Chromosome 7 Abnormalities in Children with Down Syndrome and Preleukemia Nancy Bunin, Peter C. Nowell, Jean Belasco, Narayan Shah, Michael Willoughby, Philip A. Farber, and Beverly Lange
ABSTRACT: Three children, two boys and one girl, with Down syndrome (DS) who presented with
preluekemia and loss of all or part of chromosome 7 were studied. Initial presentation, with cytopenias and 3 % of blasts stained. In addition, patient 2 had platalet peroxidase w i t h electron m i c r o s c o p y performed on bone marrow b i o p s y [17].
Immunophenotyping Bone marrow samples were analyzed with a panel of m o n o c l o n a l antibodies, i n c l u d ing those against B lineage determinants (CD10, CD19, CD20), T lineage d e t e r m i n a n t s (CD2, CD3, CD7) and m y e l o i d determinants (CD13, CD33). For patients 1 and 2, glycoprotein IIb/IIIa were utilized to assess megakaryocytic lineage [16]. Samples were considered positive w h e n > 3 0 % of cells were positive on surface fluorescence. In addition, factor VIII staining of bone marrow b i o p s y was performed for patient 3 [17].
RESULTS Patients 1 and 3 had i m m u n o p h e n o t y p i c or cytochemical evidence of acute megakaryocytic l e u k e m i a IAMKL), whereas patient 2 had undifferentiated l e u k e m i a by m o r p h o logic, cytochemical, and i m m u n o p h e n o t y p i c criteria (Table 2). Cytogenetic results on the three patients are shown in Table 3. In the original cytogenetic studies of the bone marrow of patient I (7/87, 9/67), during the preleukemic phase, a clone containing m o n o s o m y 7 and a ring marker, as well as the expected trisomy 21, was observed. These somatic changes were not
Table 3
Karyotypes at diagnosis of p r e l e u k e m i a and ANLL
Pt
Preleukemia
1
47,XY, - 7,16q-, ÷ 21, + r
2
ND 47,XY, - 7, ÷ 21, ÷ mar
3
Abbreviation: ND, not done.
ANLL 48,XY, - 7,16q-, ÷ 19, + 21, ÷ r 47,XY, - 7,16q-, ÷ 21, + r 47,XY,1q ÷, - 7,16q-, ÷ 21, ÷ r 45,XX, - 4, - 11, ÷ 21,i(7q),13q ÷ ,20q 47,XY, - 7, ÷ 21, ÷ mar
122
N. Bunin et al.
2
3
4
5
,K
B
f 7
8
9
10
11
12
C
s 13
14 D
15
16
18
17 E
%'*
.
19
20 F
i
21
22 G
X
Y
Figure 1 Karyotype from patient 1 at the time of progression to acute leukemia showing monosomy 7 and trisomy 21, with a ring probably derived from chromosome 7.
observed in a small sample of 12 cells collected in December 1987, but the same clone, with minor variations, was demonstrated in all 22 marrow metaphases examined in March 1988, when the disorder had progressed to frank leukemia (Fig. 1). The predominant karyotype was: 47,XY,- 7, + 21,1q + , 1 6 q - , + r. The ring chromosome may be derived from a portion of chromosome 7. Following remission induction, the karyotype was: 47,XY, + 21 in all cells examined. Patient 2 had only one cytogenetic study, during the leukemic phase of her disease (4/88). All six metaphases analyzed had the karyotype: 4 5 , X X , - 4 , - 1 1 , + 2 1 , i(7q),13q÷ , 2 0 q - . When patient 3 was first studied, during the preleukemic stage (3/86), 1 of 27 metaphases had, in addition to trisomy 21, an unidentified small marker replacing one #7 chromosome. The marker chromosome may be derived from a portion of chromosome 7. Six months later, this clone; 47,XY, - 7, + 21, ÷ mar, had expanded to approximately half of the cells examined (11/23) (Fig. 2). A poor specimen in November 1986, when frank leukemia had developed and treatment was in progress, yielded only two metaphases, both with this same abnormal karyotype. Six subsequent studies (11/86-6/88), following successful therapy, showed only trisomy 21 in 133 metaphases examined.
12 3
Chromosome 7 Abnormalities
1
2
3
6
7_7
s
13
14
15
tt
ii; 9
10
11
12
16
17
18
| 19
20
m,1 r
21
+ 21
~
X
Y
Figure 2 Karyotype from patient 3 at the time of progression to acute leukemia. The marker chromosome may be derived from a portion of chromosome 7.
DISCUSSION The incidence of leukemia in DS patients is 10-20 times higher than in the general population [18, 19]. However, it is unclear as to why children with DS are at increased risk for the development of leukemias. The proportion of nonlymphoid leukemias and lymphoid leukemias is similar to that found in the general pediatric population, although children with DS and ANLL tend to be younger at diagnosis than those without DS [20, 21]. The diagnosis has often been difficult to make in infants because transient myeloproliferative disease ITMD] often resembles acute nonlymphoid leukemia, although clinical features, cell culture, and ultrastructural differences are apparent in recent studies [22-26]. The three children in this series had no preceding episode of TMD in early infancy. The diagnosis of AMKL can be difficult, and electron microscopy with platelet peroxidase staining, as well as reaction with factor VIII or glycoprotein IIb/IIIa may be required for the diagnosis [17, 27, 28, 29]. Based on these various methods, the diagnosis of AMKL was established in two of the children in this series, but the third patient had a leukemia that defied classification by even extensive analysis. However, the evidence of myelofibrosis in the marrow of this child is a common feature found in patients with AMKL [30, 31]. Acute megakaryoblastic leukemia has been reported in children with DS, and trisomy 21 may be an important association with this subtype [30, 32, 33]. Cytogenetic analyses of nonoDS patients with AMKL are limited, and there are few reports of studies using banding techniques. A constitutional abnormality of chromosome 21
124
N. Bunin et al. has been reported, as well as a constitutional ring 21. In a report by Huang et al. [27], both a - 7 and 5 q - abnormality often associated with secondary leukemia were found in two patients with AMKL. These patients had normal constitutional karyotypes. Finally, in a recent study of 15 patients with AMKL, three cases of either 7 q or monosomy 7 were identified. All the cases had some features of myelodysplasia, but none of the patients in this series had DS [33]. A review of other reports has disclosed a higher percentage of either - 7 / 7 q - or - 5 / 5 q - in patients with the M7 subtype than in any other subtype of ANLL with the exception of erythroleukemia
[12]. There has been no specific cy~ogenetic abnormality identified as unique to patients with DS and ANLL.Hyperdiploidy is more common than pseudodiploidy, with gains of chromosomes 8, 19, or 22 reported [34-36]. Other cytogenetic findings have included a 6 q - marker chromosome and replacement of chromosome 7 by a ring chromosome (35], and a repoA of an infant with acute myelocy~ic leukemia and t( 8;16 )[q22 ;q24) [37]. Although cytogenetic findings in TMD include only the trisomy 21, studies have revealed clonal abnormalities if there is progression to acute leukemia [26]. These abnormalities have included a translocation between chromosome 1 and 19 [38], and trisomy 7 and monosomy 17 [36]. Preleukemia with a small percentage of marrow blasts has been described in patients with DS [24]. Nonrandom cytogenetic findings in these patients included partial trisomy of the long arm of chromosome 1 and breakpoints including 17pll [26]. It was suggested in this report that blasts in these cases of myelodysplasia arise from cells of megakaryocyte lineage or from myeloid progenitors with the capacity to differentiate into megakaryocytes. Our report is the first to demonstrate preleukemia with chromosome 7 abnormalities in patients with DS that develop into megakaryoblastic leukemia [36]. Loss of all or a portion of chromosome 7 has occasionally been noted in conjunction with other cytogenetic abnormalities in pediatric cases. These include the Philadelphia chromosome in children with acute lymphoblastic leukemia [39], as well as a report of trisomy 21 with monosomy 7 in a patient with aplastic anemia who had a normal constitutional karyotype [40]. The clinical course of children with preleukemia and - 7 / 7 q - is generally characterized by evolution of ANLL, usually of the myeloid or myelomonocytia type, or myelofibrosis. Progression to AMKL has been reported in one patient [41]. In general, even with intensive therapy, responses are of short duration, or patients may die with prolonged aplasia. It is of interest that the two patients treated in this series readily achieved remission by day 28, and one patient remains in remission more than 2 years following discontinuation of therapy. Abnormalities in chromosome 7 may not confer the same poor prognosis in this group of patients, but additional studies are needed to confirm this, particularly since a portion of the missing chromosome 7 may have been retained in case no. 3. It has been speculated that trisomy 21 increases the predisposition to leukemia by altering responses to environmental factors that may result in transformation. It has also been hypothesized that loss of activity at a single locus on 7q that normally limits myeloid proliferation can predispose to development of myelodysplasia [42]. However, evidence for this in familial monosomy 7 has not been borne out by molecular analysis [42]. The relationship between the two chromosome abnormalities, trisomy 21 and loss of part or all of chromosome 7, is intriguing, and the genetic and molecular implications remain, as yet, undefined.
REFERENCES 1. Rowley JD, Alimena G, Garson OM, Hagemeiier A, Mitelman F, Prigogina EL (19821: A
collaborative study of the relationship of the morphological type of acute nonlymphocytic leukemia with patient age and karyotype. Blood 59:1013-1022.
C h r o m o s o m e 7 Abnormalities
12 5
2. Whang-Pen 8 J, Young RC, Lee EC, Longo DL, Schechter GP, DeVita VT (1988): Cytogenetic studies in patients with secondary leukemia/dysmyelopoietic syndrome after different treatment modalities. Blood 71:403-414. 3. Nowell PC (1982): Cytogenetics of preleukemia. Cancer Genet Cytogenet 5:265-278. 4. Kaneko Y, Maseki N, Sakurai M, Shibuya A, Shinohara T, Fujimoto T, Kanno H, Nishikawa A (1989): Chromosome pattern in juvenile chronic myelogenous leukemia, myelodysplastic syndrome, and acute leukemia associated with neurofibromatosis. Leukemia 3:36-41. 5. Sieff DA, Chessells JM, Harvey AM, Pickthall VJ, Lawler SD (1981): Monosomy 7 in childhood: a myeloproliferative disorder. Br J Haematol 49:235-249. 6. Gyger M Bonny Y, Forest (1982): Childhood monosomy 7 syndrome. Am J Hematol 13:329-334. 7. Evans JPM, Czepulkowski B, Gibbons B, Swansbury GJ, Chessells JM (1988): Childhood monosomy 7 revisited. Br J Haematol 69:41-45. 8. Weiss K, Stass S, Williams D, Kalwinsky D, Dahl GV, Wang W, Johnson FL, Murphy SB, Dow LW (1987): Childhood monosomy 7 syndrome: clinical and in vitro studies. Leukemia 1:97-104. 9. Chitambar CR, Robinson WA, Glode LM (1983): Familial leukemia and aplastic anemia associated with monosomy 7. Am J Med 75:756-762. 10. Stivrins TJ, Davis RB, Sangar W, Fritz J, Purtilo DT (1984): Transformation of Fanconi's anemia to acute nonlymphocytic leukemia associated with emergence of monosomy 7. Blood 64:173-176. 11. Carroll WL, Morgan R, Glader BE (1985): Childhood bone marrow monosomy 7 syndrome: A familial disorder? J Pediatr 107:578-580. 12. Cuneo A, Mecucci C, Kerim S, Vandenbarghe E, Dal Cin P, Orshoven A, Rodhain J, Bosly A, Michaux J, Martiat P, Boogaerts M, Carli MG, Castoldi G, Van Den Berghe H (1989): Multipotent stem cell involvement in megakaryoblastic leukemia: Cytologic and cytogenetic evidence in 15 patients. Blood 74:1781-1790. 13. Borgstrom GH, Teerenhovi L, Vnopio P, De La Chapelle A, Van Den Berghe H, Brandt L, Golomb HM, Louwagie A, Mitelman F, Rowley JD, Sandberg AA (1980): Clinical implications of monosomy 7 in acute nonlymphocytic leukemia. Cancer Genet Cytogenet 2:115-126. 14. Nowell PC, Wilmoth D, Lange B (1983): Cytogenetics of childhood preleukemia. Cancer Genet Cytogenet 7:261-266. 15. ISCN (1985): An International System for Human Cytogenetic Nomenclature, Harnden DG, Klinger H, (eds.); published in collaboration with Cytogenet Cell Genet (Karger, Basel, 1985); also in Birth Defects: Original Article Series, Vol. 21, No. 1 (March of Dimes Birth Defects Foundation, New York, 1985). 16. Fourth International Workshop on Chromosomes in Leukemia, 1982: Organization (1984). Cancer Genet Cytogenet 11:259-272. 17. Bennett JM, Catovsky D, Daniel T, Flandrin G, Galton DAG, Gralnick FIR, Sultan C (1985): Criteria for the diagnosis of acute leukemia of megakaryocyte lineage (M7). Ann Int Med 103:460-462. 18. Stewart A, Webb J~ Hewitt D (1958): A survey of childhood malignancies. Br Med J 1:1495-1508. 19. Fabia J, Drolette M (1970): Malformations and leukemia in children with Down's syndrome. Pediatrics 45:60-70. 20. Rosner F, Lee SL (1972): Down's syndrome and acute leukemia: Myeloblastic or lymphoblastic? Am J Med 53:203-218. 21. Robison LL, Nesbit ME, Sathar HN, Level C, Shahidi N, Kennedy A, Hammond D (1984): Down syndrome and acute leukemia in children: A 10-year retrospective survey from Childrens Cancer Study Group. J Pediatr 105:235-242. 22. Engel RR, Hammond D, Eitzman DV, Pearson H, Krivit W (1964): Transient congenital leukemia in 7 infants with mongolism. J Pediatr 65:303-307. 23. Alarcon PA, Patil S, Golberg J, Allen JB, Shaw S (1987): Infants with Down's syndrome. Use of cytogenetic studies and in vitro colony assay for granulocyte progenitor to distinguish acute nonlymphocytic leukemia from a transient myeloproliferative disorder. Cancer 60:987-993. 24. Eguchi M, Sakakibara H, Suda J, Ozawa T, Hayashi Y, Sato T, Kojima S, Furukawa T (1989):
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27.
28. 29. 30. 31. 32.
33.
34. 35.
36. 37.
38.
39.
40.
41.
42.
Ultrastructural and ultracytochemical differences between transient myeloproliferative disorder and megakaryoblastic leukaemia in Down's syndrome. Br J Haematol 73:315-322. Wong KY, Jones MM, Srivastava AK, Gruppo RA (1988): Transient myeloproliferative disorder and acute nonlymphoblastic leukemia in Down syndrome. J Pediatr 112:18-22. Hayashi Y, Eguchi M, Sugita K, Nakazawa S, Sato T, Kojima S, Bessho F, Konishi S, Inaba T, Hanada R, Yamamoto K (1988): Cytogenetic findings and clinical features in acute leukemia and transient myeloproliferative disorder in Down's syndrome. Blood 72:15-23. Huang M, Li C, Nichols WL, Young J, Katzmann JA (1984): Acute leukemia with megakaryoo cytic differentiation: a study of 12 cases identified immunocytochemically. Blood 64:427-439. Sariban E, Oliver C, Corash L, Cossman J, Whang-Peng J, Jaffe ES, Gralnick HR, Poplack DG (1984): Acute megakaryoblastic leukemia in childhood. Cancer 54:1423-1428. Koike T (1984):Megakaryoblastic leukemia: The characterization and identification of megakaryoblasts. Blood 64:683-692. Cairney AE, McKenna R, Arthur DC, Nesbit ME, Woods WG (1986): Acute megakaryoblastic leukaemia in children. Br J Haematol 63:541-554. Chan WC, Brynes R, Kim TH, Verras A, Schick C, Green RJ, Ragab AH (1983): Acute megakaryoblastic leukemia in early childhood. Blood 62:92-98. Suarez CR, LeBeau MM, Silberman S, Fresco R, Rowley JD (1985): Acute megakaryoblastic leukemia in Down's syndrome: Report of a case and review of cytogenetic findings. Med Ped Oncol 13:225-231. Simon JH, Tebbi CK, Freeman AI, Brecher ML, Green DM, Sandberg AA (1987): Acute megakaryoblastic leukemia associated with mosaic Down's syndrome. Cancer 60:2515-2520. Kaneko Y, Rowley JD, Variakojis D, Chilcote RR, Moohr JW, Patel D (1981): Chromosome abnormalities in Down's syndrome patients with acute leukemia. Blood 58:459-465. Alimena G, Billstrom R, Casalone R, Gallo E, Mitelman F, Pasquali F (1985): Cytogenetic pattern in leukemia cells of patients with constitutional chromosome anomalies. Cancer Genet Cytogenet 16:207-218. Zipursky A, Peeters M, Poon A (1987): Megakaryoblastic leukemia and Down's syndrome: A review. Pediatr Hemat Oncol 4:211-230. Pettenati MJ, McNay JW, Chauvenet AR (1989): Translocation of the MOS gene in a rare t(8;16) associated with acute myeloblastic leukemia and Down syndrome. Cancer Genet Cytogenet 37:221-227. Morgan R, Hecht F, Cleary ML, Sklar J, Link MP (1985): Leukemia with Down's syndrome: Translocation between chromosomes I and 19 in acute myelomonocytic leukemia following transient congenital myeloproliferative syndrome. Blood 66:1466-1468. Russo C, Carroll A, Kohler S, Borowitz M, Amylon M, Homans A, Kedar A, Shuster J, Land V, Crist W, Pullen J, Link M (1991): The Philadelphia chromosome and monosomy 7 in childhood acute lymphoblastic leukemia: a Pediatric Oncology Group Study. Blood 77:1050-1056. Kirkpatrick D, Barrios N, Stine K, Varela M, Humbert J (1989): Transient expression of trisomy 21 and monosomy 7 following cyclosporine (CSA) in a patient with aplastic anemia. Blood 74:361a (abstr). Michiels JJ, Mallios-Zorbala H, Prins MEF, Hahlen K, Hagemeijer A (1986): Simple monoo somy 7 and myelodysplastic syndrome in thirteen patients without previous cytostatic treatment. Br J Haematol 64:425-433. Shannon KM, Turhan AG, Chang SSY, Bowcock AM, Rogers PCJ, Carroll WL, Cowan MJ, Glader BE, Eaves CJ, Eaves AC, Kan YW (1989): Familial bone marrow monosomy 7. Evidence that the predisposing locus is not on the long arm of chromosome 7. J Clin Invest 84:984-989.
ABSTRACT: Three children, two boys and one girl, with Down syndrome (DS) who presented with
preluekemia and loss of all or part of chromosome 7 were studied. Initial presentation, with cytopenias and 3 % of blasts stained. In addition, patient 2 had platalet peroxidase w i t h electron m i c r o s c o p y performed on bone marrow b i o p s y [17].
Immunophenotyping Bone marrow samples were analyzed with a panel of m o n o c l o n a l antibodies, i n c l u d ing those against B lineage determinants (CD10, CD19, CD20), T lineage d e t e r m i n a n t s (CD2, CD3, CD7) and m y e l o i d determinants (CD13, CD33). For patients 1 and 2, glycoprotein IIb/IIIa were utilized to assess megakaryocytic lineage [16]. Samples were considered positive w h e n > 3 0 % of cells were positive on surface fluorescence. In addition, factor VIII staining of bone marrow b i o p s y was performed for patient 3 [17].
RESULTS Patients 1 and 3 had i m m u n o p h e n o t y p i c or cytochemical evidence of acute megakaryocytic l e u k e m i a IAMKL), whereas patient 2 had undifferentiated l e u k e m i a by m o r p h o logic, cytochemical, and i m m u n o p h e n o t y p i c criteria (Table 2). Cytogenetic results on the three patients are shown in Table 3. In the original cytogenetic studies of the bone marrow of patient I (7/87, 9/67), during the preleukemic phase, a clone containing m o n o s o m y 7 and a ring marker, as well as the expected trisomy 21, was observed. These somatic changes were not
Table 3
Karyotypes at diagnosis of p r e l e u k e m i a and ANLL
Pt
Preleukemia
1
47,XY, - 7,16q-, ÷ 21, + r
2
ND 47,XY, - 7, ÷ 21, ÷ mar
3
Abbreviation: ND, not done.
ANLL 48,XY, - 7,16q-, ÷ 19, + 21, ÷ r 47,XY, - 7,16q-, ÷ 21, + r 47,XY,1q ÷, - 7,16q-, ÷ 21, ÷ r 45,XX, - 4, - 11, ÷ 21,i(7q),13q ÷ ,20q 47,XY, - 7, ÷ 21, ÷ mar
122
N. Bunin et al.
2
3
4
5
,K
B
f 7
8
9
10
11
12
C
s 13
14 D
15
16
18
17 E
%'*
.
19
20 F
i
21
22 G
X
Y
Figure 1 Karyotype from patient 1 at the time of progression to acute leukemia showing monosomy 7 and trisomy 21, with a ring probably derived from chromosome 7.
observed in a small sample of 12 cells collected in December 1987, but the same clone, with minor variations, was demonstrated in all 22 marrow metaphases examined in March 1988, when the disorder had progressed to frank leukemia (Fig. 1). The predominant karyotype was: 47,XY,- 7, + 21,1q + , 1 6 q - , + r. The ring chromosome may be derived from a portion of chromosome 7. Following remission induction, the karyotype was: 47,XY, + 21 in all cells examined. Patient 2 had only one cytogenetic study, during the leukemic phase of her disease (4/88). All six metaphases analyzed had the karyotype: 4 5 , X X , - 4 , - 1 1 , + 2 1 , i(7q),13q÷ , 2 0 q - . When patient 3 was first studied, during the preleukemic stage (3/86), 1 of 27 metaphases had, in addition to trisomy 21, an unidentified small marker replacing one #7 chromosome. The marker chromosome may be derived from a portion of chromosome 7. Six months later, this clone; 47,XY, - 7, + 21, ÷ mar, had expanded to approximately half of the cells examined (11/23) (Fig. 2). A poor specimen in November 1986, when frank leukemia had developed and treatment was in progress, yielded only two metaphases, both with this same abnormal karyotype. Six subsequent studies (11/86-6/88), following successful therapy, showed only trisomy 21 in 133 metaphases examined.
12 3
Chromosome 7 Abnormalities
1
2
3
6
7_7
s
13
14
15
tt
ii; 9
10
11
12
16
17
18
| 19
20
m,1 r
21
+ 21
~
X
Y
Figure 2 Karyotype from patient 3 at the time of progression to acute leukemia. The marker chromosome may be derived from a portion of chromosome 7.
DISCUSSION The incidence of leukemia in DS patients is 10-20 times higher than in the general population [18, 19]. However, it is unclear as to why children with DS are at increased risk for the development of leukemias. The proportion of nonlymphoid leukemias and lymphoid leukemias is similar to that found in the general pediatric population, although children with DS and ANLL tend to be younger at diagnosis than those without DS [20, 21]. The diagnosis has often been difficult to make in infants because transient myeloproliferative disease ITMD] often resembles acute nonlymphoid leukemia, although clinical features, cell culture, and ultrastructural differences are apparent in recent studies [22-26]. The three children in this series had no preceding episode of TMD in early infancy. The diagnosis of AMKL can be difficult, and electron microscopy with platelet peroxidase staining, as well as reaction with factor VIII or glycoprotein IIb/IIIa may be required for the diagnosis [17, 27, 28, 29]. Based on these various methods, the diagnosis of AMKL was established in two of the children in this series, but the third patient had a leukemia that defied classification by even extensive analysis. However, the evidence of myelofibrosis in the marrow of this child is a common feature found in patients with AMKL [30, 31]. Acute megakaryoblastic leukemia has been reported in children with DS, and trisomy 21 may be an important association with this subtype [30, 32, 33]. Cytogenetic analyses of nonoDS patients with AMKL are limited, and there are few reports of studies using banding techniques. A constitutional abnormality of chromosome 21
124
N. Bunin et al. has been reported, as well as a constitutional ring 21. In a report by Huang et al. [27], both a - 7 and 5 q - abnormality often associated with secondary leukemia were found in two patients with AMKL. These patients had normal constitutional karyotypes. Finally, in a recent study of 15 patients with AMKL, three cases of either 7 q or monosomy 7 were identified. All the cases had some features of myelodysplasia, but none of the patients in this series had DS [33]. A review of other reports has disclosed a higher percentage of either - 7 / 7 q - or - 5 / 5 q - in patients with the M7 subtype than in any other subtype of ANLL with the exception of erythroleukemia
[12]. There has been no specific cy~ogenetic abnormality identified as unique to patients with DS and ANLL.Hyperdiploidy is more common than pseudodiploidy, with gains of chromosomes 8, 19, or 22 reported [34-36]. Other cytogenetic findings have included a 6 q - marker chromosome and replacement of chromosome 7 by a ring chromosome (35], and a repoA of an infant with acute myelocy~ic leukemia and t( 8;16 )[q22 ;q24) [37]. Although cytogenetic findings in TMD include only the trisomy 21, studies have revealed clonal abnormalities if there is progression to acute leukemia [26]. These abnormalities have included a translocation between chromosome 1 and 19 [38], and trisomy 7 and monosomy 17 [36]. Preleukemia with a small percentage of marrow blasts has been described in patients with DS [24]. Nonrandom cytogenetic findings in these patients included partial trisomy of the long arm of chromosome 1 and breakpoints including 17pll [26]. It was suggested in this report that blasts in these cases of myelodysplasia arise from cells of megakaryocyte lineage or from myeloid progenitors with the capacity to differentiate into megakaryocytes. Our report is the first to demonstrate preleukemia with chromosome 7 abnormalities in patients with DS that develop into megakaryoblastic leukemia [36]. Loss of all or a portion of chromosome 7 has occasionally been noted in conjunction with other cytogenetic abnormalities in pediatric cases. These include the Philadelphia chromosome in children with acute lymphoblastic leukemia [39], as well as a report of trisomy 21 with monosomy 7 in a patient with aplastic anemia who had a normal constitutional karyotype [40]. The clinical course of children with preleukemia and - 7 / 7 q - is generally characterized by evolution of ANLL, usually of the myeloid or myelomonocytia type, or myelofibrosis. Progression to AMKL has been reported in one patient [41]. In general, even with intensive therapy, responses are of short duration, or patients may die with prolonged aplasia. It is of interest that the two patients treated in this series readily achieved remission by day 28, and one patient remains in remission more than 2 years following discontinuation of therapy. Abnormalities in chromosome 7 may not confer the same poor prognosis in this group of patients, but additional studies are needed to confirm this, particularly since a portion of the missing chromosome 7 may have been retained in case no. 3. It has been speculated that trisomy 21 increases the predisposition to leukemia by altering responses to environmental factors that may result in transformation. It has also been hypothesized that loss of activity at a single locus on 7q that normally limits myeloid proliferation can predispose to development of myelodysplasia [42]. However, evidence for this in familial monosomy 7 has not been borne out by molecular analysis [42]. The relationship between the two chromosome abnormalities, trisomy 21 and loss of part or all of chromosome 7, is intriguing, and the genetic and molecular implications remain, as yet, undefined.
REFERENCES 1. Rowley JD, Alimena G, Garson OM, Hagemeiier A, Mitelman F, Prigogina EL (19821: A
collaborative study of the relationship of the morphological type of acute nonlymphocytic leukemia with patient age and karyotype. Blood 59:1013-1022.
C h r o m o s o m e 7 Abnormalities
12 5
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