American Journal of Medical Genetics 71:463–466 (1997)
Molecular Cytogenetic Characterization of 18;21
Whole Arm Translocation Associated With
Monosomy 18p
Jin-Chen C. Wang,* L. Nemana, S.Y. Kou, R. Habibian, and M.J. Hajianpour
Alfigen/The Genetics Institute, Pasadena, California
Monosomy of the entire short arm of chro-
mosome 18 as a result of an 18;acrocentric
whole arm translocation has been reported
in over 20 patients, 3 of which were familial.
The centromeric origin in de novo cases has
not been characterized. We report molecu-
lar cytogenetic studies of two prenatally-
detected de novo cases. Amniocenteses were
performed because of sonographic findings
of fetal holoprosencephaly. Cytogenetic
studies and dual color fluorescence in situ
hybridization using Oncor a-satellite
probes for D18Z1 and D13Z1/D21Z1 showed
monosomy 18p with presence of a dicentric
18;21 chromosome in both cases [45,XY,
dic(18;21)(p11.1;p11.1)]. In one case, a sec-
ond cell line was found, which contained 46
chromosomes with a del(18)(p11.1) and an
apparently telocentric 21 not present in ei-
ther parent [46,XY,del(18)(p11.1),del(21)
(p11.1)]. The del(18)(p11.1) contained only
the 18 alphoid sequence and the telocentric
21 contained only the 21 alphoid sequence.
No centromeric break was detected. We pro-
pose that the second cell line arose from dis-
sociation of the dic(18;21) with no centro-
meric DNA break. In addition to our case,
there have been three previous reports of
dissociation of dicentric 18;acrocentric
chromosomes indicating that the transloca-
tion site can be unstable and dissociate. Am.
J. Med. Genet. 71:463–466, 1997.
© 1997 Wiley-Liss, Inc.
KEY WORDS: monosomy 18p; 18;21 whole
arm translocation; disso-
ciation of dicentric chromo-
somes
*Correspondence to: Dr. Jin-Chen C. Wang, Alfigen/The Genet-
ics Institute, 11 West Del Mar Boulevard, Pasadena, CA 91105.
Received 14 November 1996; Accepted 11 March 1997
© 1997 Wiley-Liss, Inc.
INTRODUCTION
Monosomy of the short arm of chromosome 18 was
first reported by de Grouchy et al. [1963]. This, to-
gether with 5p- [Lejeune et al., 1963, 1964], constituted
the first deletions observed in humans. Clinical pheno-
type of monosomy 18p varies widely [Jones, 1997] but
usually comprises of growth and mental deficiencies,
hypotonia, ptosis, epicanthal folds, low nasal bridge,
rounded facies, micrognathia, large protruding ears,
short neck, pectus excavatum, and small hands and
feet. Cardiac defects and genital anomalies have also
been observed. Cerebral malformations include agen-
esis of the corpus callosum, hydrocephaly, and holo-
prosencephaly-type defects.
Most reported cases of monosomy 18p were due to de
novo deletion. In some cases, the monosomy 18p results
from a whole arm translocation between chromosome
18 and another chromosome. In most cases, the other
chromosome involved is an acrocentric chromosome.
This type of whole arm translocation has been reported
in over 20 patients and accounts for approximately 16%
of all monosomy 18p patients [reviewed in Funderburk
et al., 1977 and Fryns et al., 1986; Garcia-Esquivel et
al., 1987; Einfeldt et al., 1983, abstract; Brin et al.,
1986, abstract]. In all such cases, the modal chromo-
some number is 45 with a derivative chromosome
[der(D/G;18)(q10;q10)] replacing a normal D/G and a
normal 18. In cases where parental cytogenetic studies
were available, all except 3 were de novo. In one of the
three familial cases, a reciprocal translocation with
breaks at 18p11.1 and 21q11.1 was shown by fluores-
cence in situ hybridization (FISH) using a-satellite
DNA probes [Tharapel et al., 1991, patient 1]. The cen-
tromeric origin of the derivative chromosome in de
novo cases has not been characterized. We report mo-
lecular cytogenetic studies of two additional, prena-
tally-detected de novo cases, both were ascertained by
sonographic findings of holoprosencephaly.
CLINICAL REPORTS
Case 1
A 31-year-old G2P1 woman underwent amniocente-
sis at 21 weeks of gestation due to sonographic finding
of holoprosencephaly. Routine cytogenetic studies dem-
464 Wang et al.

onstrated a 45,XY,der(18;21)(q10;q10) karyotype (Fig.

1). CBG-banding showed a single C-positive region on
this derivative chromosome. The fetus was therefore
monosomic for the entire short arm of chromosome 18.
Parental chromosomes were normal. The pregnancy
was terminated. Autopsy was not performed.
Case 2
A 22-year-old G2P1 woman underwent amniocente-
sis at 33 weeks of gestation due to sonographic finding
of holoprosencephaly. Cytogenetic study disclosed a
mosaic karyotype 45,XY,der(18;21)(q10;q10)[20]/
46,XY,del(18)(p11.1),del(21)(p11.1)[9] (Fig. 2). As in
case 1, CBG banding showed a single C-positive region
on the der(18;21) chromosome. Both cell lines were ef-
fectively monosomic for the entire short arm of chro-
mosome 18. The del(18)(p11.1) cell line had an appar-
ently telocentric chromosome 21 [del(21)(p11.1)], which
was not present in either parent. Both parents had
normal chromosomes (Fig. 3). Fig. 2. GTG-banded partial karyotypes of case 2. a: 45,XY,der(18;21)
A male infant was born at 39 weeks of gestation fol- (q10;q10). b:46,XY,del(18)(p11.1),del(21)(p11.1).
lowing a Cesarean section for increased head size and
arrest of dilatation. Birth weight was 3,260 g and Ap-
gar scores were 9/9. Holoprosencephaly with mid-facial netic convention, a dicentric chromosome. The result in
defects, including hypotelorism, absent philtrum, ab- case 2 is shown in Figure 4. Identical results were seen
sent nasal septum, and bilateral cleft lip, were noted. in case 1 (data not shown). In some cells, a small non-
Possible seizures, intermittent hyperthermia, and poor hybridized area was present between the two signals.
feeding were observed neonatally. The infant was dis- FISH, using acrocentric b-satellite probe, which hy-
charged home at age 17 days and has lost to follow up bridizes to the short arms of acrocentric chromosomes
since. at both sides of the ribosomal DNA repeats, showed no
clear hybridization signal in this area (data not shown).
Therefore, the nomenclature of the derivative chromo-
MOLECULAR CYTOGENETIC STUDIES
some was revised to dic(18;21)(p11.1;p11.1).
Methods In the 46,XY,del(18)(p11.1),del(21)(p11.1) cell line in
FISH was performed on cultured amniocytes accord- case 2, the del(18)(p11.1) contained only the chromo-
ing to the manufacturer’s standard protocol (Oncor, some 18 a-satellite sequence and the telocentric chro-
Gaithersburg, MD). The probes used were biotin- mosome 21 contained only the chromosome 21 a-satel-
labeled D13Z1/D21Z1 a-satellite probe (detected by lite sequence (Fig. 5). No centromeric break or split
FITC-green), which hybridizes to the centromeric re- centromeres were detected.
gion of chromosomes 13 and 21; digoxigenin-labeled
D18Z1 a-satellite probe (detected by rhodamine-red), DISCUSSION
which hybridizes to the centromeric region of chromo-
some 18; and digoxigenin-labeled b-satellite acrocen- Whole arm translocation involving chromosome 18
tric specific probe (detected by FITC-green), which hy- can lead to monosomy 18p when the derivative chro-
bridizes to the short arms of all acrocentric D/G group mosome containing 18p is lost. In most cases, the other
chromosomes. chromosome involved is an acrocentric chromosome
[reviewed in Fryns et al., 1986]. All five acrocentric D/G
Results chromosomes have been involved in this type of whole
Dual color FISH demonstrated that, in both cases, arm translocation. Both cases reported here presented
the derivative chromosome contained both 18 and 21 with holoprosencephaly, the severe end of the clinical
centromeric a-satellite sequences indicating that the
derivative chromosome represented, by usual cytoge-

Fig. 1. GTG-banded partial karyotype of case 1: 45,XY,der(18;21) Fig. 3. GTG-banded partial karyotypes of parents of case 2 showing
(q10;q10). chromosomes 18 and 21 homologues.
 Monosomy 18p and 18;21 Whole Arm Translocation
Fig. 4. Dual color FISH using D13Z1/D21Z1 a-satellite probe (green)
and D18Z1 a-satellite probe (red). Case 2, major cell line
[der(18;21)(q10;q10)]. Arrow denotes the derivative chromosome contain-
ing both 18 and 21 alphoid sequences. Large arrowhead denotes chromo-
some 18. Small arrowheads denotes chromosome 21.
spectrum observed in monosomy 18p. Holoprosen-
cephaly is genetically heterogeneous and at least four
different loci have been implicated, one of these (HPE4)
has been mapped to 18p11.3 [Overhauser et al., 1995].
The origin of the centromere in monosomy 18p pa-
tients with familial 18;acrocentric whole arm translo-
cation has been reported in one case using FISH [Thar-
apel et al., 1991, patient 1]. In that case, the derivative
chromosome consisted of 18q and 21q and was deter-
mined to have chromosome 18 centromere. In the same
study, Tharapel et al. [patient 2] also reported the cen-
tromeric origin of an 18;21 de novo whole arm translo-
Fig. 5. Dual color FISH using D13Z1/D21Z1 a-satellite probe (green)
and D18Z1 a-satellite probe (red). Case 2, second cell line [del(18)(p11.1),
del(21)(p11.1)]. Large arrowhead denotes chromosome 18, small arrow-
heads denotes chromosome 21. FISH was performed on previously GTG-
banded slide, which had much debris. The D18Z1 signals are large and it
is not clear which of the two represents del(18).
465
cation in a patient with complete trisomy 18q
[46,XX,+der(18)t(18;21)(p11;q11),-21]. The centromere
of the abnormal chromosome in this patient was also
from chromosome 18.
Conventional CBG banding in our patients did not
show two separate centromeric heterochromatic blocks.
However, FISH study showed that in both patients, the
derivative chromosomes contained a-satellite se-
quences of both chromosome 18 and 21, indicating that
they may represent dicentric chromosomes. No b-sat-
ellite DNA was detected between the two centromeres.
This finding is similar to the observations made in
studies of dicentric Robertsonian translocations which
revealed that the majority of such translocations did
not retain b-satellite DNA [Wolff and Schwartz, 1992;
Sullivan et al., 1996]. Parental cytogenetic studies
were normal in both cases reported here. The dicentric
chromosome arose de novo, with the loss of acentric
fragments 18p11.1-18pter and 21p11.1-21pter. This is
consistent with the prediction that in cases in which
the abnormal chromosome is dicentric, it is likely to
have arisen de novo; while in familial cases, the abnor-
mality is more likely a simple reciprocal whole arm
translocation without the formation of a dicentric chro-
mosome.
Two cases of whole arm translocation involving chro-
mosomes 18 and 20 with breaks within the chromo-
some 18 centromeric DNA, resulting in stable deriva-
tive chromosomes, have been reported [Cantú et al.,
1992; Tümer et al., 1995]. We did not observe centro-
meric breaks in either of the cases reported here.
Dissociation of dicentric chromosome into its two
component chromosomes has been reported in humans.
This has been seen in dicentrics consisting of two ac-
rocentrics [Jenkins et al., 1981; Lucas et al., 1986], in
dicentrics consisting of non-acrocentrics [Drets and
Therman, 1983], and in dicentrics consisting of an ac-
rocentric and a non-acrocentric [Niebuhr, 1972; Singh-
Kahlon et al., 1977; Dewald et al., 1979; Uehara and
Kida, 1986; Garcia-Esquivel et al., 1987]. Of the five
acrocentric/non-acrocentric cases reported, three in-
volved chromosome 18 [Singh-Kahlon et al., 1977; Ue-
hara and Kida, 1986; Garcia-Esquivel at al., 1987]. We
propose that, in our case 2, the second cell line con-
taining a telocentric 18 [del(18)(p11.1)] and a telocen-
tric 21 [del(21)(p11.1)] also arose from dissociation of
the dicentric chromosome, with no molecular cytoge-
netic evidence of breaks in the a-satellite sequences of
either chromosome 18 or 21. Our study suggests that
the dic(18;21) can be functionally stable but in some
cells the translocation site can be unstable and disso-
ciate.
ACKNOWLEDGMENTS
We are grateful to Dr. John Labavitch for reading the
manuscript. We also thank Jo Ann Rieger for aid in
preparation of the manuscript.
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