 , .

18:1: 45–49 (1998)

TRISOMY 13 MOSAICISM AT PRENATAL

DIAGNOSIS: DILEMMAS IN INTERPRETATION
 . 1*,  . 2  . .  1
1
Victorian Clinical Genetics Services, Royal Children’s Hospital, Melbourne, Australia
2
Department of Cytogenetics, Royal Women’s Hospital, Melbourne, Australia

Received 6 January 1997

Revised 16 June 1997
Accepted 20 June 1997

SUMMARY
We describe six cases of trisomy 13 mosaicism detected at prenatal diagnosis. Most level I and level II trisomy 13
mosaicism detected at prenatal diagnosis is pseudomosaicism or confined placental mosaicism. Rarely, low-level
mosaicism at chorionic villus sampling or amniocentesis reflects a true fetal mosaicism. In this case, a normal
phenotype is a possible, but not a certain, outcome. Genetic counselling is not straightforward. ? 1998 John Wiley
& Sons, Ltd.
Prenat. Diagn. 18: 45–49, 1998

 : trisomy 13; mosiacism; prenatal diagnosis; pseudomosaicism

INTRODUCTION level II is two or more cells with the same chromo-

Trisomy 13 mosaicism is infrequently detected
at prenatal diagnosis. Hsu et al. (1992) recorded
trisomy 13 in 3·3 per cent of single-cell pseudo-
mosaicism and 4 per cent of multiple-cell pseudo-
mosaicism detected at amniocentesis. The crucial
interpretation to be made is to distinguish between
pseudomosaicism and true fetal mosaicism. If it is
the latter, what predictions can be made about the
phenotype? We report six cases whose study makes
a contribution to these questions. The study was
prompted by the presentation of case 2 below at
our clinic, and we reviewed the remaining five
cases of trisomy 13 mosaicism identified at the
Royal Women’s Hospital, Melbourne, Australia,
over a 5-year period.
CASE REPORTS
We accept a definition of level I mosaicism as a
single abnormal cell found in a prenatal test, while
*Correspondence to: Dr Martin Delatycki, Victorian Clini-
cal Genetics Services, Royal Children’s Hospital, Flemington
Road, Parkville, Victoria 3052, Australia.
somal abnormality in a dispersed culture in a
single flask, or a single abnormal colony in an
in situ culture. Level III mosaicism is two or
more cells or colonies with the same chromosome
abnormality, distributed over two or more
flasks (Gardner and Sutherland, 1996). ‘Pseudo-
mosaicism’ is, by definition, mosaicism that does
not involve either fetal or extrafetal tissues in vivo,
but exists only in cultured cells in vitro. Mosaicism
involving extrafetal tissues in vivo is ‘confined
placental mosaicism’.
True mosaicism
Case 1.—A 38-year-old gravida 5, para 2,
abortia 2 Malaysian mother had amniocentesis at
14 weeks in her fifth pregnancy and level II
47,XX,+13/47,XX,+22/46,XX mosaicism was
shown. Of three cultures in three separate flasks,
one in situ culture showed 46,XX in all cells; one
dispersed culture showed 47,XX,+13 in 7 out of
50 cells; and the remaining dispersed culture
showed 5 out of 50 cells with 47,XX,+22. She
proceeded to fetal blood sampling at 17 weeks
and 100/100 cells were 46,XX. The baby was

CCC 0197–3851/98/010045–05 $17.50

? 1998 John Wiley & Sons, Ltd.
46 . .   .
born at 38 weeks, of weight 3010 g (40th centile),
length 50·8 cm (75th centile), and head circum-
ference 33·3 cm (20th centile). A cord blood
sample showed 47,XX,+13 in 3 out of 100 cells.
Other than jaundice due to ABO blood group
incompatibility which required phototherapy,
and an atrial septal defect demonstrated on
echocardiography, no clinical problems were
identified. Cranial and renal ultrasonography
was normal.
Upon review at age 5Y months, she presented as
a normal baby with no dysmorphic features and
satisfactory neurodevelopmental progress and
growth indices (weight 6·5 kg, head circumference
40·9 cm, both approximately on the 25th centile).
A skin fibroblast study showed 60/60 cells with a
46,XX karyotype. Parental karyotypes were
normal. By age 3 years, the atrial septal defect
had spontaneously closed. At the most recent
examination, at age 3 years 6 months, the child
was entirely normal, both morphologically and
developmentally. Her growth indices were as
follows: height 97·7 cm (50th centile), weight
13·9 kg (25th centile), head circumference 49 cm
(50th centile).
Case 2.—Chorionic villus sampling (CVS) for
advanced maternal age in a 42-year-old woman
showed trisomy 13 in 7 of 20 cells in one long-term
culture and in 33 of 50 cells in the second culture
(level III mosaicism). Mosaic trisomy 13 was
subsequently observed at amniocentesis, with
47,XX,+13 in 1/28 colonies of an in situ study, and
at cordocentesis 1/400 lymphocytes had the
47,XX,+13 karyotype. A decision was made to
continue the pregnancy. At birth, the child was not
dysmorphic, apart from a simple helix unilaterally,
and had normal growth indices (weight 75th per-
centile, length 50th percentile, head circumference
75th percentile). Neurological examination was
unremarkable.
An umbilical cord blood sample taken at birth
showed 1/150 cells with 47,XX,+13 and the
remaining 149 cells 46,XX. Karyotyping of placen-
tal samples revealed 47,XX,+13 in 2/32 cells in the
amnion and 0/27 cells in the smooth chorion.
Long-term culture of two villus biopsies, one adja-
cent to the cord insertion, the other near the
placental margin, showed 47,XX,+13 in 1/30 cells
and 3/30 cells, respectively.
The child is currently 17 months of age and
neurological development and growth parameters
remain entirely within the normal range.
. ., . 18: 45–49 (1998)
Possible pseudomosaicism/confined placental
mosaicism
Case 3.—This child was born following a preg-
nancy in which amniocentesis had been done for
advanced maternal age, which demonstrated
47,XX,+13[4]/46,XX[23] in one dispersed cell
culture. Three other independent cultures did not
show any cells with trisomy 13 and the interpret-
ation was of a level II mosaicism. Ultrasounds at
18 and 31 weeks’ gestation were normal. Fetal
blood sampling was declined. Examination of the
child at birth was normal and the karyotype on a
cord blood was 46,XX.
Case 4.—A 35-year-old woman had an amnio-
centesis elsewhere at 14 weeks’ gestation and a
level II trisomy 13 mosaicism was identified. Two
of three independent cultures (one in situ, one
suspension) showed 46,XY. The third, a suspen-
sion culture, had 6/20 metaphases with
47,XY,+13, with the remaining 14/20 being
46,XY. She came to our service for fetal blood
sampling at 18 weeks and 100/100 cells were
46,XY; at repeat amniocentesis, 50/50 colonies
from an in situ study were 46,XY. The pregnancy
continued and at birth the child was morphologi-
cally normal. There was a normal karyotype
(46,XY) in umbilical blood (45 cells) and from
three different placental sites.
Case 5.—A 31-year-old woman had CVS for a
linkage study in the setting of a family history of
haemophilia A. Karyotyping was done as part of
the study and this showed 47,XX,+13 in all 10
cells in short-term culture and in all 15 cells in
long-term culture. The pregnancy was terminated
and fetal skin was karyotyped, revealing 46,XX in
50 cells. No other tissues were available for further
study once this result became available. The CVS
material was restudied, and 35 further cells from
the long-term culture were analysed. Five were
46,XX and the remaining 30 were 47,XX,+13.
Case 6.—A 38-year-old woman had CVS per-
formed at 11 weeks’ gestation for advanced mater-
nal age. Trisomy 13 mosaicism was observed in
two independently established long-term cultures,
with 5 of 15 cells showing 47,XY,+13 in the first
culture and 4 of 15 cells showing 47,XY,+13 in the
second. The patient proceeded to amniocentesis at
15 weeks’ gestation. Fetal anatomy on ultrasound
at that time was unremarkable. Examination of 32
? 1998 John Wiley & Sons, Ltd.
  13
colonies from an in situ study revealed a 46,XY
karyotype in all. The child was recently born at
term with a birth weight of 3·1 kg (15th centile),
length of 49 cm (25th centile), and a head circum-
ference of 33·5 cm (10th centile). The baby was not
dysmorphic. Further cytogenetic studies were not
undertaken.
DISCUSSION
We report six cases of trisomy 13 mosaicism at
prenatal diagnosis, of which two (cases 1 and 2)
showed demonstrably true low-grade mosaicism
and four (cases 3–6) may represent pseudo-
mosaicism or confined placental mosaicism. In
case 1, we assume that there had been a very low
grade fetal–placental mosaicism, with no discern-
ible effect on the phenotype. The existence of the
trisomy 22 cell line at amniocentesis is unexplained
and may represent cultural artefact. The picture in
case 2 was similar, with the trisomic cell line
apparently comprising only a very small fraction
of the placenta and an extremely small fraction of
at least those fetal and neonatal tissues that were
sampled.
Trisomy 13 mosaicism detected at prenatal diag-
nosis, especially if at a low level, is a dilemma for
genetic counsellors and families. Is this true mosai-
cism, involving the fetus; and if so, what would be
the phenotypic outcome? The phenotype of true
mosaicism for trisomy 13 mosaicism is very broad,
although it is rare that normal intellect is present in
reported cases (Delatycki and Gardner, 1997).
Albeit follow-up investigations (amniocentesis
after CVS, fetal blood sampling after an amnio-
centesis) may show a normal karyotype and
ultrasonography may indicate a morphologically
normal fetus, it can never be excluded that there is
a true minor cell line in the fetus. If this ‘minor
line’ were to involve brain tissue, a significant
effect on the intellect could eventuate. Cytogenetic
findings can be incongruent between tissue types,
as case 1 illustrates. The amniotic fluid sample
(which includes cells shed from the fetal skin)
showed mosaicism and yet this was not confirmed
at skin fibroblast culture, and the normal karyo-
type from the fetal blood was followed by the
finding of mosaicism on cord blood analysis. Poss-
ibly, this may be due to sampling variation in
which the true fraction of abnormal cells is very
low (for example, in counting 60 cells, a true 3 per
cent mosaicism would be undetected in 14 per cent
? 1998 John Wiley & Sons, Ltd.
 47
of analyses). Equally, at least in skin, there could
be a variegated tissue distribution, with the biop-
sied region happening to be 46,N while other areas
of skin may have included 47,+13 cells.
Hsu et al. (1992), in a major review of mosaicism
detected at amniocentesis, documented 15 cases of
trisomy 13 mosaicism. Eleven of these were fol-
lowed up and five were recorded as abnormal,
although the details of the abnormalities are not
given. In the U.K. CVS study (Association of
Clinical Cytogeneticists Working Party, 1994),
there was one case of mosaic trisomy 13 detected
among 88 mosaic CVS cases. Here, non-mosaic
trisomy 13 was found on karyotyping of fetal
tissue after a spontaneous abortion. Wang et al.
(1994) reported five cases of mosaic trisomy 13 at
CVS. In three cases, the trisomic cell line was
present on direct preparation but not on culture
and a normal outcome was recorded. Another case
was of mosaicism for i(13q) in the direct prep-
aration but not on culture and a follow-up amnio-
centesis showed 46,XX. The fifth case showed
47,XX,+13[12]/48,XX,+7,+13[6]/46,XX[2] on
direct preparation and 48,XX,+7,+13[10]/
46,XX[63] on culture, and amniocentesis yielded a
normal result. The outcome of the pregnancy is
not recorded. In the U.S. collaborative study on
CVS (Ledbetter et al., 1992), there were seven cases
of mosaic trisomy 13; five in the direct preparation
only, the other two on culture only. Five were
considered confined placental mosaicism and
the other two (one each from the direct prep-
aration and culture groups) were therapeutically
aborted with no follow-up on fetal tissue. Two of
these cases were mosaic for the presence of a
Robertsonian translocation involving two copies
of chromosome 13q (one each from the direct
preparation and culture groups), both resulting
in a liveborn normal child. Malin et al. (1987)
reported three cases of level II mosaic trisomy 13
diagnosed on amniocentesis, each of which was
followed by the birth of a child with a normal
karyotype and normal 1-year follow-up examina-
tion, and these authors made the presumption of
pseudomosaicism. Fejgin et al. (1992) recorded
a case in which termination was elected on the
finding of 4/10 trisomy 13 cells in amniotic fluid
and 1/160 at fetal blood sampling, but at patho-
logical examination 25 cells from kidney, dia-
phragm, heart, blood, skin, and placenta were
all 46,XX.
Other reports of mosaic trisomy 13 with a
normal outcome include one case from Smidt-
. ., . 18: 45–49 (1998)
. ., . 18: 45–49 (1998)

48
Table I—Features of the six cases of prenatally diagnosed mosaic trisomy 13

Indication Final
Initial for Cytogenetic Further Cytogenetic Postnatal interpretation Phenotype
Case prenatal prenatal outcome of prenatal outcome of Ultrasound Pregnancy cytogenetic of the of the
No. test done test test test(s) this test(s) findings outcome analysis mosaicism child

1 Amnio AMA Level II FBS 46,XX NAD Liveborn CB True ASD,

47,XX,+13/ infant 47,XX,+13/ mosaicism otherwise
47,XX,+22/ 46,XX (3/100) NAD
46,XX SF 46,XX
2 CVS AMA Level III Amnio Amnio NAD Liveborn CB True Unilateral
47,XX,+13/ FBS 47,XX,+13/ infant 47,XX,+13/ mosaicism simple
46,XX 46,XX (1/28) 46,XX (1/150) helix,

. .   .
FBS Placenta otherwise
47,XX,+13/ 47,XX,+13/ NAD
46,XX 46,XX (6/119)
(1/400)
3 Amnio AMA Level II Declined — NAD Liveborn CB 46,XX PS/CPM NAD
47,XX,+13/ infant
46,XX
4 Amnio AMA Level II FBS 46,XY NAD Liveborn CB 46,XY PS/CPM NAD
47,XX,+13/ infant Plancenta
46,XY 46,XY
5 CVS Linkage Non-mosaic — — — TOP Fetal skin PS/CPM —
study for 47,XX,+13 46,XX
haemophilia initially.
A Later
47,XX,+13/
46,XX (5/35)
? 1998 John Wiley & Sons, Ltd.

6 CVS AMA Level III Amnio 46,XY NAD Liveborn Not done PS/CPM NAD
47,XY,+13/ infant
46,XY

AMA=Advanced maternal age; Amnio=amniocentesis; CB=umbilical cord blood sample; CVS=chorionic villus sampling; FBS=fetal blood sampling; NAD=no
abnormality detected; ASD=atrial septal defect; PS/CPM=possible pseudomosaicism/confined placental mosaicism; TOP=termination of pregnancy.
 
Jensen et al. (1993) and three cases from Pittalis
et al. (1994). Roland et al. (1994) had one case of
mosaic trisomy 13 among 26 cases of confined
placental mosaicism. They found no difference
in outcome comparing these 26 cases with 52
age- and parity-matched controls but the specific
outcome of the mosaic trisomy 13 case is not
stated. Of 39 cases of mosaic aneuploidy reported
by Fryburg et al. (1993), there was one of
level III trisomy 13 mosaicism which was proven
to be genuine on a karyotype undertaken
post-termination.
In a major review by the European Collabora-
tive Research on Mosaicism in CVS (Hahnemann
and Vejerslev, 1997), 192 examples of mosaicism
studied in considerable detail were gleaned from
1415 cases of CVS mosaicism or non-mosaic fetal–
placental discordance from a total of 92 246 CVS
procedures. Of these 192, 15 had trisomy 13 mosai-
cism. In 13 of these, the fetus was normal; the
trisomic line was confined to trophoblast in seven
of the 13, in two it was confined to villus mesen-
chyme, and in two both trophoblast and villus
contained the trisomic line. In the remaining two
examples, all three lineages (fetal, trophoblast,
mesenchyme) showed trisomy, either mosaic or
non-mosaic.
Thus, it appears that most but not all level II
47,+13/46 mosaicism may be pseudomosaicism,
due to cultural artefact. Our case 1 is instructive in
making the point that even if the fetus actually has
a 47,+13 cell line in the context of a level II
mosaicism, it is not necessarily the case that this
would have a noticeable phenotypic effect. As
Malin et al. (1987) point out, ‘couples need to
know and often rely on the outcome of similar
cases in order to make an informed decision
regarding the continuation or termination of
the pregnancy’, and the cases that we describe add
to the limited body of knowledge bearing on the
issue.
Two other issues warrant mention. Could
mosaicism be the result of a full trisomy self-
correcting to disomy, and therefore could uni-
parental disomy (UPD) be present? Slater et al.
(1994, 1995) have shown that neither maternal nor
paternal UPD 13 is associated with an abnormal
phenotype, and thus, to the best of our present
understanding, the possibility of UPD 13 need not
be a concern. Secondly, since there is a theoretical
possibility that mosaicism could include gonadal
tissue, parents will need to understand that their
child should, at an appropriate age, learn of the
? 1998 John Wiley & Sons, Ltd.
13  49
advisability of prenatal diagnosis for him or
herself.
Case 5 demonstrates that what can initially
appear as non-mosaic trisomy 13 could never-
theless be a cytogenetically normal fetus, although
with mosaic trisomy 13 in extrafetal tissues. This
experience led us to change our laboratory policy
and we now count 30, rather than 15, cells in
long-term CVS culture in cases of apparent non-
mosaic trisomy 13 associated with normal ultra-
sound findings. If the finding of mosaicism had
been known initially, the couple would have been
offered the option of proceeding to amniocentesis.
Case 6 appears to be an example of confined
placental mosaicism with the trisomy 13 cell line
not being detected at amniocentesis.
In conclusion, the finding of mosaic trisomy 13
at prenatal diagnosis often represents pseudo-
mosaicism or confined placental mosaicism, but
even true fetal mosaicism is not necessarily associ-
ated with congenital defects and/or mental abnor-
mality, at any rate in the context of low-level
(single-digit percentage) mosaicism. If there are
no trisomy 13 cells at fetal blood sampling
and if ultrasonography is normal, an optimistic
approach can be taken. Nevertheless, low-level
mosaicism of the fetus cannot be completely
excluded and in that case, neither can the
possibility of some effect on the phenotype and
intellectual function.

We thank J. A. Sullivan of the Dunedin
Hospital for details of the cytogenetics in the first
amniocentesis and postnatal studies in case 4.
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