Acute leukemias are 20 times more frequent during the first decade of
life in children with Down's syndrome than in normal children . They include
lymphoblastic leukemia (ALL), myeloblastic leukemia (ANLL) and, particularly,
megakaryoblastic leukemia . These leukemias can also involve the trisomy 21
cell population of mosaic subjects , occasionally revealing the mosaicism
. We report a case of acute lymphoblastic leukemia in a girl with known
trisomy 21 mosaicism.
Patient and methods
The propositus is a girl born to a 35-year-old woman following an
uneventful pregnancy. Trisomy 21 was suspected at day 45 on the basis of slight
morphologic defects (left epicanthus, small flat nose, flat neck,
brachymesophalangia of the 5th digits, incomplete median palmar fold of the
right hand). Karyotyping revealed mosaicism (Table 1). There was no visceral
malformation. Psychomotor development was good and schooling was relatively
uneventful (IQ = 92). The trisomy 21 phenotype attenuated with age and was only
slightly noticeable at the age of 10 years, apart from a macroglossia. She was
admitted to the hospital at the age of 11 years for unexplained fever, with
asthenia, anorexia, pallor, and persistent pancytopenia 1 month after
appendectomy. The hemoglobin was 7.7 g/dL, and the white blood-cell count was
1.8 x 109/L, with 55 % polymorphonuclear neutrophils, 38 %
lymphocytes, 2 % monocytes, and 5 % blast cells; the platelet count was 86 x
109/L. The clinical examination was normal.
Cytology and Cytochemistry
Bone marrow smear showed cell paucity, with 85 % lymphoblasts and
occasional normal megakaryocytes. Type-L1 acute lymphoblastic leukemia was
diagnosed on the basis of the FAB classification. A biopsy revealed a normal
cellularity, with discrete myelofibrosis and a diffuse blast infiltrate.
Immunologic typing by means of indirect immunofluorescence with monoclonal
antibodies showed that the blast cells were HLA--DR+ , CD19+ , CD10+ , and
CD19- (early pre-B type).
A series of tests was run on peripheral blood, bone marrow, and skin
fibroblasts. Peripheral blood cells were cultured for 72 hours with PHA, bone
marrow cells for 24 hours, and fibroblasts for 3 weeks. The chromosomes were
stained with G-band methods.
At the time of ALL diagnosis, 27 spontaneous mitoses were examined
in marrow (Table 1); nine were diploid with a 46,XX karyotype, while 18 showed
hyperdiploidy, 55,XX, + X, + 1,t(1;1)(q21;q44), + 4, + 5, + 6, + 11, + 15, +
20, + 21. Non-clonal abnormalities included tetrasomy 4, 5, 21, and the loss of
1q material from the der(1) (Fig. 1).
Treatment and Outcome
The patient was given high-dose chemotherapy (FRALLE-87 Protocol,
group A: vincristine, cyclophosphamide, daunorubicine asparaginase) and
achieved complete hematologic (normal bone marrow, with the presence of the
three cell lineages, devoid of blasts) and cytogenetic remission at day 30
(Table 1). For safety reasons, the iv methotrexate ire the first consolidation
course was given at half the usual (3 g/m2) dose. Subsequently, as
it had been very well tolerated both clinically and biologically, it was given
at the normal dose for the following courses and during maintenance treatment
(mercaptopurine, methotrexate). The patient is disease free 39 months after
initial diagnosis. Growth and pubertal status are normal.
Table 1 Cytogenetic data
||Time after diagnosis of leukemia
||Total cells counted
||Karyotypes (number of cells)
||Mosaic % 47,XX, + 21c/46,XX
||47,XX, + 21c
|Abbreviations: Y = year; M = month; W = week; B
= blood; BM = bone marrow; F = fibroblasts.
Figure 1. - G-banded metaphase from marrow
aspirate taken at diagnosis: hyperdiploidy >50, with a
The frequency of mosaicism in trisomy 21 is underestimated (2.7 %
according to Giraud ) because of the weak phenotypic impact of diluted
mosaics . This probably explains why mosaics are over-represented (5.1 %)
among cases of leukemia among Down's patients . Leukemia can reveal trisomy
21 mosaicism  in patients who also have fewer visceral malformations and
therefore a better vital prognosis than those with homogenous trisomy 21.
Changes in the mosaic cell population with time in favor of cells with a normal
karyotype is a well-known phenomenon, both with regard to the constitutional
karyotype  and the bone marrow during chemotherapy [7, 9]. Indeed, trisomy
21 is associated with a very high degree of sensitivity to methotrexate both in
vitro and in vivo , and the standard iv dose is toxic. Our patient had a
relatively high proportion of trisomic 21 cells (about 20 %), with possible
variations in different tissue types. It is difficult to estimate the role of
methotrexate in reducing the fraction of trisomic 21 cells in the blood and
bone marrow during the course of treatment.
ALL is less frequent than ANLL in trisomy 21 patients and chromosome
abnormalities acquired during ALL in these patients are the same as those which
occur in normal children . In the case we report, we found hyperdiploidy
>50 chromosomes, the good prognosis of which was attenuated by the presence
of structural abnormalities , although a rearrangement of chromosome 1 is
not particularly deleterious  and may even improve the prognosis . The
presence of this balanced t(1;1) in the hyperdiploid cells occurred secondary
to the establishment of trisomy 1 as a normal chromosome 1 was found next to
the translocated chromosomes. Hyperdiploid cells possessed three or four
chromosomes 21, but it was not possible to determine whether they were derived
from normal cells or trisomic 21 cells of the bone marrow, even though the
latter possibility seems most probable . Chromosome 21 is by far the most
common excessive chromosome in ALL  and the only one which is particularly
never lost in near-haploidy. In subjects with a normal constitutional
karyotype, the acquisition of trisomy 21 in the marrow may be the initial event
in the development of hyperdiploidy. In this case, hyperdiploidy should be
over-represented among cases of ALL occurring in trisomy 21 patients. However,
the available data suggest that the cytogenetic profile of ALL in Down's
syndrome does not differ from that of ALL in normal children .
Unfortunately, the series published to date have been small and biased; larger
studies should shed light on the role of chromosome 21 in the genesis of
leukemic transformation .
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