Acute Lymphoblastic Leukemia with Trisomy 21 Constitutional Mosaicism

Claude Léonard, Manuel Rolando Avalos, Françoise Miélot, Marc Poissonnier, Jean Paul Dommergues, Jérôme Lejeune, and Gil Tchernia

Cancer Genet Cytogenet 66:70-72 (1993)

Résumé :

ABSTRACT: Acute lymphoblastic leukemia was diagnosed in an 11-year-old girl with mild signs of Down's syndrome. She was known since birth to have a constitutional mosaicism (46,XX/47,XX, + 21c). At initial diagnosis of acute leukemia, additional chromosome changes were found in bone marrow blasts: hyper-diploidy >50, with a structural abnormality. She was treated with a standard chemotherapeutic protocol, and has remained in complete remission for more than 3 years. The constitutional mosaicism evolved toward normalization year after year in the blood and under the effect of chemotherapy in the bone marrow.




Acute leukemias are 20 times more frequent during the first decade of life in children with Down's syndrome than in normal children [1]. They include lymphoblastic leukemia (ALL), myeloblastic leukemia (ANLL) and, particularly, megakaryoblastic leukemia [2]. These leukemias can also involve the trisomy 21 cell population of mosaic subjects [3], occasionally revealing the mosaicism [4]. We report a case of acute lymphoblastic leukemia in a girl with known trisomy 21 mosaicism.


Patient and methods


Case Report

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).


Chromosome Studies

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.




Cytogenetic Analysis

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
Age Time after diagnosis of leukemia Tissue sample Blasts (%) Total cells counted Karyotypes (number of cells) Mosaic % 47,XX, + 21c/46,XX
Hyperdiploid 47,XX, + 21c 46, XX
1M 2W-B-752575 %
11Y 7M 3W0BM852718090 %
.1M 3WBM01030257824 %
.B01000217921 %
.1Y 2WBM0200061943 %
.3Y 4WBM0100001000 %
.B0135081276 %
.F-87-355240 %
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 t(1;1)(q21;q44).



The frequency of mosaicism in trisomy 21 is underestimated (2.7 % according to Giraud [5]) because of the weak phenotypic impact of diluted mosaics [6]. This probably explains why mosaics are over-represented (5.1 %) among cases of leukemia among Down's patients [7]. Leukemia can reveal trisomy 21 mosaicism [4] 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 [8] 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 [13], 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 [7]. In the case we report, we found hyperdiploidy >50 chromosomes, the good prognosis of which was attenuated by the presence of structural abnormalities [10], although a rearrangement of chromosome 1 is not particularly deleterious [11] and may even improve the prognosis [12]. 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 [9]. Chromosome 21 is by far the most common excessive chromosome in ALL [14] 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 [7]. 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 [15].



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