY fetus described by Betts and colleagues (48). A number of