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Clinical significance of chimerism.

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American Journal of Medical Genetics Part C (Seminars in Medical Genetics) 151C:148– 151 (2009)
Clinical Significance of Chimerism
Twins have been previously classified as either monozygotic or dizygotic. In recent years, fascinating, nontraditional mechanisms of twinning have been uncovered. We define chimerism versus mosaicism,
touch on chimerism in the animal world, and explain timing of chimerism in humans. In addition, we
discuss when to suspect chimerism in patients, and how to proceed with diagnostic evaluation and
confirmation. ß 2009 Wiley-Liss, Inc.
KEY WORDS: chimerism; intermediate twinning
How to cite this article: Abuelo D. 2009. Clinical significance of chimerism. Am J Med Genet
Part C Semin Med Genet 151C:148–151.
‘‘She was the mother of Chimaera
who breathed raging fire, a creature
fearful, great, swift-footed and
strong, who had three heads, one
of a grim-eyed lion; in her hinderpart, a dragon; and in her middle, a
goat, breathing forth a fearful blast
of blazing fire. Her did Pegasus and
noble Bellerophon slay.’’ Hesiod,
Most of us have been taught that twins
are either identical or non-identical
[Hall, 2003], that is, either monozygotic
(MZ), having arisen from one fertilized
egg, or dizygotic (DZ), from two eggs
fertilized by two sperm. However,
reports of the occurrence of monozyDr. Dianne Abuelo is Associate Professor
of Pediatrics at the Warren Alpert School
of Medicine of Brown University and the
Director of the Genetic Counseling Center at
Rhode Island Hospital and Hasbro Children’s
Hospital. She has authored over 60 publications, travels to Latin American to teach
genetic courses, and she is actively involved
in resident and fellowship education.
*Correspondence to: Dianne Abuelo,
M.D., Genetic Counseling Center, Rhode
Island Hospital and Hasbro Children’s
Hospital, Warren Alper School of Medicine
of Brown University, 593 Eddy Street,
Providence, Rhode Island 02903.
DOI 10.1002/ajmg.c.30213
Published online 17 April 2009 in Wiley
InterScience (
ß 2009 Wiley-Liss, Inc.
gous twins of unlike sex [Edwards et al.,
1966] or unlike karyotypes [O’Donnell
et al., 2004] have uncovered some
fascinating, non-traditional mechanisms
for twinning, which do not conform to
either of the two traditional categories.
These unusual cases are more common
than have been appreciated up to now
and have raised doubts about the validity
of the accepted tests for zygosity testing,
which divide results into simple MZ
or DZ categories. Many of the cases of
unusual types of twinning involve
the formation of individuals who are
Chimerism has been imagined since
ancient times, for example, in Greek
mythology, the chimera was a monstrous
creature composed of the body of a
lioness, the head of a goat and the tail of
a snake. Nowadays, we know that
chimerism, although not as dramatic in
presentation, exists in animals and also in
humans. They are fascinating individuals
who are composed of two genetically
different types of cells. Only recently
with current technology, have we been
able to understand the causes, clinical
manifestations and complications. Here
we present a simplified classification,
with the aim of raising physicians’
awareness about when to suspect chimerism in their patients, and then once
suspected, how to proceed with diagnostic evaluation and confirmation.
First, chimerism must be distinguished from mosaicism. In chimerism
cells derive from more than one
genetically distinct zygote. In mosaicism
there are also different cell types, but
they come from a single zygote.
First, chimerism must be
distinguished from mosaicism.
In chimerism cells derive from
more than one genetically
distinct zygote. In mosaicism
there are also different cell types,
but they come from a
single zygote.
For example, an individual who is
mosaic for trisomy 21 has one cell line
that is normal and another cell line with
47 chromosomes including an extra
chromosome number 21. In the mosaic
individual, both cell lines have arisen
from a single fertilized egg. It is possible
for a chimeric individual to have a similar
karyotype, that is, a mixture of normal
and trisomy 21 cells, but these cell
lines can be shown to have originated
from separate zygotes, as exemplified by
the set of twins described below by
O’Donnell et al. [2004].
The phenomenon of freemartinism in
cows and other animals has been recognized for many years [Lillie, 1917] and
explained the observation of intersex in
these animals. It was known that in some
pairs of bovine mixed-sex twins, the
females were born with both ovaries and
testes. This was explained by placental
connections between the female and
her male co-twin. Not only does an
exchange of hematopoietic cells occur,
but also primitive gonadal cells can
migrate from one twin to the other. In
cows, this has been found to be a
relatively frequent phenomenon in
mixed sex twins, but it has not yet been
found in human counterparts.
When considering the various possible
mechanisms of chimerism, it is helpful to
think about the timing of the causative
event. We should distinguish chimerism
that occurs during fetal, childhood, and
adult life from that which occurs during
fertilization and embryogenesis.
Childhood or Adult Life
An iatrogenic form of chimerism is
produced by bone marrow or other
tissue or organ transplantation. There is
a large literature related to transplantation immunology, which will not be
considered here, except for a description
of one instructive case (described below
in the section on chimerism in individuals) discovered during preparation
for transplantation.
Fetal Life
Fetomaternal cell trafficking can lead
to ‘‘microchimerism:’’ Many normal
women in the population develop
chimerism during pregnancy, and
there is much current interest in the
resulting short-term and long-term
effects. An example of a short-term
effect is the dermatologic condition
known as ‘‘pruritic urticarial papules
and plaques of pregnancy,’’ or PUPPP.
Fetomaternal cell trafficking
can lead to ‘‘microchimerism:’’
Many normal women in the
population develop chimerism
during pregnancy, and there is
much current interest in the
resulting short-term and
long-term effects. An example
of a short-term effect is the
dermatologic condition known
as ‘‘pruritic urticarial papules
and plaques of pregnancy’’,
The skin eruption appears during the
last trimester of pregnancy and/or early
postpartum period, and is due to migration of cells from a male fetus through
the placenta and maternal circulation, to
the mother’s skin [Aractingi et al., 1998].
A recent study of microchimerism
following induced or spontaneous
abortion [Sato et al., 2008] showed that
52.8% of women who had male chorions had detectable Y chromosomal
DNA in their peripheral blood specimens following the abortion; these cells
slowly decreased and became undetectable by 30 days. However, fetal cells can
be sequestered and persist in other
maternal tissues for considerable time
and it has been hypothesized that they
may play a role in the development of
autoimmune disorders many years after
childbirth [Evans et al., 1999].
Trafficking of cells also occurs in the
other direction, from mother to fetus.
Maloney et al. [1999] discovered that
maternal cells can persist in their offspring even into adult life.
Embryonic Life
We will be focusing on the phenomenon
of chimerism that takes place during
the earliest times of fertilization and
embryogenesis. Examples will be
given of chimerism in MZ twins, in
DZ twins and even within a single
Chimerism in Monozygotic Twins
Theoretically, MZ twins cannot have
chimerism as they are supposed to have
the identical genetic makeup. However,
chimerism can occur, but it is probably
underdetected, since it is only considered if the twins have dramatically
different phenotypes. For instance, there
have been several reports of monochorionic (MC) twins who are discordant for sex, including one by Souter et al.
[2003], who reported an example of
chimerism that occurred during early
embryogenesis. In another example,
chimerism was recognized because a
pair of MZ twins was discordant for
Down syndrome [O’Donnell et al.,
2004]. In this case report, the MC
diamniotic (DA) pregnancy was thought
to be suspicious for Down syndrome in
one of the twins based on thick nuchal
translucency measurements in one twin.
A chorionic villous specimen at 13 weeks
showed a normal result; amniocentesis
from both sacs was suggested but refused
by the parents. At delivery, one twin had
a normal phenotype and the other
showed the dysmorphic features of
Down syndrome. Blood from both
twins showed an admixture of normal
and trisomic cells, indicating hematopoietic chimerism. However, tissue
studies of skin and buccal cells of the
dysmorphic twin showed only trisomy
21 cells, whereas buccal cells from the
normal twin showed only normal cells.
Zygosity studies by microsatellite analysis on blood genomic DNA showed that
the twins were indeed ‘‘identical,’’ in
the sense that they were derived from the
same zygote. The extra chromosome
21 was paternally derived. Possible
mechanisms include a normal 46, XY
conception followed by postzygotic gain
of the extra chromosome in one twin, or
a paternal meiosis II error followed by
trisomy rescue (considered less likely).
In any event, this case illustrates that
zygosity studies should ideally be performed on both blood and fibroblast
cells to make it possible to distinguish
hematopoietic chimerism from mosaicism.
Chimerism in Dizygotic Twins
Souter et al. [2003] reported twins who
had a MC placenta and were originally
assumed to be MZ. In the second
trimester, discordance for sex was noted.
They found blood chimerism in the
twins, that is, a mixture of XX and XY
cells, but skin fibroblasts were 46,XX in
the female twin and 46,XY in the male
twin. Each of the twins carried
two populations of lymphocytes, the
major subgroup from the male and
a minor subgroup from the female.
Fluid injection of the placenta showed
fine arterial-to-arterial anastomoses
on the fetal surface. The pregnancy
had been established by in vitro fertilization, which is considered to be one of
the risk factors for chimerism. One of
the possible explanations involves fusion
of the trophoblasts from the two
embryos before implantation. Another
theoretical explanation involves double
fertilization of the meiotic products
of a single oocyte with two sperm,
which was ruled out in this case by
DNA marker studies. Continued consideration of this mechanism awaited
a subsequent report, also by Souter
et al. [2007] as described in the
next section.
In cases of twins with no external
phenotypic abnormalities, chimerism
can be cryptic. For example, Aoki et al.
[2006] described a case of MC twins
(again, would have been assumed to be
MZ), conceived by induced ovulation,
who were found to be discordant for
blood types. The twins were also
discordant in other tissues, that is, blood
lymphoctes and hair roots. Thus, they
were discovered to have DZ chimerism.
The authors concluded that determination of zygosity in twins conceived via
assisted reproduction should be done
with caution.
Chimerism in Intermediate
Types of Twinning
Souter et al. [2007] reported a pair of
spontaneously conceived twins with
46,XX/46XY karyotypes in lymphocytes,
skin fibroblasts and gonads. The chimerism
was discovered because one twin had
ambiguous genitalia. Molecular genetic
studies were very surprising: there was a
single maternal contribution, but two
paternal genetic contributions. Thus, these
twins were more genetically alike than DZ
twins, but less alike than MZ twins.
Different mechanisms for this intermediate
type of twinning were hypothesized, but
the cause remains uncertain.
Chimerism in a Single Individual
A landmark case in chimerism was
reported by Yu et al. [2002]. This involved
a phenotypically normal woman with
renal failure who was being evaluated for
renal transplantation. Results of the usual
histocompatibility testing suggested that
she was not the biologic mother of two of
her three sons. To explain this surprising
result, multiple studies on a variety of
tissues were done, including blood grouping, HLA studies, cytogenetic testing,
analysis of short tandem-repeat microsatellite markers, mixed-lymphocyte culture and cell-mediated lysis. Blood studies
showed only a single cell line in the patient,
but her other tissues showed chimerism.
The mechanism in this patient is thought
to involve separately fertilized XX zygotes,
which then went on to fuse together early
in development; thus she is a ‘‘tetragametic’’ chimera. The frequency of this
condition is unknown and will remain
undetected if blood is the only tissue that is
studied. The authors note that the increase
in twinning associated with in vitro fertilization can also theoretically lead to an
increase in tetragametic chimerism, due to
either double fertilization of an ovum with
two nuclei, or close contact and fusion
between the embryos before implantation.
The earliest circumstance in which
chimerism should be suspected is when
there is apparent mosaicism in chorionic
villus sampling (CVS) specimens. Prenatal diagnosis by CVS can sometimes
give puzzling results involving apparent
mosaicism, with two different cell lines
when there is only one fetus present.
This can be due to either confined
placental mosaicism or to confined
placental chimerism. In the case
reported by Falik-Borenstein et al.
[1994], a CVS specimen had a normal
female cell line and also included a cell
line with 47,XY þ9. Subsequent
amniocentesis and postdelivery peripheral blood specimens were normal. The
abnormal cell line most likely came from
a vanished twin. Examination of the
placenta proved the existence and
demise of the karyotypically abnormal
Postnatally, chimerism can be suspected when MC twins have discordant
phenotypes or blood groups, as
described above. In addition, other
unusual signs, such as peculiar skin
pigmentary findings, especially in products of assisted reproductive technology,
should raise the possibility of chimerism
Postnatally, chimerism can be
suspected when MC twins
have discordant phenotypes or
blood groups, as described
above. In addition, other
unusual signs, such as
peculiar skin pigmentary
findings, especially in products
of assisted reproductive
technology, should raise the
possibility of chimerism
In singletons, clinical clues include
patchy skin pigmentation, as described
by Lipsker et al. [2008], whose patient
had bicolored skin pigmentation and
another patient described by GerardBlanluet et al. [2008], who also had
unusual pigmentary abnormalities,
iris heterochromia and hemihypertophy.
In addition, a history of a vanishing
twin raises suspicion, especially if the
surviving twin has any abnormalities.
Making a diagnosis of chimerism can be
present a challenge, since few clinicians
know how to order or interpret testing.
Major clinical laboratories that offer
chimerism testing focus on evaluation
pre- and post-bone marrow transplant
rather than twins. While the testing
seems complex and impractical to
obtain, most molecular genetic laboratories across the country have the
technological ability to offer testing
and could be requested to do so on a
case-by-case basis. As Malan et al. [2006]
outline the principle behind the testing
is fairly straightforward: to distinguish
chimerism from mosaicism by using
autosomal markers (DNA testing). If a
single maternal and paternal contribution is found for all markers (at all loci),
mosaicism can be diagnosed. However,
if two or more alleles are demonstrated
(at least at one locus), chimerism is likely.
At this point, more complex studies can
be initiated in attempt to document and
elucidate the mechanism of chimeric
It is important to emphasize that
when blood karyotype does not correlate with the clinical phenotype in
twins, tissues in addition to blood
should be tested. Making the diagnosis
of chimerism involves comparing blood,
skin biopsy, and/or buccal smears [Bourthoumieu et al., 2006].
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