i×rN\1\i ni\cNosis, voi.

17:3: 201–242 (1997)
RARE TRISOMY MOSAICISM DIAGNOSED IN
AMNIOCYTES, INVOLVING AN AUTOSOME
OTHER THAN CHROMOSOMES 13, 18, 20, AND
21: KARYOTYPE/PHENOTYPE CORRELATIONS
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18
1
Prenatal Diagnosis Laboratory of New York City/Medical and Health Research Association of N.Y., Inc., NY,
U.S.A.;
2
New York University School of Medicine, New York City, NY, U.S.A.;
3
Genzyme Genetics, Santa Fe,
NM, U.S.A.;
4
Henry Ford Hospital, Detroit, MI, U.S.A.;
5
University of Connecticut Health Center, Farmington,
CT, U.S.A.;
6
University of California, San Diego, CA, U.S.A.;
7
Baylor College of Medicine, Houston, TX, U.S.A.;
8
Allina Cytogenetics Laboratory, Minneapolis, MN, U.S.A.;
9
SouthWest Genetics, San Antonio, TX, U.S.A.;
10
Brigham & Women’s Hospital, Boston, MA, U.S.A.;
11
Children’s Hospital Eastern Ontario, Ottawa, Canada;
12
University of Utah, School of Medicine, Salt Lake City, UT, U.S.A.;
13
Credit Valley Hospital, Mississauga,
Ontario, Canada;
14
University of Washington, Seattle, WA, U.S.A.;
15
Kaiser Medical Center, San Jose, CA,
U.S.A.;
16
University of British Columbia, Vancouver, B.C., Canada;
17
British Columbia Children’s Hosp.,
Vancouver, B.C., Canada;
18
North York General Hospital, Toronto, Canada
Received 20 June 1996
Revised 14 October 1996
Accepted 22 October 1996
SUMMARY
In order to determine the significance of trisomy mosaicism of an autosome other than chromosomes 13, 18, 20,
and 21, 151 such cases diagnosed prenatally through amniocentesis were reviewed. These rare trisomy mosaicism
cases include 54 from 17 cytogenetic laboratories, 34 from a previous North American mosaicism survey, and 63
from published reports. All were cases of true mosaicism with information available on pregnancy outcome, and
with no evidence of biased ascertainment. There were 11 cases of 46/47,+2; 2 of 46/47,+3; 2 of 46/47,+4; 5 of
46/47,+5; 3 of 46/47,+6; 8 of 46/47,+7; 14 of 46/47,+8; 25 of 46/47,+9; 2 of 46/47,+11; 23 of 46/47,+12; 5 of
46/47,+14; 11 of 46/47,+15; 21 of 46/47,+16; 7 of 46/47,+17; 1 of 46/47,+19; and 11 of 46/47,+22. As to the risk
of an abnormal outcome, the data showed a very high risk (>60 per cent) for 46/47,+2, 46/47,+16, and 46/47,+22;
a high risk (40–59 per cent) for 46/47,+5, 46/47,+9, 46/47,+14, and 46/47,+15; a moderately high risk (20–39 per
cent) for 46/47,+12; a moderate risk (up to 19 per cent) for 46/47,+7 and 46/47,+8; a low risk for 46/47,+17; and
an undetermined risk, due to lack of cases, for the remaining autosomal trisomy mosaics. Most cases were evaluated
at birth or at termination, so subtle abnormalities may have escaped detection and developmental retardation was
not evaluated at all. Comparison of the phenotypes of prenatally diagnosed abnormal cases and postnatally
diagnosed cases with the same diagnosis showed considerable concordance. Since the majority of anomalies noted
are prenatally detectable with ultrasound, an ultrasound examination should be performed in all prenatally
diagnosed cases. In cytogenetic confirmation studies, the data showed much higher confirmation rates in cases with
abnormal outcomes than in cases with normal outcomes [81 per cent vs. 55 per cent for fibroblasts (from skin, fetal
tissue, and/or cord); 88 per cent vs. 46 per cent for placental cells; 22 per cent vs. 10 per cent for blood cells]. The
confirmation rate reached 85 per cent when both fibroblasts and placental tissues were studied in the same case (with
trisomic cells found in one or the other, or both). Therefore, one must emphasize that both fibroblasts and placental
Addressee for correspondence: Lillian Y. F. Hsu, MD, Prenatal Diagnosis Laboratory of New York City, 455 First
Avenue—Room 027, New York, NY 10016, U.S.A.
CCC 0197–3851/97/030201–42 $17.50
1997 by John Wiley & Sons, Ltd.
tissues should be studied. Except for 46/47,+8 and 46/47,+9, PUBS is of limited value for prenatal diagnosis of rare
trisomy mosaicism. DNA studies for UPD are suggested for certain chromosomes with established imprinting
effects, such as chromosomes 7, 11, 14, and 15, and perhaps for chromosomes 2 and 16, where imprinting effects are
likely. 1997 by John Wiley & Sons, Ltd.
xrx vo×ns: rare trisomy mosaicism; amniocytes; prenatal cytogenetic diagnosis
INTRODUCTION
Excluding marker chromosomes, true mosaic-
ism involving an autosome accounts for 44–47 per
cent of all mosaic cases diagnosed in amniocytes
(Hsu et al., 1992, 1996). In an earlier survey of 277
autosomal trisomy mosaic cases, 193 cases (70 per
cent) were mosaic for a common trisomy [trisomy
20 (103 cases), trisomy 21 (60 cases), trisomy 18 (15
cases), and trisomy 13 (15 cases)], whereas 84 cases
(30 per cent) involved a cell line with an autosomal
trisomy other than these four better known types
(Hsu et al., 1992). The significance of rare auto-
somal trisomy mosaicism was not fully determined
because of the lack of cases, inadequate infor-
mation on phenotypic outcome, and limited
confirmation studies.
Today it is well recognized that the phenotypic
outcome of a prenatally diagnosed trisomic mosaic
case may be influenced by many factors, such as
the possibility of confined placental mosaicism and
the potential effect of imprinting in uniparental
disomy (UPD) secondary to rescue of an initial
trisomy (Ledbetter and Engel, 1995). We wished to
review all known cases of rare trisomy mosaicism
diagnosed in amniocytes and to place the available
data into proper perspective for a better under-
standing of risk and significance. We note some
karyotype/phenotype correlations by comparing
the phenotypic abnormalities observed in pre-
natally diagnosed cases with those in postnatally
diagnosed cases.
MATERIALS AND METHODS
We reviewed 151 prenatally diagnosed cases of
trisomy mosaicism involving an autosome other
than chromosomes 13, 18, 20, and 21 detected in
amniocytes. Fifty-four cases were collected from
17 cytogenetic laboratories in this collaboration;
34 were derived from a previous North American
chromosome mosaicism survey (Hsu, 1992b) and
63 cases were from published reports or abstracts.
In order to have meaningful karyotype/
phenotype correlations, the following inclusion
criteria were established:
(a) Chromosome mosaicism must have been
diagnosed in a minimum of two independent
culture vessels.
(b) There must be one cell line with a complete
autosomal trisomy (other than 13, 18, 20 and
21) (not a partial trisomy).
(c) There must be a normal cell line.
(d) There must be information available on the
phenotypic outcome of the pregnancy.
(e) There may not be evidence of biased ascertain-
ment, such as a prior abnormal ultrasound
finding.
Because of these requirements, many cases of
rare trisomy mosaicism could not be included in
this review. Therefore, the proportions of various
categories of trisomy mosaicism do not reflect the
occurrence rates. Information on the following
items was requested in this collaboration:
v Indication for the amniocentesis.
v Maternal age at expected date of delivery.
v Detailed data on the phenotype, including birth
weight.
v Information on gestational age at delivery to rule
out intrauterine growth retardation.
v Clinical follow-up data on psychomotor devel-
opment of liveborns.
v Pathology report on abortuses.
v Cytogenetic confirmation data, such as PUBS,
cord blood, cord, fetal or liveborn tissues,
placental tissues.
v Other cytogenetic data, such as FISH studies of
interphase nuclei or metaphases.
v Data on molecular studies, including studies of
DNA for an evaluation of UPD.
RESULTS AND DISCUSSION
Of the 151 cases reviewed, there were 11 cases
of 46/47,+2; 2 cases of 46/47,+3; 2 cases of
46/47,+4; 5 cases of 46/47,+5; 3 cases of 46/47,+6;
8 cases of 46/47,+7; 14 cases of 46/47,+8; 25 cases
of 46/47,+9; 2 cases of 46/47,+11; 23 cases of
46/47,+12; 5 cases of 46/47,+14; 11 cases of
202 i. x. r. nsi r1 \i.
46/47,+15; 21 cases of 46/47,+16; 7 cases of
46/47,+17; 1 case of 46/47,+19; and 11 cases
of 46/47,+22 (Table I). There are no known cases
of 46/47,+1 or 46/47,+10 diagnosed in amnio-
cytes. Data on all categories from trisomy 2
mosaics to trisomy 22 mosaics are presented
according to the numerical sequence (Tables
II–XVII); comparison of phenotypic abnormalities
between prenatal and postnatal cases are shown in
Tables XVIIIa and XVIIIb. Abbreviations are
summarized in the Appendix.
46/47,+2
Eleven cases of 46/47,+2 were collected and
reviewed (Table II). Except for one (II-1), all cases
resulted in abnormal outcomes: seven abnormal
offspring, two stillborns and one fetal demise. The
seven phenotypically abnormal offspring included
four full-term liveborns, one premature infant, and
two abortuses. They showed variable phenotypic
abnormalities with no specific pattern (Table II).
Three other cases resulted in stillbirth (two cases)
or intrauterine death (one case). The only case with
a normal outcome (II-1) had only 4 per cent
trisomy 2 cells in the amniocytes. It is not known
whether the normal outcome should be attributed
to this low percentage of trisomic cells. Mosaicism
was not confirmed in either blood or placental
tissue. Two other cases, both with 6 per cent
trisomy 2 cells, resulted in intrauterine death (II-6)
or stillbirth (II-5) and in both cases mosaicism was
confirmed in placental tissue.
Among the seven cases with an abnormal
phenotype, cytogenetic confirmation of 46/47,+2
was achieved in five cases in which fibroblasts
and/or placental cells were studied. Three blood
cultures showed only cells with normal karyotypes.
No confirmation study information was available
on two other cases (Tables II and XIX).
Chromosome 2 is frequently involved in pseudo-
mosaicism, both in multiple-cell and in single-cell
cases with trisomy 2 (Hsu, 1992b). However, when
cells with trisomy 2 are found in two or more
cultures, a diagnosis of true trisomy 2 mosaicism is
established and should be taken seriously. High-
resolution serial ultrasound examination of the
fetus can be used to detect major abnormalities to
help the parents make an informed decision about
the pregnancy.
Since non-mosaic trisomy 2 was found in
approximately 5–6 per cent of first-trimester
spontaneous abortuses (Warburton et al., 1991),
trisomy 2 mosaicism may be a result of a self-
correction or rescue process from trisomy. Abnor-
mal phenotypic outcome may be related to the
Table I—Outcome of cases with rare autosomal trisomy mosaicisms diagnosed in amnio-
cytes
Type
Abnormal outcomes
Abnormal
phenotype
(No. with IUGR) FD/SB Total No. of cases
46/47,+2 10/11 (90·9%) 7 (2) 3
46/47,+3 1/2 — 1 0
46/47,+4 1/2 — 1 0
46/47,+5 2/5 (40·0%) 2 (2) 0
46/47,+6 0/3 — 0 0
46/47,+7 1/8 (12·5%) 1 0
46/47,+8 1/14 (7·1%) 1 0
46/47,+9 14/25 (56·0%) 14 (2) 0
46/47,+11 0/2 — 0 0
46/47,+12 6/23 (26·1%) 4 2
46/47,+14 2/5 (40·0%) 2 0
46/47,+15 6/11 (54·5%) 6 (3) 0
46/47,+16 15/21 (71·4%) 15 (8) 0
46/47,+17 0/7 — 0 0
46/47,+19 0/1 — 0 0
46/47,+22 7/11 (63·6%) 6 (2) 1
See Appendix for abbreviations.
203 ×\×r 1×isoxx xos\icisx ni\cNosrn iN \xNiocx1rs
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)
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(
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)

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(
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(
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k
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(
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y

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t
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U
c
h
i
d
a
,
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*
3
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c
a
t
i
o
n
.
204 i. x. r. nsi r1 \i.
possible imprinting effect in maternal UPD of
chromosome 2; one case with proven maternal
UPD 2 showed IUGR, as well as postnatal growth
retardation (II-8) (Harrison et al., 1995).
Confined placental mosaicism may very well be
a contributing cause for the fetal death or still-
births of three cases (II-5, II-6, II-11). This possi-
bility is further supported by the finding of cells
with trisomy 2 in the placental cultures in two of
these cases.
There was one postnatally diagnosed case of
46/47,+2 mosaicism. The infant had IUGR, dys-
morphic facies, and a clinical diagnosis of Pfeiffer
syndrome (Cramer et al., 1993) (Table XVIIIa).
46/47,+3
Only two cases were collected in this category
(Table III). One case (III-1) had 5 per cent of
trisomy 3 cells and resulted in a grossly normal
male liveborn. Both PUBS and skin fibroblasts
from foreskin showed only normal karyotypes.
The other case (III-2), with 35·7 per cent trisomy
3 cells, resulted in an abnormal liveborn with
MCA who died at 18 months of age due to
CHD. Trisomy 3 mosaicism was confirmed in
skin fibroblasts and amnion cultures, whereas
blood cultures showed only cells with a normal
karyotype.
At least three cases of 46/47,+3 have been
diagnosed postnatally (Table XVIIIa). One adult
was reported to have severe mental retardation,
short stature, and dysmorphic facies (Kuhn et al.,
1987). One adult had short stature, coloboma,
hip dislocation, and Bartter syndrome (DeKeyser
et al., 1988). One infant with minor dysmorphism
died at 5 months following a severe failure to
thrive (Metaxotou et al., 1981). In this last case,
blood cells showed only 47,+3 and skin fibroblasts
showed only a normal karyotype.
Trisomy 3 mosaicism has been noted in the
discrepancies between chorionic villus sampling
(CVS) and amniocytes or fetal chromosomes. In at
least eight cases, trisomy 3 mosaicism was found in
direct CVS preparations, but not in amniocytes or
fetal cells (Hsu, 1992a). It is possible that confined
placental mosaicism of trisomy 3 has a phenotypic
effect on the fetus. As of today, no information
is available regarding any imprinted genes on
chromosome 3.
46/47,+4
Two cases of 46/47,+4 were diagnosed in
amniocytes (Table IV). One case (IV-1), with 10
per cent trisomy 4 cells in amniocytes, resulted in a
normal liveborn who was developmentally normal
at 1 year of age with normal cells found in PUBS
and foreskin. The other case (IV-2), with 31 per
cent trisomy 4 cells, resulted in an abnormal
liveborn with MCA, facial dysmorphism, and
CHD, yet with no significant developmental delay
at 1 year of age. 46/47,+4 was confirmed in the
forearms and in placental tissue (Tables IV and
XIX). The fact that cells with trisomy 4 were not
detected in blood cultures in IV-2 may explain
why, in addition to its high lethality, trisomy 4
mosaicism has not been more widely reported
postnatally.
46/47,+5
Five cases of 46/47,+5 were reviewed (Table V).
All pregnancies went to term; three resulted in
grossly normal liveborns and two of these were
developmentally normal at 6–7 months of age.
Two liveborns were reported to be abnormal with
facial dysmorphysm, CHD, and IUGR.
In both cases with abnormal phenotypes,
46/47,+5 was confirmed: one in cord tissue (V-2)
and one in skin and placenta (V-4). Of the three
normal-appearing liveborns, two had follow-up
studies; only cells with a normal karyotype were
found in blood, skin, and placenta. These limited
data appear to show a correlation between the
phenotypic outcome and cytogenetic confirmation
of 46/47,+5 in fibroblast cultures.
Thus far, PUBS does not appear to be helpful
for work-up of this type of mosaicism. High-
resolution ultrasound examination, however,
should be recommended.
The percentage of trisomy 5 cells in amniocytes
seems to have no bearing on the pregnancy
outcome. This is illustrated especially in case V-3,
where 80 per cent of the amniocytes (from two
independent amniocenteses) showed trisomy 5
cells, and the pregnancy resulted in a normal
liveborn with no developmental delay at 6
months and with a normal karyotype in somatic
tissues and placental tissues. It is possible that the
trisomy 5 cell line in this case started as an
extraembryonic event or was confined to the
placenta because the extra chromosome 5 was
lost from the fetus in a rescue process. Thus
far, there has been no report of imprinted
genes on chromosome 5 (Ledbetter and Engel,
1995).
205 ×\×r 1×isoxx xos\icisx ni\cNosrn iN \xNiocx1rs
T
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206 i. x. r. nsi r1 \i.
T
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n
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207 ×\×r 1×isoxx xos\icisx ni\cNosrn iN \xNiocx1rs
T
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0
6
)
P
l
a
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e
n
t
a

4
6
(
5
4
)
/
4
7
,
+
5
(
4
6
)
S
k
i
n

4
6
(
3
2
)
/
4
7
,
+
5
(
8
)
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n
x
i
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t
y
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0
S
c
i
o
r
r
a
e
t
a
l
.
,
1
9
9
2
V
-
5
4
6
,
X
X
/
4
7
,
X
X
,
+
5
6
·
7
%
3
0
N
l
F
(
L
B
)
N
A
F
H
o
f
N
T
D
3
4
S
h
a

e
r
,
L
.
4
1
7
8
8
208 i. x. r. nsi r1 \i.
46/47,+6
Three cases of low-level trisomy 6 mosaicism
were collected (Table VI). All had 6 per cent
trisomy 6 cells in amniocytes and all three resulted
in normal liveborns. One had blood chromosome
studies that showed a normal karyotype in 300
cells. No placental tissues were studied. It is poss-
ible that all three cases were the result of confined
placental mosaicism.
46/47,+7
Eight cases of 46/47,+7 were collected (Table
VII). All eight continued to term. Seven resulted in
normal liveborns, four of whom had follow-up
from 4 months to 4
1
2
years and were reported to be
developmentally normal. Two of these (VII-1 and
VII-2, both with follow-up to 4 years of age) had
trisomy 7 mosaicism confirmed in foreskin fibro-
blasts. The only abnormal liveborn (VII-4) showed
mild developmental delay, facial asymmetry, and
hypomelanosis of Ito. In this case, amniocytes
showed trisomy 7 in all 9 cells of one flask and
46,XY in all 30 cells of the other flask. In fact,
while the prenatal diagnosis of 46/47,+7 true
mosaicism was not really established, 46/47,+7
mosaicism was confirmed in the skin fibroblasts at
age 7 years.
Placental tissues were studied in two of the seven
cases with normal outcome; both showed only
normal cells.
Trisomy 7 is known to be a relatively frequent
(non-random) observation in amniocytes, as
single-cell or multiple-cell pseudomosaicism (fre-
quency is next to the most common finding of
trisomy 2) (Hsu, 1992b). Cells with trisomy 7
found in direct CVS preparations have led to
several cases of discrepancies between CVS and
fetal karyotypes (Hsu, 1992a). It would be helpful
to know how frequently trisomy 7 mosaicism is
confined to the placenta.
Trisomy 7 mosaicism has been diagnosed post-
natally at least six times (reviewed by Hsu et al.,
1992; Newlin et al., 1995). Three of these cases
were associated with renal agenesis (Potter
syndrome) or renal dysplasia (XVIIIa).
Interestingly, among the seven prenatal cases
with known indication for amniocentesis, an
abnormal maternal serum alpha-fetoprotein
(MSAFP) concentration was noted for four; three
had elevated MSAFP and one had low MSAFP.
High MSAFP may reflect conditions other
than fetal NTDs, such as fetal distress, fetal
death, placental pathology or other fetal/placental
conditions (Milunsky, 1992).
As to possible imprinted genes on chromosome
7, it is now quite certain that maternal UPD has
clinical significance (Ledbetter and Engel, 1995).
When there is evidence for prenatal and/or post-
natal growth retardation in an infant with a
prenatal diagnosis of 46/47,+7, a DNA study is
suggested to rule out maternal UPD 7 (Langlois
et al., 1995).
46/47,+8
Fourteen cases of 46/47,+8 were collected
(Table VIII). One case (VIII-1) that showed 77 per
cent trisomy 8 cells was reported to be abnormal
(with no detailed description and no confirmatory
studies). The remaining 13 cases all resulted in
grossly normal-appearing abortuses (eight cases)
or liveborns (five cases) with trisomy 8 cells in
amniocytes ranging from 3·8 to 40 per cent. The
outcome observation is not surprising, as it is
known that a clinical diagnosis of mosaic or
non-mosaic trisomy 8 in a liveborn is difficult.
Recognition of subtle abnormalities in an abortus,
such as thick lips, prominent ears, absent or dys-
plastic patellae, deep plantar/palmar skin furrows,
or a narrow pelvis could be even more difficult
(Jones, 1988; Schinzel, 1993). There was no
follow-up information on the five grossly normal
liveborns.
Of eight normal-appearing abortuses, seven had
fibroblast studies and 46/47,+8 mosaicism was
found in five. In three cases (all abortuses) with
placental studies, trisomy 8 mosaicism was con-
firmed in two. Among five cases with PUBS and/or
blood cultures, cells with trisomy 8 were detected
in two (Tables VIII and XIX).
When a prenatal diagnosis of 46/47,+8 is made
in amniocytes, PUBS may help to confirm the
diagnosis. Yet a finding of only normal cells cer-
tainly does not rule out trisomy 8 mosaicism and,
in fact, may provide a false sense of security.
Trisomy 8 mosaicism was involved in a few cases
with discrepancy between CVS diagnosis and fetal
or amniocyte karyotypes (Hsu, 1992a). In these
cases, the fetuses all had a normal karyotype and it
is reasonable to conclude that confined placental
mosaicism of trisomy 8 can occur. The high prob-
ability of identifying a grossly normal-appearing
offspring after a prenatal diagnosis of 46/47,+8
may therefore be related to both the inability to
209 ×\×r 1×isoxx xos\icisx ni\cNosrn iN \xNiocx1rs
T
a
b
l
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V
I

D
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t
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n
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6
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4
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s
(
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f
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s
)
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d
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M
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(
y
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r
s
)
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o
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r
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b
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r
(
s
)
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%
A
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e
l
l
s
C
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x
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m
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d
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m
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l
A
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m
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l
V
I
-
1
4
6
,
X
X
/
4
7
,
X
X
,
+
6
6
·
0
%
1
3
3
N
l
F
(
L
B
)
N
A


D
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*
V
I
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2
4
6
,
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Y
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4
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,
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Y
,
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6
6
·
4
%
4
7
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l
M
(
L
B
)
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l
o
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d

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l
(
3
0
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)

2
9
P
a
d
r
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-
M
e
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d
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z
a
e
t
a
l
.
,
1
9
7
9
V
I
-
3
4
6
,
X
X
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4
7
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X
X
,
+
6
6
·
0
%
3
0
N
l
F
(
L
B
)
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W
e
l
b
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m
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a
t
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n
.
210 i. x. r. nsi r1 \i.
T
a
b
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V
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D
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f

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m
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(
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+
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4
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·
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%
2
5
c
l
N
l
M
(
L
B
)
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a
t
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1
/
2
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e
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r
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N
l
(
1
0
0
)
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o
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s
k
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n

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6
(
1
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)
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7
(
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t
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p
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8
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3
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(
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(
2
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3
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)
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(
2
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)
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1
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-
9
1
V
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4
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4
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,
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+
7
5
·
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%
1
4
1
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(
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(
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3
9
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b
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(
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)

a
t
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7
;
m
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d
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N
l
(
6
0
)
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k
i
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4
6
(
1
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)
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4
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7
(
2
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4
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4
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%
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l
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(
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(
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)
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(
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.
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W
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4
6
,
X
X
/
4
7
,
X
X
,
+
7
2
6
·
7
%
1
5
c
l
N
l
F
(
L
B
)
N
A
E
l
e
v
a
t
e
d
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S
h
C
G
2
9
N
e
u
,
R
.
L
.
C
a
s
e
A
A
V
I
I
-
7
4
6
,
X
Y
/
4
7
,
X
Y
,
+
7
1
5
·
0
%
2
0
N
l
M
(
L
B
)
N
l
a
t
2
5
m
o
n
t
h
s
P
U
B
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N
l
(
3
0
)
A
M
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3
9
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h
a

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r
,
L
.
(
4
1
0
2
6
)
V
I
I
-
8
4
6
,
X
Y
/
4
7
,
X
Y
,
+
7
1
1
·
4
%
4
4
N
l
M
(
L
B
)
N
l
a
t
4
m
o
n
t
h
s
N
A
A
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3
7
V
a
n
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y
k
e
,
D
.
A
9
4
-
2
8
2
4
1
*
P
e
r
s
o
n
a
l
c
o
m
m
u
n
i
c
a
t
i
o
n
.

T
r
i
s
o
m
y
7
c
e
l
l
s
f
o
u
n
d
i
n
a
l
l
9
c
e
l
l
s
i
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e

a
s
k
b
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t
i
n
3
0
c
e
l
l
s
o
f
o
t
h
e
r

a
s
k
.
211 ×\×r 1×isoxx xos\icisx ni\cNosrn iN \xNiocx1rs
T
a
b
l
e
V
I
I
I

D
e
t
a
i
l
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f

n
d
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r
4
6
/
4
7
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m
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r
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r
(
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)
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n
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e
%
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l
s
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s
e
x
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m
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d
N
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m
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l
A
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m
a
l
V
I
I
I
-
1
4
6
,
X
X
/
4
7
,
X
X
,
+
8
7
7
·
0
%
2
7
A
b
n
F
(
A
B
)

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o
d
e
t
a
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l
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A


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n
t
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e
y
,
R
.
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.
*
V
I
I
I
-
2
4
6
,
X
X
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4
7
,
X
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,
+
8
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A
8
c
u
l
t
u
r
e
s
N
l
F
(
L
B
)
P
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B
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4
6
(
9
9
7
)
/
4
7
,
+
8
(
3
)
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l
o
o
d

4
6
(
9
9
3
)
/
4
7
,
+
8
(
7
)
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k
i
n

N
l
(
4
0
1
)
P
r
e
v
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a
l
f
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C
a
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t
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l
.
,
1
9
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8
V
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3
4
6
,
X
Y
/
4
7
,
X
Y
,
+
8
8
·
6
%
4
6
N
l
M
(
A
B
)
F
e
t
a
l
t
i
s
s
u
e
s

4
6
(
N
A
)
/
4
7
,
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8
(
N
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)


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r
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d
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l
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.
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V
I
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I
-
4
4
6
,
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4
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,
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8
2
7
·
2
%
1
4
c
l
N
l
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(
A
B
)
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l
(
5
0
)
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r
a
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n

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l
(
5
0
)
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l
a
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t
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4
6
(
4
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)
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4
7
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X
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+
8
4
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·
0
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7
7
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l
M
(
A
B
)
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k
i
n

t
r
i
s
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y
8
c
e
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s
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0
%
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l
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n
t
a

t
r
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s
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m
y
8
c
e
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s
5
0
%


M
a
r
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,
G
.
,
N
o
r
w
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d
,
T
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s
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e
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.
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k
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.
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V
I
I
I
-
6
4
6
,
X
X
/
4
7
,
X
X
,
+
8
1
3
·
0
%
5
3
N
l
F
(
A
B
)
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e
t
a
l
t
i
s
s
u
e
s

m
o
s
a
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s
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r
m
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d


M
e
n
n
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t
t
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,
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.
*
V
I
I
I
-
7
4
6
,
X
Y
/
4
7
,
X
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,
+
8
1
1
·
8
%
1
7
c
l
N
l
M
(
L
B
)
P
U
B
S

N
l
(
5
0
)
R
e
t
a
p

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l
(
1
8
c
l
)
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M
A
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5
N
e
u
,
R
.
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a
s
e
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.
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.
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I
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8
4
6
,
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Y
/
4
7
,
X
Y
,
+
8
3
·
4
%
5
8
N
l
M
(
A
B
)
S
k
i
n

4
6
(
4
)
/
4
7
,
+
8
(
1
6
)
A
M
A
3
5
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D
L
5
0
9
2
V
I
I
I
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9
4
6
,
X
X
/
4
7
,
X
X
,
+
8
8
·
4
%
5
9
N
l
F
(
A
B
)
N
o
g
r
o
w
t
h
A
M
A
3
9
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D
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6
3
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6
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1
0
4
6
,
X
X
/
4
7
,
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X
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+
8
3
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8
%
5
2
N
l
F
(
L
B
)
B
l
o
o
d

N
l
(
5
0
)
A
M
A
a
n
d
e
l
e
v
a
t
e
d
M
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F
P
3
5
P
D
L
4
0
2
5
1
V
I
I
I
-
1
1
4
6
,
X
Y
/
4
7
,
X
Y
,
+
8
2
8
·
0
%
1
8
c
l
N
l
M
(
A
B
)
R
t
a
r
m

4
6
(
7
0
)
/
4
7
,
+
8
(
3
3
)
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t
l
e
g

4
6
(
8
5
)
/
4
7
,
+
8
(
5
6
)
L
i
v
e
r
,
t
e
s
t
i
s
,
c
o
r
d
,
p
l
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c
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n
t
a
,
b
r
a
i
n
,
k
i
d
n
e
y
,
l
u
n
g
,
a
m
n
i
o
n

N
l
(
5
0
e
a
c
h
)
A
M
A
3
6
S
w
i
s
s
h
e
l
m
e
t
a
l
.
,
1
9
8
1
V
I
I
I
-
1
2
4
6
,
X
Y
/
4
7
,
X
Y
,
+
8
4
·
0
%
1
0
0
N
l
M
(
L
B
)
P
U
B
S

N
l
(
5
0
)
B
l
o
o
d

N
l
(
5
0
)
A
M
A
3
7
V
e
k
e
m
a
n
s
e
t
a
l
.
,
1
9
8
1
V
I
I
I
-
1
3
4
6
,
X
Y
/
4
7
,
X
Y
,
+
8
7
·
5
%
4
0
N
l
M
(
L
B
)
N
A


W
e
l
b
o
r
n
a
n
d
L
e
w
i
s
,
1
9
9
0
V
I
I
I
-
1
4
4
6
,
X
Y
/
4
7
,
X
Y
,
+
8
3
7
·
5
%
1
6
c
l
N
l
M
(
A
B
)
B
l
o
o
d

4
6
(
5
)
/
4
7
,
+
8
(
5
)
A
M
A
3
6
W
y
a
t
t
,
P
.
R
.
A
9
2
0
2
9
0
*
P
e
r
s
o
n
a
l
c
o
m
m
u
n
i
c
a
t
i
o
n
.
212 i. x. r. nsi r1 \i.
recognize subtle clinical features of trisomy 8 and
the possibility of confined placental mosaicism.
46/47,+9
Twenty-five cases of 46/47,+9 were collected
(Table IX). Twenty-one elected termination. Of
these, 13 resulted in grossly abnormal abortuses:
eight had MCA; two had minor abnormalities (one
with a short neck and a large mouth; and one with
the right big toe flexed upward); and no detailed
information was available for the other three. The
eight remaining abortuses appeared normal.
Among the four cases that elected to continue
the pregnancy, one resulted in an abnormal live-
born with IUGR and features of trisomy 9 syn-
drome (IX-15). The remaining three liveborns (two
term deliveries and one premature infant) showed
no noticeable abnormalities. One liveborn was
reported to be developmentally normal at age 3
years 8 months (IX-2).
In 14 cases with an abnormal outcome, fibroblast
cultures were obtained for eight (seven abortuses
and one liveborn). All seven fibroblast cultures
from abnormal abortuses showed trisomy 9 mosai-
cism and only a normal cell line was found in the
abnormal liveborn. In four abnormal cases with
blood cultures, three showed 46/47,+9 (two abor-
tuses and one liveborn) (Tables IX and XIX).
Thus, in all nine abnormal cases with confirma-
tion studies, trisomy 9 mosaicism was confirmed in
fibroblast and/or blood cultures, whereas in nine
cytogenetic confirmation studies of grossly normal
offspring, trisomy 9 mosaicism was confirmed in
only three [two in fibroblasts (abortuses) and one
in blood (premature infant)]. Trisomy 9 mosaicism
was found in three out of four placental studies in
the normal outcome group and in the only pla-
centa studied in the abnormal outcome category
(Table XIX).
Since cells with trisomy 9 are detectable in blood
cultures and major congenital anomalies including
IUGR may be diagnosable through an ultrasound
scan of the fetus, PUBS and a high-resolution
ultrasound examination should be recommended.
Trisomy 9, mosaic or non-mosaic, is a distinct
clinical entity. Over 40 cases have been diagnosed
postnatally (Arnold et al., 1995; Schinzel, 1993;
Wooldridge and Zunich, 1995). The major pheno-
typic abnormalities include growth and mental
retardation, dysmorphic facies with low-set mal-
formed ears, microphthalmia, a bulbous nose,
CHD (especially VSD), renal anomalies, and
skeletal abnormalities, such as a dislocated hip.
Comparison of the major phenotypic abnormali-
ties noted in the prenatal versus the postnatal cases
shows rather comparable features (Table XVIIIa).
The available prenatal data suggest a high risk,
namely 56 per cent (14/25), for the fetus to have a
noticeably abnormal phenotype.
To date, it appears unlikely that chromosome 9
carries imprinted genes and UPD should not there-
fore be a major concern (Ledbetter and Engel,
1995).
46/47,+11
Only two cases of 46/47,+11 were collected
(Table X). Both cases had a low degree of
mosaicism (2·7 and 5·5 per cent) and both resulted
in grossly normal offspring (one liveborn and one
abortus). The liveborn was developmentally nor-
mal at 15 months. Only cells with a normal karyo-
type were found in the confirmatory studies [PUBS
in case X-1 and skin fibroblasts in X-2 (abortus)].
No placental tissues were studied.
Trisomy 11 mosaicism has been detected at least
three times in direct CVS preparations but not
in amniocytes or fetal cells of these three cases
(Hsu, 1992a). This suggests that the cases with
trisomy 11 mosaicism may have reflected confined
placental mosaicism.
If a prenatal diagnosis of 46/47,+11 is made
from a CVS preparation or in amniocytes, one
may have to be concerned about the possibility of
UPD, because it is now certain that paternal UPD
of chromosome 11 shows an imprinting effect
(Ledbetter and Engel, 1995). At least 15 cases of
paternal UPD 11 have been described in associ-
ation with the Beckwith–Wiedemann syndrome
(Ledbetter and Engel, 1995). DNA studies for
UPD are suggested.
46/47,+12
Twenty-three cases of 46/47,+12 mosaicism
were collected (Table XI). Twelve patients opted to
continue the pregnancy. Of these, two had a fetal
demise (one with IUGR), one delivered a prema-
ture infant with MCA, two resulted in abnormal
liveborns with MCA, and the remaining seven
gave birth to grossly normal liveborns. Among the
latter, three had follow-up from 5 months to 5
years and all were reported to be developmentally
normal. Eleven patients elected termination. One
abortus was grossly abnormal with MCA; the ten
213 ×\×r 1×isoxx xos\icisx ni\cNosrn iN \xNiocx1rs
T
a
b
l
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D
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t
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4
6
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4
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.
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a
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m
a
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s
(
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.
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(
s
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-
1
4
6
,
X
X
/
4
7
,
X
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,
+
9
2
8
·
0
%
2
5
c
l
N
l
F
(
A
B
)
S
k
i
n

4
6
(
5
1
)
/
4
7
,
+
9
(
7
)
A
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4
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e
n
n
,
P
.
A
.
A
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-
6
5
7
8
I
X
-
2
4
6
,
X
X
/
4
7
,
X
X
,
+
9
8
3
·
9
%
3
1
c
l
N
l
F
(
L
B
)
N
l
(
3
y
e
a
r
s
8
m
o
n
t
h
s
)
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B
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l
(
1
0
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)
A
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A
4
8
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e
n
n
,
P
.
A
.
A
F
-
V
-
2
7
3
7
I
X
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3
4
6
/
4
7
,
+
9
(
s
e
x
n
o
t
k
n
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w
n
)
N
A
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A

A
b
n

(
A
B
)
(
n
o
d
e
t
a
i
l
s
)
N
A


D
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h
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r
t
y
,
R
.
*
I
X
-
4
4
6
,
X
X
/
4
7
,
X
X
,
+
9
5
0
·
0
%
4
8
A
b
n
F
(
A
B
)
(
n
o
d
e
t
a
i
l
s
)
P
l
a
c
e
n
t
a

4
6
(
2
)
/
4
7
,
+
9
(
8
)
F
e
t
a
l
t
i
s
s
u
e

4
6
(
1
1
)
/
4
7
,
+
9
(
7
)


F
l
e
c
k
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r
,
D
.
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a
r
v
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r
,
K
.
*
8
8
-
1
4
1
A
F
I
X
-
5
4
6
,
X
X
/
4
7
,
X
X
,
+
9
8
6
·
6
%
3
0
A
b
n
F
(
A
B
)

M
C
A
,
F
a
c
D
y
s
(
m
i
c
r
o
g
n
a
t
h
i
a
,
l
o
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-
s
e
t
e
a
r
s
)
,
G
R
,
a
m
b
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g
u
o
u
s
e
x
t
e
r
n
a
l
g
e
n
i
t
a
l
i
a
F
e
t
a
l
t
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s
s
u
e

4
6
(
0
)
/
4
7
,
+
9
(
5
)


G
o
l
b
u
s
,
M
.
*
1
0
4
9
2
I
X
-
6
4
6
,
X
X
/
4
7
,
X
X
,
+
9
2
4
·
0
%
5
8
N
l
F
(
L
B
)
B
l
o
o
d

N
l
(
7
5
)
A
m
n
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n

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l
(
7
5
)
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3
9
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r
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l
.
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1
9
8
2
I
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7
4
6
,
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X
/
4
7
,
X
X
,
+
9
/
4
7
,
X
X
,
+
M
a
r
3
8
·
0
%
(
f
o
r
4
7
,
+
9
)
3
8
·
0
%
(
f
o
r
4
7
,
+
M
a
r
)
3
1
(
2
1
c
l
)
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b
n
F
(
A
B
)

v
e
r
y
s
h
o
r
t
n
e
c
k
,
F
a
c
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y
s
(
l
a
r
g
e
m
o
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t
h
)
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U
B
S

4
6
(
1
3
)
/
4
7
,
+
9
(
3
)
/
4
7
,
+
M
a
r
(
3
4
)
B
l
o
o
d

4
6
(
5
7
)
/
4
7
,
+
9
(
0
)
/
4
7
,
+
M
a
r
(
1
2
9
)
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0
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e
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n
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e
t
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l
.
,
1
9
8
9
I
X
-
8
4
6
,
X
Y
/
4
7
,
X
Y
,
+
9
3
0
·
4
%
2
3
c
l
N
l
M
.
P
r
e
m
a
t
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r
e
b
i
r
t
h
(
2
3
w
e
e
k
s
)
5
2
0
g
.
D
i
e
d
a
t
4
d
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s
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o
r
d
b
l
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d

4
6
(
2
7
)
/
4
7
,
+
9
(
3
)
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l
a
c
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n
t
a

a
l
l
a
b
n
.
4
7
,
+
9
(
1
0
)
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2
H
i
g
g
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n
s
,
R
.
R
.
9
4
A
1
3
5
3
I
X
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9
4
6
,
X
X
/
4
7
,
X
X
,
+
9
8
·
3
%
1
5
5
N
l
F
(
A
B
)
S
k
i
n

N
l
(
5
0
)
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u
n
g

N
l
(
5
0
)
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M
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3
8
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s
u
e
t
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l
.
,
1
9
7
8
I
X
-
1
0
4
6
,
X
X
/
4
7
,
X
X
,
+
9
4
2
·
0
%
4
0
A
b
n
F
(
A
B
)

M
C
A
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A


M
a
r
t
i
n
,
G
.
,
N
o
r
w
o
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d
,
T
.
,
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s
t
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e
,
C
.
,
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a
l
k
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.
*
I
X
-
1
1
4
6
,
X
X
/
4
7
,
X
X
,
+
9
1
0
·
0
%
3
9
N
l
F
(
A
B
)
F
e
t
a
l
t
i
s
s
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e
s

N
l
(
N
A
)


M
a
r
t
i
n
,
G
.
,
N
o
r
w
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d
,
T
.
,
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.
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l
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.
*
I
X
-
1
2
4
6
,
X
Y
/
4
7
,
X
Y
,
+
9
1
2
·
0
%
1
0
2
A
b
n
M
(
A
B
)

I
U
G
R
,
M
C
A
,
h
y
d
r
o
c
e
p
h
a
l
u
s
,
d
o
l
i
c
h
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c
p
h
a
l
y
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c
y
s
t
i
c
k
i
d
n
e
y
P
U
B
S

N
l
(
1
0
0
)
S
k
i
n

4
6
(
8
3
)
/
4
7
,
+
9
(
1
7
)
L
u
n
g

4
6
(
8
6
)
/
4
7
,
+
9
(
1
4
)
A
M
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3
9
M
e
r
i
n
o
e
t
a
l
.
,
1
9
9
3
.
C
a
s
e
B
I
X
-
1
3
4
6
,
X
X
/
4
7
,
X
X
,
+
9
2
5
·
0
%
3
2
c
l
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.
215 ×\×r 1×isoxx xos\icisx ni\cNosrn iN \xNiocx1rs
T
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c
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.
216 i. x. r. nsi r1 \i.
remaining abortuses appeared to be normal.
Therefore, of the 23 cases, six (26·1 per cent) had
abnormal outcomes (four—MCA; two—fetal
demise).
Among these six cases with an abnormal out-
come, only three had confirmation studies (Table
XIX). In one case with MCA (XI-21), trisomy 12
mosaicism was confirmed in skin fibroblasts and
placental cultures, but not in PUBS and post-
natally sampled blood. Two other abnormal cases
had blood studies showing only normal cells.
Among the 17 cases with a normal outcome, 11
had confirmation studies. Trisomy 12 mosaicism
was found in seven out of ten fibroblast cultures
(all abortuses), three out of five placental cultures,
and one out of seven blood cultures. The only
positive blood culture showed only 1 per cent
trisomy 12 cells (Table XIX).
Combining both abnormal and normal outcome
cases, the cytogenetic confirmation rate of trisomy
12 mosaicism is eight out of 11 in fibroblast
cultures and four out of six in placental cultures. In
any case, PUBS or blood culture seems useless for
the diagnostic work-up.
In one grossly normal abortus (XI-17), fibro-
blast studies showed only cells with a normal
karyotype, but placental cultures showed cells with
trisomy 12. This case is likely to have been the
result of confined placental mosaicism. Previously
reported cases in which trisomy 12 mosaicism was
found in CVS cultures and not in fetal cells may
also have reflected confined placental mosaicism
(Hsu, 1992a).
When a diagnosis of 46/47,+12 is made in
amniocytes, it should not be taken lightly. The risk
of the fetus being abnormal is much higher than
that in trisomy 20 mosaicism, which is 9 per cent
(Hsu, 1992b). Again, a high-resolution ultrasound
examination of the fetus must be recommended.
A comparison was made in an attempt to see
whether there is a difference between the percent-
age of trisomy 12 cells in the abnormal outcome
group and the percentage of trisomy 12 cells in the
normal outcome group.
In six cases with an abnormal outcome, the
percentage of trisomic cells varied from 23 to 62
per cent (with four cases >40 per cent), whereas
the percentage of trisomic cells varied from 6 to 64
per cent in the 17 cases with a normal outcome
(with 11 cases ^20 per cent). Therefore, there may
be a small tendency for an association between a
higher percentage of trisomy 12 cells and the
chance of an abnormal outcome.
For 21 cases, the indication for amniocentesis
was provided. Advanced maternal age was cited
for 13, abnormal maternal serum screening for
five (with high MSAFP in four and abnormal
triple screen in one), and other reasons for the
remaining three. Of the four cases with elevated
MSAFP, two had an abnormal outcome (one
abortus with MCA and one fetal demise) and
two had normal liveborns. These are consistent
with the suggestion that unexplained high
MSAFP is associated with an increased risk for
an adverse perinatal outcome (Brazeral et al.,
1994) and fetal aneuploidy (Feuchtbaum et al.,
1995; Kaffe and Hsu, 1992).
To our knowledge, only three cases of
46/47,+12 mosaicism have been reported post-
natally (Table XVIIIb). Two had dysmorphism,
short stature, and scoliosis. One of these was
retarded and the other had CHD and abnormal
skin pigmentation, but normal mental develop-
ment. The third was a man with infertility, situs
inversus, and normal mental development.
To date, there have been no reports regarding
any imprinted genes on chromosome 12 or cases of
phenotypic abnormality associated with UPD of
chromosome 12 (Ledbetter and Engel, 1995).
46/47,+14
Five cases of 46/47,+14 were reviewed (Table
XII). Three patients opted to continue the preg-
nancy; all resulted in grossly normal liveborns. All
three had confirmatory studies on PUBS, blood,
and/or skin fibroblasts, and all showed only nor-
mal cells. Two other patients elected termination.
One fetus was found to have hydrocephaly on
ultrasound before the termination. The other abor-
tus had facial dysmorphism and MCA. Neither
case had confirmatory studies. Placental tissue was
not studied in any of the five cases.
Thus far, at least 15 cases of 46/47,+14 have
been diagnosed postnatally (Fujimoto et al., 1992;
Vachvanichsanong et al., 1991). The major clinical
features reported are growth and mental retard-
ation, CHD (especially tetralogy of Fallot and
septal defects), and body and/or facial asymmetry
(Table XVIIIb). In these postnatally diagnosed
cases, trisomy 14 cells have been found in 4–70
per cent of blood cells and in 0–16 per cent of
skin fibroblasts. There appears to have been no
correlation between the percentage of trisomy 14
cells and the severity of the clinical manifestation.
Here PUBS and a high-resolution ultrasound
217 ×\×r 1×isoxx xos\icisx ni\cNosrn iN \xNiocx1rs
T
a
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I

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(
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)
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9
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9
8
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6
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3
%
b
a
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p
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0
%
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2
c
l
3
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N
l
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(
A
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)
S
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b
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4
6
(
1
0
7
)
/
4
7
,
+
1
2
(
2
)
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l
a
d
d
e
r

N
l
(
7
0
)
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e
m
b
r
a
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e

N
l
(
3
4
)
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e
r
i
t
o
n
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m

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l
(
6
3
)
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u
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g

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l
(
6
0
)
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l
a
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e
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t
a

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l
(
3
5
)
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l
o
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d

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l
(
9
7
)
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1
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y
a
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e
t
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.
,
1
9
9
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a
s
e
#
1
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2
2
4
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,
X
X
/
4
7
,
X
X
,
+
1
2
1
1
·
0
%
6
3
N
l
F
(
A
B
)
F
e
t
a
l
l
u
n
g

4
6
(
4
7
)
/
4
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,
+
1
2
(
3
)
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3
6
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y
a
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t
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l
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,
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9
9
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a
s
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#
2
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I
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2
3
4
6
,
X
X
/
4
7
,
X
X
,
+
1
2
6
·
7
%
6
0
N
l
F
(
A
B
)
N
A
A
M
A
3
6
W
y
a
n
d
t
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t
a
l
.
,
1
9
9
0
.
C
a
s
e
#
3
*
P
e
r
s
o
n
a
l
c
o
m
m
u
n
i
c
a
t
i
o
n
.
219 ×\×r 1×isoxx xos\icisx ni\cNosrn iN \xNiocx1rs
T
a
b
l
e
X
I
I

D
e
t
a
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6
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4
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+
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o
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C
a
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e
N
o
.
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y
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A
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s
P
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n
a
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y
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c
o
m
e
C
o
n

r
m
a
t
o
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y
s
t
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s
(
N
o
.
o
f
c
e
l
l
s
)
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d
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M
a
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g
e
(
y
e
a
r
s
)
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r
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r
(
s
)
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e
n
c
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%
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l
l
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6
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/
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,
+
1
4
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·
0
%
2
0
A
b
n
F
(
A
B
)

h
y
d
r
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8
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X
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+
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4
1
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0
%
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0
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l
N
l
F
(
L
B
)
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5
3
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8
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u
,
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.
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.
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6
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X
,
+
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4
2
8
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6
%
2
1
c
l
N
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(
L
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)
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U
B
S

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(
2
5
)
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7
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l
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v
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t
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3
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6
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M
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h
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(
+
)
.
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4
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4
7
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X
Y
,
+
1
4
1
9
·
0
%
5
8
A
b
n
M
(
A
B
)

F
a
c
D
y
s
(
l
o
w
-
s
e
t
e
a
r
s
)
s
i
m
i
a
n
l
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e
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l
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d
a
c
t
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e
q
u
i
n
o
v
a
r
u
s
,
r
o
c
k
e
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-
b
o
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t
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e
e
t
,
a
b
n
h
i
p
(
b
y
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-
r
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)
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A


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t
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w
s
k
y
,
H
.
*
X
I
I
-
5
4
6
,
X
Y
/
4
7
,
X
Y
,
+
1
4
1
4
·
6
%
8
9
N
l
M
(
L
B
)
B
l
o
o
d

N
l
(

)
S
k
i
n

N
l
(

)

(
C
o
m
b
i
n
e
d
2
4
6
c
e
l
l
s
)
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o
r
e
s
k
i
n

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l
(
N
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)
A
M
A
4
0
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a
n
D
y
k
e
,
D
.
A
8
1
-
3
8
0
*
P
e
r
s
o
n
a
l
c
o
m
m
u
n
i
c
a
t
i
o
n
.
220 i. x. r. nsi r1 \i.
examination may be helpful for diagnosis and
counselling.
An imprinting effect in maternal UPD 14 has
now been documented and is possible in paternal
UPD 14 (Ledbetter and Engel, 1995). Unless DNA
studies are performed, a normal karyotype in
the fetus or liveborn after a prenatal diagnosis
of 46/47,+14 does not rule out the possibility
of UPD.
The finding of hydrocephaly in one case (XII-1)
is compatible with the clinical features reported in
a case with maternal UPD 14 (Healey et al., 1994).
Unfortunately, no DNA studies were performed in
this case.
46/47,+15
Eleven cases of 46/47,+15 were collected (Table
XIII). Six resulted in abnormal offspring (five
abortuses; one liveborn). Of these, three (two
abortuses; one liveborn) had multiple heart
defects; one abortus had malrotation of the intes-
tine and a two-vessel cord. Two abortuses had
IUGR; one of them had arrhinencephaly, contrac-
tures of the hands, and low-set ears; the other had
narrowing of the proximal segment of the cord.
Trisomy 15 mosaicism was confirmed in all six
cases (six in fibroblasts; four in placental cells)
(Tables XIII and XIX).
The five remaining cases were associated with
grossly normal outcomes (three liveborns, one
premature infant, and one abortus). Trisomy 15
mosaicism was, however, confirmed in fibroblasts
and placental cells of only one liveborn (XIII-11).
Blood cultures of two other normal-appearing
liveborns yielded only normal cells (Table XIX).
Cells with trisomy 15 have been detected in
lymphocyte cultures and have led to the diagnosis
of trisomy 15 mosaicism in one liveborn (Coldwell
et al., 1981) and in one third-trimester fetus
(through cordocentesis) (Bennett et al., 1992).
However, in four cases diagnosed in amniocytes,
successful blood cultures showed cells with trisomy
15 in only one case (XIII-1). Therefore, PUBS
appears to be of limited value.
The percentage of trisomy 15 cells in amniocytes
was compared with the outcome of pregnancy. Of
six abnormal outcome cases, five had _40 per cent
trisomy 15 cells and one had 9·8 per cent trisomy
15 cells in the cultures from an initial amnio-
centesis and 5·9 per cent trisomy 15 cells in the
cultures from a second amniocentesis. Among five
normal outcome cases, four had six per cent or less
trisomy 15 cells and one had 31 per cent. It seems
that a higher percentage of trisomy 15 cells (_40
per cent) tends to be associated with an abnormal
outcome. This association appears to hold in
fibroblast cultures.
Trisomy 15 was observed in 8 per cent of all
trisomic first-trimester abortuses (Warburton
et al., 1991), yet it is rare in liveborns. Non-mosaic
trisomy 15 was reported only twice (Coldwell
et al., 1981; Kuller and Laifer, 1991). One infant
died at 4 days of age and one at 9 h. Mosaic
trisomy 15 was reported in six infants (Table
XVIIIb). All six of these cases had facial dysmor-
phism; three had CHD (one had multiple heart
defects), skeletal anomalies, and/or hypotonia.
Since imprinting effects are known for both
maternal and paternal UPD 15 (Ledbetter and
Engel, 1995), DNA studies for UPD are suggested
when a prenatal diagnosis of 46/47,+15 is estab-
lished (ASHG/ACMG Report, 1996). In fact,
DNA studies of two of the abortuses reviewed here
(XIII-4 and XIII-6) showed maternal UPD 15.
Both fell into the abnormal outcome category (one
had IUGR and the other had malrotation of the
intestine, and both had abnormal umbilical cords).
The finding of maternal UPD 15 is associated
with Prader–Willi syndrome. Had these two
fetuses gone to term, they would presumably have
developed Prader–Willi syndrome.
Here, high-resolution ultrasound examination
must be re-emphasized. CHD, especially when
there are multiple heart defects, should be
detectable.
46/47,+16
Twenty-one cases of 46/47,+16 were collected
(Table XIV). Thirteen patients opted to continue
the pregnancy. Among these 13 pregnancies, eight
resulted in phenotypically abnormal offspring (five
term births; three premature infants); five liveborns
were reported to be normal. Eight patients elected
termination: seven of these resulted in phenotypi-
cally abnormal abortuses and one was reported to
be grossly normal. Thus, 15 out of 21 cases (71·4
per cent) resulted in abnormal offspring. Thirteen
had some dysmorphic features; ten had CHD
(most often VSD or ASD, next often double out-
let of the right ventricle). The other features in-
cluded skeletal anomalies in six, gastrointestinal
anomalies in five, renal anomalies in four, and
other abnormalities (Table XVIIIb).
It is known that trisomy 16 is one of the most
common chromosome abnormalities found in
221 ×\×r 1×isoxx xos\icisx ni\cNosrn iN \xNiocx1rs
T
a
b
l
e
X
I
I
I

D
e
t
a
i
l
s
o
f

n
d
i
n
g
s
f
o
r
4
6
/
4
7
,
+
1
5
m
o
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s
m
C
a
s
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o
.
K
a
r
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t
y
p
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A
m
n
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s
P
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C
o
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r
m
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y
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t
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(
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r
s
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t
r
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(
s
)
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n
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e
%
A
b
n
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l
l
s
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e
l
l
s
e
x
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m
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d
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l
A
b
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l
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I
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I
-
1
4
6
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X
/
4
7
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X
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+
1
5
6
6
·
0
%
R
e
t
a
p
3
7
·
0
%
2
4
3
0
A
b
n
F
(
A
B
)

I
U
G
R
,
F
a
c
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s
(
l
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p
h
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4
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(
4
)
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4
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+
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5
(
7
)
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(
c
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7
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+
1
5
(
6
)
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l
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4
6
(
2
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4
7
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+
1
5
(
5
)
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k
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n

4
6
(
1
2
)
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4
7
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+
1
5
(
8
)
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3
8
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s
t
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d
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l
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1
5
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h
r
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s
t
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a
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t
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l
.
,
1
9
9
6
.
C
a
s
e
#
2
X
I
I
I
-
2
4
6
,
X
Y
/
4
7
,
X
Y
,
+
1
5
6
·
0
%
5
0
N
l
M
p
r
e
m
a
t
u
r
e
i
n
f
a
n
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a
t
2
8
w
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k
s
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A
3
5
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N
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s
t
u
d
i
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s
r
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1
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h
r
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s
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l
.
,
1
9
9
6
.
C
a
s
e
#
3
X
I
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I
-
3
4
6
,
X
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4
7
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X
X
,
+
1
5
5
5
·
5
%
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e
t
a
p
2
9
·
2
%
3
6
1
5
4
A
b
n
F
(
A
B
)

F
a
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s
(
f
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(
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2
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4
6
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4
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5
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5
)
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(
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6
(
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(
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4
6
(
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,
1
9
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4
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c
a
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e
.
226 i. x. r. nsi r1 \i.
first-trimester spontaneous abortuses. It was
observed in 31 per cent of all trisomic abortuses in
one large study (Warburton et al., 1991). Trisomy
16 mosaicism was also the most common chromo-
some mosaicism detected in all chromosomally
mosaic abortuses. Trisomy 16 (non-mosaic and
mosaic) constitutes 20 per cent of all chromosomal
abnormalities in first-trimester abortuses. Due to
the high lethality of trisomy 16, there has, so far,
been no liveborn diagnosed to have non-mosaic
trisomy 16. Two cases of mosaic trisomy 16 have
been diagnosed postnatally (Gilbertson et al.,
1990; Greally et al., 1990). Both cases showed
IUGR and CHD; one also had dysmorphic
features and MCA (Table XVIIIb).
Among the prenatal cases, 11 out of 15 in the
abnormal outcome group had 20 per cent or more
trisomy 16 cells, whereas four of the six cases with
a normal outcome had 10 per cent or less trisomic
cells. The proportion of trisomic cells in the two
groups overlaps and the small difference noted
may not be meaningful.
Of 15 cases with an abnormal outcome, 14 had
confirmatory studies. Trisomy 16 mosaicism was
confirmed in fetal or liveborn tissues in nine cases
(seven out of 12 fibroblast studies and two out of
12 blood cultures). Cells with trisomy 16 were
found in nine out of ten placental tissues.
Of nine cases in which both fibroblasts and
placental cells were studied, five showed trisomy 16
cells in both cultures and three showed trisomy 16
cells in the placenta but not in fibroblasts, suggest-
ing the possibility of confined placental mosaicism.
One case showed only normal cells in both
tissues.
Among 6 cases with a normal outcome, two
liveborns had placental tissue studies and in both
cases, cells with trisomy 16 were found; one abor-
tus showed trisomy 16 cells in both skin and lung
fibroblasts. Three other liveborns did not have
confirmatory studies. This information indicates
that in the diagnosis of 46/47,+16 from amnio-
centesis, there is a high probability that placental
cells will show trisomy 16. Confined placental
mosaicism of trisomy 16 has been a frequent cause
of diagnostic discrepancies between CVS and fetal
karyotypes: at least 12 instances are known (Hsu,
1992a).
Nevertheless, based on the available prenatal
data, a diagnosis of trisomy 16 mosaicism in
amniocytes indicates a high risk for fetal abnor-
malities. A high-resolution ultrasound of the
fetus must be recommended. One may need serial
ultrasound examinations for a more definitive
assessment. PUBS is of very limited value.
Since there is evidence to suggest a possible
imprinting effect in maternal UPD 16 (Ledbetter
and Engel, 1995), DNA studies for UPD were
performed in nine cases with a prenatal diagnosis
of 46/47,+16 mosaicism (Table XIV). Five cases
showed maternal UPD 16; four of these (three
abortuses; one liveborn) had an abnormal out-
come: two had MCA, two had IUGR (one was
also dysmorphic); one liveborn appeared normal
(at 13 months) but had hypospadias. UPD was
excluded in four cases (two term liveborn, one
premature infant, and one abortus); all four were
phenotypically abnormal, with IUGR and MCA
in three cases and CHD in the fourth. Thus,
because almost all cases with or without maternal
UPD 16 were phenotypically abnormal, the limited
data on UPD studies in trisomy 16 mosaicism in
amniocytes show no significant difference between
UPD cases and non UPD cases in the effect on
phenotypic outcome.
Among 17 cases with available information
regarding the indication for amniocentesis,
elevated MSAFP and/or MShCG were listed in
eight (elevated MSAFP without testing MShCG
in five; elevated MShCG and MSAFP in two,
and elevated MShCG alone in one). All but one
of these had an abnormal outcome. However,
seven out of nine cases with other indications
(eight with AMA and one with a ‘lemon-shaped
skull’) also resulted in abnormal offspring. It is
known that elevated MSAFP and/or MShCG
may suggest an increased risk for an adverse
perinatal outcome (Brazerol et al., 1994; Benn
et al., 1996). High MSAFP, as well as high
MShCG in trisomy 16 mosaicism, implies a poss-
ible association between these two findings
(Vaughan et al., 1994; Zimmerman et al., 1995).
It is especially interesting to note that the level of
MShCG in 46/47,+16 mosaicism is extremely
high (Benn et al., 1995).
46/47,+17
Seven cases of 46/47,+17 were collected (Table
XV). All seven resulted in grossly normal offspring
(six liveborns; one abortus). Four liveborns had
follow-up information ranging from 10 to 18
months and all were reported to be develop-
mentally normal. The percentage of trisomy 17
cells varied from 5 to 25 per cent in six cases and
was 88 per cent in the seventh case (XV-4: 100 per
227 ×\×r 1×isoxx xos\icisx ni\cNosrn iN \xNiocx1rs
T
a
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4
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4
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%
6
8
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l
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(
L
B
)
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1
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(
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H
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4
7
,
X
Y
,
+
1
7
1
0
·
7
%
R
e
t
a
p
9
·
1
%
2
8
c
l
2
2
N
l
M
(
L
B
)
N
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A
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3
4
N
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u
,
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.
L
.
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s
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.
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X
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-
4
4
6
,
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/
4
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,
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,
+
1
7
1
0
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·
0
%
R
e
t
a
p
7
5
·
0
%
2
6
c
l
2
0
c
l
N
l
F
(
L
B
)
N
1
a
t
1
y
e
a
r
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l
o
o
d

N
l
(
3
0
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l
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7
2
5
·
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%
4
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N
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(
A
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)
A
b
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u
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l
(
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6
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6
4
6
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4
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X
X
,
+
1
7
9
·
1
%
8
7
N
l
F
(
L
B
)
N
l
a
t
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a
r
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l
o
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d

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l
(
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h
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.
a
n
d
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h
a
h
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.
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.
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V
-
7
4
6
,
X
X
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4
7
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X
X
,
+
1
7
5
·
0
%
1
6
8
N
l
F
(
L
B
)
B
l
o
o
d

N
l
(
N
A
)
A
m
n
i
o
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l
(
N
A
)


W
i
l
s
o
n
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t
a
l
.
,
1
9
8
9
*
P
e
r
s
o
n
a
l
c
o
m
m
u
n
i
c
a
t
i
o
n
.
228 i. x. r. nsi r1 \i.
T
a
b
l
e
X
V
I

D
e
t
a
i
l
s
o
f

n
d
i
n
g
s
f
o
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4
6
/
4
7
,
+
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9
m
o
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a
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e
N
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m
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s
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m
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o
n

r
m
a
t
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t
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s
(
N
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f
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s
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d
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g
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(
y
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a
r
s
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t
r
i
b
u
t
o
r
(
s
)
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r
r
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n
c
e
%
A
b
n
c
e
l
l
s
C
e
l
l
s
e
x
a
m
i
n
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d
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m
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l
A
b
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o
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m
a
l
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V
I
-
1
4
6
,
X
X
/
4
7
,
X
X
,
+
1
9
3
·
0
%
6
0
N
l
F
(
L
B
)
N
A
A
M
A
3
5
P
D
L
1
3
1
9
8
229 ×\×r 1×isoxx xos\icisx ni\cNosrn iN \xNiocx1rs
T
a
b
l
e
X
V
I
I

D
e
t
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f

n
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4
6
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4
7
,
+
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m
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r
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(
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%
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6
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+
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1
8
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%
1
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c
l
A
b
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F
(
L
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)

F
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s
(
a
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)
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k
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4
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(
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s

4
6
(
2
)
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(
1
8
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c
l

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M
(
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9
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%
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3
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(
A
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)
K
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(
1
9
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4
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b
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(
A
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F
a
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s
(
l
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k
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4
6
(
N
A
)
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4
7
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N
A
)
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l
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a

a
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4
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%
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l
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F
(
L
B
)
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1
0
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8
·
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%
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t
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p
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%
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1
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1
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t
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l
(
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6
0
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m
n
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l
(
1
7
)
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l
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d

N
l
(
2
0
0
)
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i
b
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o
b
l
a
s
t

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l
(
2
0
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)
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h
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c
v
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M
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4
7
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t
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l
.
,
1
9
8
9
X
V
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9
4
6
,
X
X
/
4
7
,
X
X
,
+
2
2
3
·
6
%
5
6
A
b
n
F
(
A
B
)

F
a
c
D
y
s
(
s
h
o
r
t
n
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,
c
l
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f
t
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r
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)
,

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g
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l
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k
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c
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r
v
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t
u
m
A
m
n
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o
n

N
l
(
4
8
)
A
M
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3
4
V
a
n
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y
k
e
,
D
.
X
V
I
I
-
1
0
4
6
,
X
X
/
4
7
,
X
X
,
+
2
2
1
6
·
7
%
1
2
c
l
A
b
n
F
(
L
B
)

F
a
c
D
y
s
(
b
i
l
a
t
e
r
a
l
e
a
r
t
a
g
s
)
,
t
e
t
r
a
l
o
g
y
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f
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l
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t
,
m
i
c
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e
p
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l
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,
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D
.
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t
1
4
1 2
m
o
n
t
h
s
m
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t
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r
s
k
i
l
l
s

7

8
m
o
n
t
h
s
B
l
o
o
d

N
l
(
3
0
)
P
l
a
c
e
n
t
a

4
6
(
1
8
)
/
4
7
,
+
2
2
(
2
)
A
M
A
4
4
W
a
n
g
,
H
.
S
.
A
9
2
0
4
5
9
X
V
I
I
-
1
1
4
6
,
X
X
/
4
7
,
X
X
,
+
2
2
2
0
·
0
%
1
0
F
e
t
a
l
d
e
m
i
s
e

1
5
w
e
e
k
s

g
e
s
t
a
t
i
o
n
N
A


W
e
l
b
o
r
n
a
n
d
L
e
w
i
s
,
1
9
9
0
*
P
e
r
s
o
n
a
l
c
o
m
m
u
n
i
c
a
t
i
o
n
.
230 i. x. r. nsi r1 \i.
Table XVIIIa—Phenotypic abnormalities in mosaicism diagnosed postnatally vs. prenatally
46/47,+2 46/47,+3
Postnatal Prenatal Postnatal Prenatal
1 case 10 cases 3 cases 1 case
1 (F) Infant with
IUGR, hypertelorism,
midface hypoplasia,
frontal bossing,
craniosynostosis,
‘Pfeiffer syndrome’,
scoliosis (blood—
46,XX; skin—trisomy
2 in 40%)
(Cramer et al., 1993)
Fetal death
MCA with IUGR
Fac Dys, CHD
Fac Dys and other
minor
abnormalities
NTD
Ambiguous genitalia
Hemimelia
Dolichocephaly
IUGR and postnatal
GR
3
1
1
1
1
1
1
1
1 (F) Infant with
prominent forehead,
low-set malformed
ears, glaucoma,
clenched hands and
overlapping fingers,
PDA. Died at 5
months
(Metaxotou et al., 1981)
1 (F) 32-year-old with
severe MR, short
stature, microcephaly,
high forehead, small
flat midface, short
philtrum, simian lines,
dislocated hips,
scoliosis, short neck
and petus excavatum
(Kuhn et al., 1987)
1 (F) 21-year-old with
Bartter syndrome,
short stature,
coloboma, dislocated
left hip
(DeKeyser et al., 1988)
Bilateral cleft lip and
palate, tetralogy of
Fallot, pulmonary
stenosis,
microphthalmia,
cataracts, left ear
hypoplasia, multiple
vertebral
abnormalities, DD.
Died at 18 months
due to CHD
46/47+7 46/47,+9
Postnatal Prenatal Postnatal Prenatal
6 cases 1 case >40 cases 14 cases
Potter syndrome
Renal dysplasia
Goldenhar syndrome
with unilateral radial
hypoplasia
Mental illness (mother
and daughter)
MCA with CHD and
hypomelanosis of Ito
(Newlin et al., 1995)
(quoted in Hsu et al.,
1992)
2
1
1
1
1
Facial asymmetry,
hypomelanosis of Ito,
mild DD
GR, MR, cranial facial
dysmorphism such as
low-set malformed
ears, microphthalmia,
bulbous nose
CHD especially VSD
Renal abnormalities
Skeletal abnormalities
such as hip
dislocation
(Arnold et al., 1995;
Schinzel, 1993;
Wooldridge and Zunich,
1995)
MCA
Fac Dys
CHD
IUGR
Uro-genital
abnormalities
Skeletal abnormalities
No details
8
7
4
3
3
3
3
See Appendix for abbreviations.
231 ×\×r 1×isoxx xos\icisx ni\cNosrn iN \xNiocx1rs
Table XVIIIb—Phenotypic abnormalities in mosaicism diagnosed postnatally vs. prenatally (continued)
46/47,+12 46/47,+14
Postnatal Prenatal Postnatal Prenatal
3 cases 6 cases 15 cases 2 cases
1 (F) with MR, Fac
Dys, short stature,
microcephaly,
scoliosis, and muscle
atrophy
(Patil et al., 1983)
1 (F) with Fac Dys,
short stature,
scoliosis, CHD, abn
skin pigmentation
and normal mental
development
(English et al., 1994)
1 (M) with infertility,
situs inversus, and
normal mental
development
(Richer et al., 1977)
Fetal demise
CHD
Fac Dys
Skeletal abnormalities
Renal abnormalities
2
4
2
2
1
GR
MR
Broad nose
Abn and/or low-set ears
Micrognathia
Large mouth
Short neck
CHD
Body asymmetry
Abn skin pigmentation
Micropenis and
cryptorchidism
(Fujimoto et al., 1992)
1 with Fac Dys (low-set
ears), equinovarus,
rocker-bottom feet,
abn hip
1 with hydrocephaly
46/47,+15 46/47,+16
Postnatal Prenatal Postnatal Prenatal
6 cases 6 cases 2 cases 15 cases
Fac Dys
CHD (one with multiple
heart defects)
Hypotonia
Skeletal abnormalities
IUGR
Hydrops
(Bühler et al., 1996;
Coldwell et al., 1981;
Fryns et al., 1993;
Kuller and Laifer, 1991;
Milunsky et al., 1996;
Stallard and Sommer,
1989)
6
3
3
3
2
1
IUGR
CHD (all 3 cases had
multiple heart defects;
1 also had MCA,
renal and
gastrointestinal
abnormalities
Malrotation of intestine
Fac Dys
Arrhinencephaly
3
3
2
2
1
1 girl with multiple CHD
(including VSD, PDA,
coartation of aorta),
IUGR and postnatal
GR
(Greally et al., 1990)
1 male infant with
IUGR, Fac Dys
(cranial asymmetry,
abn scalp hair pattern,
hypertelorism,
coloboma of left iris,
short nose, flat nasal
bridge, low-set abn
ears), VSD, musculo-
skeletal abnormalities
(scoliosis, overlapping
fingers, etc.)
(Gilbertson et al., 1990)
IUGR
Fac Dys
CHD
VSD or ASD
DORV
Tetralogy of Fallot
Dextrocardia
Skeletal abnormalities
Gastrointestinal
abnormalities
Renal abnormalities
Psychomotor delay
Microcephaly
Skin pigmentation
8
11
10
6
3
1
1
5
5
4
2
1
1
Table XVIIIb continued on next page
232 i. x. r. nsi r1 \i.
cent in cells from an initial amniocentesis and 75
per cent in cells from a second amniocentesis).
Six cases with confirmation studies (including
four with PUBS or blood studies, one abortion
fluid, and one case with blood and amnion studies)
showed only normal cells. It seems that trisomy 17
cells are likely to be of extraembryonic origin and
not representative of the fetus.
Previous data showed that chromosome 17 is
one of six chromosomes that tend to show a
non-random involvement in multiple cell trisomy
pseudomosaicism (Hsu, 1992b). This observation
is compatible with the suggestion of confined
placental mosaicism. In fact, in one CVS
case, trisomy 17 mosaicism was established
to be confined to the placenta (Kalousek et al.,
1987).
Nevertheless, trisomy 17 mosaicism in the fetus
is compatible with survival to term. It has been
diagnosed at least twice postnatally (Bullerdiek
and Bartnitzke, 1982; Shaffer et al., 1996). One
case was a newborn with severe malformations and
the other was a boy with MR, growth retardation,
seizures, autism, microcephaly, and hearing loss.
Therefore, when a diagnosis of 46/47,+17 is
established in amniocytes, it should not be taken
lightly.
46/47,+19
Only one case is known to us (Table XVI). The
pregnancy resulted in a phenotypically normal
liveborn. Unfortunately, neither follow-up studies
nor developmental evaluation was possible.
Trisomy 19 was not observed in first-trimester
studies of abortuses (Warburton et al., 1991), yet
mosaic trisomy 19 was diagnosed at least twice
postnatally (Chen et al., 1981; Rethore et al.,
1981). In both of these cases, facial dysmorphism
was the major finding. One presented as a still-
born and one died neonatally. Cells with trisomy
19 were recovered in blood cultures in both
cases. Therefore, for further work-up of a prenatal
diagnosis of such mosaicism, PUBS could be
considered.
46/47,+22
Eleven cases of 46/47,+22 were collected (Table
XVII). Seven (63·6 per cent) had an abnormal
outcome, including two liveborns with CHD and
dysmorphic features, one neonatal death with
IUGR and hydrocephaly, one Caesarean section
premature infant (33 weeks) with IUGR, two
abortuses with dysmorphic features and/or skeletal
Table XVIIIb—continued from previous page
46/47,+22
Postantal* Prenatal
19 cases 7 cases
IUGR
Microcephaly
Hypoplastic or low-set ears
Hypoplastic midface
Cleft palate and/or lip
Webbed neck/redundant
skin
CHD
Renal abnormalities
Ear pits/tags
Hypertelorism
(Bacino et al., 1995)
*Includes 47,+22 and
46/47,+22
IUGR
Fac Dys or abn ears or
ear tags
CHD
DORV
Long fingers
Cleft lip
Microcephaly
Hydrocephaly
Skeletal abnormalities
Facial asymmetry
Fetal death
2
3
2
1
2
1
1
1
1
1
1
See Appendix for abbreviations
233 ×\×r 1×isoxx xos\icisx ni\cNosrn iN \xNiocx1rs
T
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7
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·
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%
8
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·
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%
3
3
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9
8
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·
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%
6
7
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9
1
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·
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%
1
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.
234 i. x. r. nsi r1 \i.
anomalies, and one fetal demise at 15 weeks’
gestation.
Four cases (two liveborns; two abortuses) had
two or more features of trisomy 22 syndrome, such
as abnormal ears or ear tags, CHD, and long
fingers (Table XVIIIb). Four cases had a normal
outcome (two liveborns and two abortuses). The
percentage of trisomy 22 cells ranged from 3·6 to
28 per cent for the seven cases with an abnormal
outcome and from 5 to 20 per cent for the four
cases with a normal outcome. Thus, there was no
noticeable difference in the proportion of abnor-
mal cells between the cases with an abnormal
outcome and those with a normal outcome.
As to the cytogenetic confirmation of trisomy 22
mosaicism, six of the abnormal outcome group
had confirmation studies. Cells with trisomy 22
were found in three fibroblast cultures (out of four
studied) (XVII-1, XVII-2, XVII-6) and in placental
cells in three cases (out of four studied) (XVII-6,
XVII-8, XVII-10). One case (XVII-6) showed
trisomy 22 cells in both fibroblasts and placental
cells (Table XIX). Thus, trisomy 22 mosaicism
was confirmed in five of seven cases with an
abnormal outcome. Among four cases with a
normal outcome, there were two cases with con-
firmatory studies (one with fibroblasts, placental
cells, and blood; and one with placental cells and
blood). Only cells with a normal karyotype were
found.
Although trisomy 22 is the second most com-
mon autosomal trisomy found in first-trimester
spontaneous abortuses (Warburton et al., 1991),
liveborns with trisomy 22 (non-mosaic or mosaic)
have occasionally been reported. In the last 25
years, trisomy 22 has been diagnosed postnatally
over 20 times (Hsu et al., 1971, 1992; Bacino et al.,
1995). The major clinical features associated with
trisomy 22 syndrome are IUGR, microcephaly,
abnormal ears, ear tags, webbed neck/redundant
skin, CHD, and long fingers. Again, ultrasound
examination is essential in the work-up.
Cytogenetic confirmation studies
The cytogenetic confirmation studies of trisomy
mosaicism in fibroblasts, placental cells, fibro-
blasts and placental cells (in the same case) and
blood cells, including PUBS and cord blood (Table
XIX), are summarized according to ‘normal out-
come’ versus ‘abnormal outcome’ in Table XX.
The combined data show much higher confir-
mation rates in cases with abnormal outcomes
than in cases with normal outcomes, with 80·5 per
cent versus 54·5 per cent for fibroblasts, 87·5 per
cent versus 45·8 per cent for placental cells, 66·7
per cent versus 33·3 per cent for simultaneous
studies and confirmation on both fibroblasts and
placental cells, and 21·9 per cent versus 9·8 per cent
for blood cells. The overall confirmation rates were
73·6 per cent for tissues and 15·1 per cent for
blood cells (Table XIX), but when fibroblasts and
placental cells were studied simultaneously, the
finding of trisomy cells in one or the other or both
was 84·6 per cent. Therefore, we must emphasize
that for cytogenetic confirmation, both fibroblasts
and placental tissues should be studied. There is a
good chance (95·8 per cent) that for cases with an
abnormal outcome, trisomic cells will be detected
in either fibroblasts or placental cells or both
(Table XX).
Blood cultures (and/or PUBS) are not a good
tissue source for cytogenetic confirmation. Except
for cases with trisomy 8, 9, 13, 18, and 21 mosaic-
ism, PUBS should not be recommended for fur-
ther evaluation of an established diagnosis of
mosaicism in amniocytes.
Table XX—Overall cytogenetic confirmation in cases with normal vs. abnormal outcome
Normal Abnormal
Fibroblasts 18/33 (54·5%) 33/41 (80·5%)
Placental cells 11/24 (45·8%) 28/32 (87·5%)
Both fibroblasts and placental cells* 5/15 (33·3%) 16/24 (66·7%)
Fibroblasts or placental cells or both* 10/15 (71·4%) 23/24 (95·8%)
Blood 4/41 (9·8%) 7/32 (21·9%)
*When both tissues were studied.
235 ×\×r 1×isoxx xos\icisx ni\cNosrn iN \xNiocx1rs
Effect of the percentage of cells with a trisomy on
the phenotypic outcome
The data on the percentage of cells with a tri-
somy in 145 cases were recorded for a statistical
comparison. They were categorized as having a
‘normal outcome’ versus an ‘abnormal outcome’.
The study included nine cases of 46/47,+2, two
cases of 46/47,+3, two cases of 46/47,+4, five cases
of 46/47,+5, three cases of 46/47,+6, eight cases of
46/47,+7, 13 cases of 46/47,+8, 22 cases of 46/
47,+9, two cases of 46/47,+11, 23 cases
of 46/47,+12, five cases of 46/47,+14, 11 cases of
46/47,+15, 21 cases of 46/47,+16, seven cases of
46/47,+17, one case of 46/47,+19, and 11
cases of 46/47,+22. It appears that cases with a
relatively high proportion of trisomic cells are
more likely to be associated with an abnormal
outcome than those with a low proportion of tri-
somic cells (Fig. 1) (a median of 11·00 per cent for
normal outcomes versus a median of 29·00 per cent
for abnormal outcomes; a mean of 21·20 per cent
for normal outcomes versus a mean of 33·05 per
cent for abnormal outcomes). Since the overlap is
notable and the standard deviations are large, the
difference observed here should be interpreted with
caution.
CONCLUSION
The overall data indicate that the risk for an
abnormal outcome, including phenotypically
abnormal offspring and/or IUGR and/or fetal
demise or stillbirth, varies for mosaic trisomies of
Fig. 1—Relationship between the percentage of trisomy cells in amniocytes and the
phenotypic outcome
236 i. x. r. nsi r1 \i.
different chromosomes. Since the majority of the
cases in this review were evaluated either at birth
or at termination, subtle abnormalities may have
escaped detection and developmental or postnatal
growth retardation would not be diagnosed. It is
critical for all liveborns with a prenatal diagnosis
of trisomy mosaicism to have long-term
follow-up for developmental evaluation.
To avoid biased ascertainment, cases with prior
abnormal ultrasound findings were excluded in
this review. However, the possibility of preferential
reporting of cases with an abnormal outcome still
exists; this could cause some exaggeration of the
abnormal outcome rate. In this review, 35 (53·0 per
cent) of the 66 cases with an abnormal outcome
were derived from publications, whereas 25 (29·4
per cent) of the 85 normal outcome cases were
abstracted from published reports.
In categories with five or more cases, the data
showed a wide range of risk (from 0 to 91 per cent)
(Table I). The risks for abnormal outcome are very
high (>60 per cent) for 46/47,+2, 46/47,+16, and
46/47,+22; high (40–59 per cent) for 46/47,+5,
46/47,+9, 46/47,+14, and 46/47,+15, and moder-
ately high (26 per cent) for 46/47,+12. In catego-
ries with a small number of cases (three cases or
less), the risk was not well defined. However, the
finding of one out of two cases with an abnormal
phenotype in 46/47,+3 and 46/47,+4 mosaicism
may suggest a high risk.
Since phenotypic manifestations of prenatally
diagnosed cases and postnatally diagnosed cases
are quite comparable and major abnormalities are
detectable with high-resolution ultrasound, this
procedure should be performed in all prenatally
diagnosed cases.
As to the cytogenetic confirmation studies of
other tissues, except for trisomy 8 or trisomy 9
mosaicism, PUBS is of limited value as part of a
work-up. The confirmation rate reaches 85 per
cent when both fibroblasts and placental tissues
are studied.
Lastly, since imprinting effects are documented
for several chromosomes, DNA studies for UPD
are recommended for 46/47,+7, 46/47,+11,
46/47,+14, and 46/47,+15. DNA studies for UPD
are suggested for 46/47,+2 and 46/47,+16 where
imprinting effects are likely.
\cxNovirncrxrN1s
This work was supported by the New York City
Department of Health, Maternal and Child Health
Block Grant. We would like to thank Eva Kahn
for the helpful suggestions, Shichuan Lu for prep-
aration of Fig. 1, and Josephine Benabu for prep-
aration of the manuscript. We are grateful to the
following geneticists, cytogeneticists, and physi-
cians for providing or collecting the valuable data:
Antley, R. M., Blue Ridge Radiology Assoc.,
Morganton, NC; Bernstein, R., University of
California, Irvine, CA; Cramer, D., Henry Ford
Hospital, Detroit, MI; Crandall, B. F., UCLA
Medical Center, Los Angeles, CA; Dawson, L.,
Ottawa, Ontario, Canada; Doherty, R., Founda-
tion Blood Research, Scarborough, ME; Elder, F.,
University of Texas Health Center, Houston, TX;
Fadness, P., Buffalo, NY; Farrell, S. A., Credit
Valley Hospital, Ontario, Canada; Flecker, D.,
Western Penn. Hospital, Pittsburgh, PA; Garver,
K. L., Verona, PA; Golbus, M. S., University of
California, San Francisco, CA; Hersch, J. H.,
Child Evaluation Center, Louisville, KY; Hershey,
D., Prenatal Diagnosis Center, Sacramento, CA;
Howard-Peebles, P. N., Genetics and IVF
Institute, Fairfax, VA; Jones, O. W., University of
California, San Diego, La Jolla, CA; Martin, G.,
University of Washington, Seattle, WA; Mengden,
G. A., Southwest Genetics, San Antonio, TX;
Mennutti, M., University of Pennsylvania,
Philadelphia, PA; Mikkelsen, M., John F.
Kennedy Institute, Glostrup, Denmark; Minka,
D., Denver, CO; Nitowsky, H. M., Albert Einstein
College of Medicine, Bronx, NY; Norwood, T.,
University of Washington, Seattle, WA; Patil,
S. R., University of Iowa Hospital, Iowa City, IA;
Priest, J., Shodair Hospital, Helena, MT; Richkind,
K., Integrated Genetics, Santa Fe, NM; Salk, D.,
University of Washington, Seattle, WA; Sciorra,
L., Robert Wood Johnson Medical School, New
Brunswick, NJ; Shah, H. O., North Shore Hospital,
NY; Shaham, M., North Shore Hospital, NY;
Shapiro, L. R., Westchester County Medical
Center, Valhalla, NY; Uchida, I., McMaster
University, Ontario, Canada; Vekemans, Michel
J. J., currently with Hopital Necker Enfants
Malades, Paris, France; Warburton, D., Columbia
Presbyterian Medical Center, NY; Ying, K. L.,
Seal Beach, CA; Yu, C. W., University of
Mississippi Medical Center, Jackson, MS.
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APPENDIX
List of abbreviations
AB abortus
Abn abnormal
AChE acetylcholinesterase
AFAFP amniotic fluid alpha-fetoprotein
AMA advanced maternal age
ASD atrial septal defect
BW birth weight
CHD congenital heart disease
cl colony
DD developmental delay
DORV double outlet right ventricle
DX diagnosis
F female
Fac Dys facial dysmorphism
FD fetal death
FH family history
FISH fluorescence in situ hybridization
GR growth retardation
HC head circumference
ht height
IUGR intrauterine growth retardation
LB liveborn
lt left
M male
mat maternal
MCA multiple congenital abnormalities
MR mental retardation
MSAFP maternal serum alpha-fetoprotein
MShCG maternal serum human chorionic
gonadotrophin
MOM multiple of mean
NA not available
Nl normal
NTDs neural tube defects
pat paternal
PDA patent ductus arteriosus
PDL Prenatal Diagnosis Laboratory of New
York City
PUBS periumbilical blood sampling
241 ×\×r 1×isoxx xos\icisx ni\cNosrn iN \xNiocx1rs
rt right
SB stillbirth/stillborn
SD standard deviation
UPD uniparental disomy
U/S ultrasound
VSD ventricular septal defect
wt weight
242 i. x. r. nsi r1 \i.