Acute Myeloblastic Leukemia with a Pericentric Inversion

of Chromosome 6 in a Child with Down Syndrome

Sofia Shekhter-Levin, Joseph Mirro, Lila Penchansky, Maureen E. Sherer, Niel Wald, and Susanne M. Gollin

ABSTRACT: Cytogenetic analysis of bone marrow cells demonstrated a pericentric inversion of chromo- some 6 when acute myeloblastic leukemia (AML) was diagnosed in a 15-month-old child with Down syn- drome. The abnormal clone with inv(6)(p24q16) was associated with FAB-M1 AML and disappeared when a complete remission was achieved. This is a unique cytogenetic abnormali ty for FAB-M1 AML in a child with Down syndrome and, to our knowledge, is only the second case of a pericentric inversion of chromo- some 6 reported in AML.

INTRODUCTION

Structural rearrangements involving chromosome 6 are in- frequently reported in AML. Abnormalities of the short arm have been observed primarily in translocations, with the most common being the translocation, t(6; 9) (p23;q34) [1, 2]. The long arm of chromosome 6 is even less frequently involved, usually in deletions [3]. Rearrangements involving both arms of chromosome 6 appear to be extremely rare. In a case reported previously, a pericentric inversion of chromosome 6, inv(6)(p12q27), was accompanied by the translocation, t(15;17), in an elderly patient with acute promyelocytic leuke- mia [4]. We present a unique case of AML in a boy with Down syndrome whose leukemic clone contained a pericentric in- version of chromosome 6, inv(6)(p24q16), as the sole acquired chromosome abnormality. The karyotype 47,XY, inv(6)(p24q16), + 21c was present at diagnosis and after the child achieved a complete remission, karyotyping revealed only 47,XY, + 21c.

MATERIALS AND METHODS

Clinical Summary A 15-month-old boy with Down syndrome underwent an un- complicated left orchiopexy for an undescended testis. Nine days later, he was admitted with a 1-day history of fever, petechial rash, and irritability. On physical examination, he had the obvious stigmata of trisomy 21. In addition, he had multiple petechiae and his spleen tip was palpable I cm be-

From the Departments of Human Genetics (S. S.-L., M. E. S., S. M. G.), Pediatrics (J. M.), Pathology (L. P.), and Environmental and Occupational Health (N. W.), University of Pittsburgh, Chil- dren's Hospital of Pittsburgh, and the Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.

Address reprint requests to: Dr. Sofia Shekhter-Levin, Univer- sity of Pittsburgh Clinical Cytogenetics Laboratory, A-549 Scaife Hall, Terrace and DeSoto Streets, Pittsburgh, PA 15261.

Received May 10, 1993; accepted August 31, 1993.

© 1994 Elsevier Science Inc. 655 Avenue of the Americas , New York, NY 10010

low the left costal margin. Laboratory evaluation revealed leukocyte count of 4.9 × 109/L, hemoglobin 11.1 g/dl, and hematocrit of 32%; the platelet count was 17 x 109/L. A bone marrow aspirate revealed 23% blasts. Using FAB criteria [5], a diagnosis of myelodysplastic syndrome (RAEB-IT) was made, but the differential diagnosis included evolving my- eloblastic leukemia.

The patient was followed without any clinical problems for 2 weeks, at which time he developed circulating blasts. Bone marrow aspirate demonstrated hypercellularity with 55% blasts (Fig. 1). These blasts are large, with nucleoli and basophilic cytoplasm; approximately 9% contained azuro- philic granules. Immunophenotypic studies by flow cytom- etry revealed expression of the following antigens: CD7 (82 %), CD11b (50%), CD13 (56%), HLA-DR (23%), CD33 (63%), CD34 (34%), double-color CD7-CD33 (78%), and CD7-CD13 (51%). Less than 20% positive cells was considered a nega- tive result and not reported. Based on these findings, the diagnosis of CD7-positive AML (FAB-M1) was made [6].

A complete remission was achieved with induction ther- apy that included two cycles of daunorubicin, cytosine arabinoside (ara-C), etoposide (VP-16), 6-thioguanidine (6- TG), and dexamethasone. Following induction, he received consolidation therapy with high-dose ara-C followed by L-asparaginase.

The patient then received maintenance therapy with two 28-day cycles of 6-TG, vincristine, ara-C, 5-azacytidine, and cyclophosphamide, along with intrathecal therapy of ara-C followed by a final cycle of VP-16, daunorubicin, ara-C, 6-TG, and dexamethasone. He completed all planned chemother- apy and remains in first complete remission more than I year later.

Cytogenetics Cytogenetics analysis of unstimulated bone marrow cells was performed on five occasions, once at diagnosis (1/30/92) and

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158 S. Shekhter-Levin et al.

Bone marrow aspirate; AML blast infiltration (Wright-Giemsa × 1000). Figure 1

four times at remission (3/2/92, 5/28/92, 7/20/92, and 4/13/93). Direct harvest and harvest after 24-hour culture were car- ried out using standard cytogenetic techniques [7]. Metaphase chromosomes were trypsin-Giemsa banded, karyotyped, and designated according to the International System of Human Cytogenetic Nomenclature [8].

Analysis of twenty cells studied at the time of diagnosis revealed a mosaic karyotype. Nine cells had a 47,XY, + 21c chromosome pattern and 11 cells showed a 47,XY, inv(6) (p24q16), + 21c chromosome pattern. A representative karyo- type with the inv(6) is shown in Figure 2. Four subsequent studies of 21, 25, 21, and 20 cells, respectively, performed during remission, revealed only cells with a 47,XY, + 21c chro- mosome pattern, consistent with the clinical diagnosis of Down syndrome.

DISCUSSION

The increased risk of acute leukemia in Down syndrome pa- tients is well established [9-12]. According to the large retrospective studies of these cases, the number of Down syn- drome patients developing AML is equal to the number de- veloping ALL [11, 12]. This is a much higher incidence of AML than among other age-matched leukemia patients. Mitelman et al. [13] reviewed 52 reported cases of acute leuke- mia in Down syndrome patients who were studied using banded chromosome analysis. Among these patients, 34 had AML, 16 had ALL, and two had acute undifferentiated leuke- mia. In addition, two patients with acute mixed lineage leuke- mia in association with Down syndrome were reported re- cently [14]. The immunophenotype of our patient revealed expression of CD7. Patients with CDT-positive AML are con-

sidered to have a leukemic conversion of a pluripotent lym- phohematopoietic cell [15]. Unlike our patient, however, such patients have been reported to have a poor outcome.

Rearrangements of the short arm of chromosome 6 in the region 6p21-p24 have been seen in AML [1, 2], while arrange- ments of the long arm in the region 6q15-q24 are significantly more frequent in ALL than in AML [3, 16]. Therefore, simul- taneous involvement of both regions by a pericentric inver- sion in our patient might explain the expression of CD7 and myeloid antigens. Evaluation of the clinical significance of an inv(6) is not possible on the basis of only two cases, ours and one previously reported [4], especially because these two cases are very different. The previously reported patient was an elderly man with acute promyelocytic leukemia with a 1-month survival, whereas our patient is a young child with AML-M1 who achieved a complete remission that has now continued for more than 13 months. In the previously re- ported case, the inversion of chromosome 6 had different breakpoints, inv(6)(p12q27), and was present along with the translocation, t(15;17)(q22;q12), while we observed the inv(6) (p24q16) as the sole chromosome abnormality associated with the leukemia. When our patient went into remission, the ab- normal clone was no longer seen in four subsequent cyto- genetic studies of the bone marrow.

This case demonstrates a very rare chromosome rearrange- ments involving chromosome 6 in a Down syndrome child with AML. The extremely rare occurrence of this inversion and the rare finding of CD7 expression on myeloblasts makes this case interesting. Evaluation of the clinical significance of the inv(6) found in our patient awaits other reports of this abnormality and molecular studies of the genes at these breakpoints.

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We are grateful to Jane Zhou for excellent technical assistance and to Ms. Louise Foreman for typing the manuscript.

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