- Email: [email protected]
Isochromosome 14q in refractory anemia
ELSEVIER
SHORT COMMUNICATIONS Isochromosome 14q in Refractory Anemia M. G. Boavida, P. Ambr6sio, D. Dhermy, C. Silva, and M. E. Correia, Jr.
ABSTRACT: Trisomy 14 in hematologic disease is a rare finding and is almost exclusively associated
with myeloid cell lineage. We present a case of refractory anemia (MDS-RA) with the u n c o m m o n features of marked elliptocytosis and schistocytosis in the peripheral blood and isochromosome 14q. The analysis of the clinical outcome of this case and of others of myelodysplastic (MDS)/myeloproliferative syndromes with trisomy 14 as the sole abnormality suggests that it does not confer an unfavorable prognosis. © Elsevier Science Inc., 1997 INTRODUCTION
Trisomy 14 as a primary clonal change is found rarely in hematologic disease and is mostly confined to myeloid disorders. To our knowledge, only 38 cases of patients with trisomy 14 as the sole chromosome anomaly have been reported in the literature [1-3]. In all but 2 [4, 5], this change was identified in disorders of myeloid lineage. We report another case of trisomy 14 due to the presence of an isochromosome 14q in a ]~atient with myelodysplastic syndrome, refractory anemia (MDS-RA), with specific features. This case also presents another unusual feature in hematopoietic dysplasia that consists of pronounced elliptocytosis and some schistocytes in the peripheral blood [6-8]. CASE REPORT AND CYTOGENETIC FINDINGS
AS, an 81-year-old man, was referred for anemia and asthenia. There was no family history of hematologic disease or of exposure to toxic agents. Peripheral blood examination revealed the following: hemoglobin 86 g/L; mean cell volume 87.4 fl; white blood cells 9.1 x 109/L (neutrophils 58%; eosinophils 2%; basophils 0%; lymphocytes 26%; monocytes 14%); platelet count 149 x 109/L. The blood film showed mild to moderate anisopoikilocytosis with many elliptocytes and schistocytes. Familial elliptocytosis was excluded by carrying out the biochemical study of the
From the Department of Human Genetics, National Institute of Health, Lisbon, Portugal (M. G. B., P. A.). Laboratory of Hematology, Santa Cruz Hospital, Carnaxide, Portugal (C. S., M. E. C. J.); INSERM U409, Medical Faculty Xavier Bichat, Paris, France (D. D.). Address reprint requests to: M. G. Boavida, Department of Human Genetics, National Institute of Health, Avenue Padre Cruz, 1699 Lisbon Codex, Portugal. Received July 5, 1996; accepted September 1, 1996. Cancer Genet Cytogenet 9 7 : 1 5 5 - 1 5 6 (•997) © Elsevier Science Inc., 1997 655 Avenue of the Americas, N e w York, NY 10010
erythrocyte membrane proteins in SDS polyacrylamide gel electrophoresis [9-11]. A qualitatively and quantitatively normal profile of spectrin, ankyrin, and protein 4.1 and 4.2 was found. Bone marrow aspiration and biopsy, carried out 6 months later, showed hypercellular bone marrow with mild hyperplastic erythropoiesis. Megakaryocytes were increased and exhibited slight dysplastic changes (monolobulated nuclei). Marrow iron stores were normal and ringed sideroblasts were observed in 3% of the erythroblasts. Reticulin levels were not increased. A diagnosis of primary myelodysplastic syndrome, refractory anemia was made (FAB type, RA). The patient's condition has remained stable 10 months after diagnosis, without treatment. A cytogenetic study of bone marrow by synchronized short-term culture and standard G-banding technique showed the following karyotypes:46,XY,i(14) (q10)[15]/46,XY[35].
DISCUSSION
Trisomy 14 as a sole chromosome abnormality is considered a rare, but specific, cytogenetic abnormality in myeloid disorders. At least 38 cases have been reported, 18 in association with myelodysplastic (MSD)/myeloproliferative syndromes, 13 with acute nonlymphoblastic leukemia (ANLL), 6 with atypical chronic myelogenous leukemia (CML), and 1 with pancytopenia [1-3]. This rare primary chromosomal change preferentially occurs in elderly male adults (median age: 65 years, range 40-84 years, 75% of patients are males). To our knowledge this is the 19th reported case of trisomy 14 associated with myelodysplastic/ myeloproliferative disorders and the 10th with an i(14q) [1]. Interestingly, this variant form of trisomy 14 was exhibited by 4 of the 5 rheumatoid arthritis cases with (RA) (4, 12-14). Isochromsomes frequently are observed in hematologic malignancies [15], either as the sole abnormality or with
0165-4608]97/$17.00 PII S0165-4608(96)00334-2
156
other structural and numerical aberrations. Sometimes, as with i(17q) and i(7q), isochromosomes appear in terminal phase of diseases. However, the presence of an i(14q), as well as of simple trisomy 14, does not seem to be related to the exacerbation of the condition, as illustrated by the present case and by others reported in the literature [1] that had favorable clinical outcomes. Although the biologic basis of trisomy 14 in myeloid disorders is u n k n o w n , a gene dosage effect and/or gene activation is a likely m e c h a n i s m for the onset or progression of the disease. Our patient presents an u n u s u a l feature in RA, which consists of evident elliptocytosis and schistocytosis in the peripheral blood. To our knowledge this is the 4th published case of MDS with elliptocytosis and schistocytosis [6-8]. As no qualitative or functional anomalies of the erythrocyte m e m b r a n e proteins studied were detected, familial elliptocytosis could be excluded. This finding may simply be interpreted as an elliptocytosis secondary to a hematopoietic dysplasia.
REFERENCES 1. Poirel H, Jonveaux P, Daniel MT, Berger R (1995): Trisomy 14: A recurring cytogenetic abnormality associated with myeloid disorders. Leuk Lymphoma 17:455-457. 2. Heim S, Mitelman F (1986): Numerical chromosome aberrations in human neoplasia. Cancer Genet Cytogenet 22:99-108. 3. United Kingdom Cancer Cytogenetics Group (UKCCG) (1992): Primary, single, autosomal trisomies associated with hematological disorders. Leuk Res 16:841-851. 4. Brizard A, Guilhot F, Babin P, Burucoa C, Tanzer J, Huret JL (1992): Four additional cases of trisomy 14 as the sole anomaly in various hematological malignancies. Leuk Res 16:537-540.
M.G. Boavida et al. 5. Loughran TP, Kadin ME, Starkebaum G, Abkowitz JL, Clark EA, Disteche C, Lum LG, Slichter SJ (1995): Leukemia of large granular lymphocytes: Association with clonal chromosomal abnormalities and autoimmune neutropenia, thrombocytopenia and hemolytic anemia. Ann Int Med 102:169-175. 6. Schumacher HR, Nand S (1995): Approach to diagnosis and treatment. In: Myelodysplastic Syndromes. Igaku-shoin, New York, pp. 11-13. 7. Hartz JW, Buss DH, White DR, Bond MG, Scharyj M (1984): Marked elliptocytosis and schistocytosis in hematopoietic dysplasia. Am J Clin Pathol 82:354-359. 8. Rummens JI, Verfaillie C, Criel A, Hidajat M, Vanhoof A, Van den Berghe H, Lonwagie A (1986): Elliptocytosis and schistocytosis in myelodisplasia. Report of two cases. Acta Haematol. 75:174-177. 9. Lecomte MC, Gautero H, Garbrz M, Boivin P, Ghermy D (1990): Abnormal tryptic peptide from the spectrin c~-chain resulting from c~- or B-chain mutations: Two genetically distinct forms of the Spo~T M variant. Br J Haematol 76:406-413. 10. Fairbanks G, Steck TL, Wallach DFH (1971): Electrophoretic analysis of the major polypeptides of the human erythrocyte membrane. Biochemistry 10:2606-2617. 11. Laemmli UK (1970): Cleavage of structural proteins during the assembly of the head of the bacteriophage T4. Nature 74:680-685. 12. Maucini M, Cedrone M, Nanni M, Rondinelli MB, Petti MC, De Cuia MR, Alimena G (1992): Trisomy 14 in hematologic diseases. Cancer Genetic Cytogenet 66:39-42. 13. Sol~ F, Caballfn MR, Coil MD, Woessner S, Besses C, Palou L, Egozcue J (1991): Isochromosome 14q in myeloid dysplastic disorder. Cancer Genet Cytogenet 54:133-134. 14. Pinkerton PH, London B, Dub6 ID, Senn JS (1990): Trisomy 14q in myelodysplastic syndromes. Cancer Genetic Cytogenet 49:113-116. 15. Labal de Vinuesa M, Slavutsky I, Larripa I (1987): Presence of isochromosomes in hematologic diseases. Cancer Genetic Cytogenet 25:47-54.
SHORT COMMUNICATIONS Isochromosome 14q in Refractory Anemia M. G. Boavida, P. Ambr6sio, D. Dhermy, C. Silva, and M. E. Correia, Jr.
ABSTRACT: Trisomy 14 in hematologic disease is a rare finding and is almost exclusively associated
with myeloid cell lineage. We present a case of refractory anemia (MDS-RA) with the u n c o m m o n features of marked elliptocytosis and schistocytosis in the peripheral blood and isochromosome 14q. The analysis of the clinical outcome of this case and of others of myelodysplastic (MDS)/myeloproliferative syndromes with trisomy 14 as the sole abnormality suggests that it does not confer an unfavorable prognosis. © Elsevier Science Inc., 1997 INTRODUCTION
Trisomy 14 as a primary clonal change is found rarely in hematologic disease and is mostly confined to myeloid disorders. To our knowledge, only 38 cases of patients with trisomy 14 as the sole chromosome anomaly have been reported in the literature [1-3]. In all but 2 [4, 5], this change was identified in disorders of myeloid lineage. We report another case of trisomy 14 due to the presence of an isochromosome 14q in a ]~atient with myelodysplastic syndrome, refractory anemia (MDS-RA), with specific features. This case also presents another unusual feature in hematopoietic dysplasia that consists of pronounced elliptocytosis and some schistocytes in the peripheral blood [6-8]. CASE REPORT AND CYTOGENETIC FINDINGS
AS, an 81-year-old man, was referred for anemia and asthenia. There was no family history of hematologic disease or of exposure to toxic agents. Peripheral blood examination revealed the following: hemoglobin 86 g/L; mean cell volume 87.4 fl; white blood cells 9.1 x 109/L (neutrophils 58%; eosinophils 2%; basophils 0%; lymphocytes 26%; monocytes 14%); platelet count 149 x 109/L. The blood film showed mild to moderate anisopoikilocytosis with many elliptocytes and schistocytes. Familial elliptocytosis was excluded by carrying out the biochemical study of the
From the Department of Human Genetics, National Institute of Health, Lisbon, Portugal (M. G. B., P. A.). Laboratory of Hematology, Santa Cruz Hospital, Carnaxide, Portugal (C. S., M. E. C. J.); INSERM U409, Medical Faculty Xavier Bichat, Paris, France (D. D.). Address reprint requests to: M. G. Boavida, Department of Human Genetics, National Institute of Health, Avenue Padre Cruz, 1699 Lisbon Codex, Portugal. Received July 5, 1996; accepted September 1, 1996. Cancer Genet Cytogenet 9 7 : 1 5 5 - 1 5 6 (•997) © Elsevier Science Inc., 1997 655 Avenue of the Americas, N e w York, NY 10010
erythrocyte membrane proteins in SDS polyacrylamide gel electrophoresis [9-11]. A qualitatively and quantitatively normal profile of spectrin, ankyrin, and protein 4.1 and 4.2 was found. Bone marrow aspiration and biopsy, carried out 6 months later, showed hypercellular bone marrow with mild hyperplastic erythropoiesis. Megakaryocytes were increased and exhibited slight dysplastic changes (monolobulated nuclei). Marrow iron stores were normal and ringed sideroblasts were observed in 3% of the erythroblasts. Reticulin levels were not increased. A diagnosis of primary myelodysplastic syndrome, refractory anemia was made (FAB type, RA). The patient's condition has remained stable 10 months after diagnosis, without treatment. A cytogenetic study of bone marrow by synchronized short-term culture and standard G-banding technique showed the following karyotypes:46,XY,i(14) (q10)[15]/46,XY[35].
DISCUSSION
Trisomy 14 as a sole chromosome abnormality is considered a rare, but specific, cytogenetic abnormality in myeloid disorders. At least 38 cases have been reported, 18 in association with myelodysplastic (MSD)/myeloproliferative syndromes, 13 with acute nonlymphoblastic leukemia (ANLL), 6 with atypical chronic myelogenous leukemia (CML), and 1 with pancytopenia [1-3]. This rare primary chromosomal change preferentially occurs in elderly male adults (median age: 65 years, range 40-84 years, 75% of patients are males). To our knowledge this is the 19th reported case of trisomy 14 associated with myelodysplastic/ myeloproliferative disorders and the 10th with an i(14q) [1]. Interestingly, this variant form of trisomy 14 was exhibited by 4 of the 5 rheumatoid arthritis cases with (RA) (4, 12-14). Isochromsomes frequently are observed in hematologic malignancies [15], either as the sole abnormality or with
0165-4608]97/$17.00 PII S0165-4608(96)00334-2
156
other structural and numerical aberrations. Sometimes, as with i(17q) and i(7q), isochromosomes appear in terminal phase of diseases. However, the presence of an i(14q), as well as of simple trisomy 14, does not seem to be related to the exacerbation of the condition, as illustrated by the present case and by others reported in the literature [1] that had favorable clinical outcomes. Although the biologic basis of trisomy 14 in myeloid disorders is u n k n o w n , a gene dosage effect and/or gene activation is a likely m e c h a n i s m for the onset or progression of the disease. Our patient presents an u n u s u a l feature in RA, which consists of evident elliptocytosis and schistocytosis in the peripheral blood. To our knowledge this is the 4th published case of MDS with elliptocytosis and schistocytosis [6-8]. As no qualitative or functional anomalies of the erythrocyte m e m b r a n e proteins studied were detected, familial elliptocytosis could be excluded. This finding may simply be interpreted as an elliptocytosis secondary to a hematopoietic dysplasia.
REFERENCES 1. Poirel H, Jonveaux P, Daniel MT, Berger R (1995): Trisomy 14: A recurring cytogenetic abnormality associated with myeloid disorders. Leuk Lymphoma 17:455-457. 2. Heim S, Mitelman F (1986): Numerical chromosome aberrations in human neoplasia. Cancer Genet Cytogenet 22:99-108. 3. United Kingdom Cancer Cytogenetics Group (UKCCG) (1992): Primary, single, autosomal trisomies associated with hematological disorders. Leuk Res 16:841-851. 4. Brizard A, Guilhot F, Babin P, Burucoa C, Tanzer J, Huret JL (1992): Four additional cases of trisomy 14 as the sole anomaly in various hematological malignancies. Leuk Res 16:537-540.
M.G. Boavida et al. 5. Loughran TP, Kadin ME, Starkebaum G, Abkowitz JL, Clark EA, Disteche C, Lum LG, Slichter SJ (1995): Leukemia of large granular lymphocytes: Association with clonal chromosomal abnormalities and autoimmune neutropenia, thrombocytopenia and hemolytic anemia. Ann Int Med 102:169-175. 6. Schumacher HR, Nand S (1995): Approach to diagnosis and treatment. In: Myelodysplastic Syndromes. Igaku-shoin, New York, pp. 11-13. 7. Hartz JW, Buss DH, White DR, Bond MG, Scharyj M (1984): Marked elliptocytosis and schistocytosis in hematopoietic dysplasia. Am J Clin Pathol 82:354-359. 8. Rummens JI, Verfaillie C, Criel A, Hidajat M, Vanhoof A, Van den Berghe H, Lonwagie A (1986): Elliptocytosis and schistocytosis in myelodisplasia. Report of two cases. Acta Haematol. 75:174-177. 9. Lecomte MC, Gautero H, Garbrz M, Boivin P, Ghermy D (1990): Abnormal tryptic peptide from the spectrin c~-chain resulting from c~- or B-chain mutations: Two genetically distinct forms of the Spo~T M variant. Br J Haematol 76:406-413. 10. Fairbanks G, Steck TL, Wallach DFH (1971): Electrophoretic analysis of the major polypeptides of the human erythrocyte membrane. Biochemistry 10:2606-2617. 11. Laemmli UK (1970): Cleavage of structural proteins during the assembly of the head of the bacteriophage T4. Nature 74:680-685. 12. Maucini M, Cedrone M, Nanni M, Rondinelli MB, Petti MC, De Cuia MR, Alimena G (1992): Trisomy 14 in hematologic diseases. Cancer Genetic Cytogenet 66:39-42. 13. Sol~ F, Caballfn MR, Coil MD, Woessner S, Besses C, Palou L, Egozcue J (1991): Isochromosome 14q in myeloid dysplastic disorder. Cancer Genet Cytogenet 54:133-134. 14. Pinkerton PH, London B, Dub6 ID, Senn JS (1990): Trisomy 14q in myelodysplastic syndromes. Cancer Genetic Cytogenet 49:113-116. 15. Labal de Vinuesa M, Slavutsky I, Larripa I (1987): Presence of isochromosomes in hematologic diseases. Cancer Genetic Cytogenet 25:47-54.