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Transient myeloproliferative disorder (TMD) is a leukemia found in approximately 10% of newborns with trisomy 21 (Down syndrome). Although this disorder normally resolves spontaneously within the first few months of life, patients are at increased risk of developing acute myeloid leukemia later in life. Studies have shown that mutations in GATA1 lead to a proliferation of multiple cell types that are responsible for this syndrome. Documented cases of TMD reflect this proliferation with a predominance of blasts in the peripheral blood.
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Transient Myeloproliferative Disorder: What’s Eosinophilia Got to Do With It?
Transient myeloproliferative disorder (TMD) is a leukemia found in approximately 10% of newborns with trisomy 21 (Down syndrome). Although this disorder normally resolves spontaneously within the first few months of life, patients are at increased risk of developing acute myeloid leukemia later in life. Studies have shown that mutations in GATA1 lead to a proliferation of multiple cell types that are responsible for this syndrome. Documented cases of TMD reflect this proliferation with a predominance of blasts in the peripheral blood.
Transient myeloproliferative disorder (TMD) is a leukemia found in approximately 10% of newborns with trisomy 21 (Down syndrome). Although this disorder normally resolves spontaneously within the first few months of life, patients are at increased risk of developing acute myeloid leukemia later in life. Studies have shown that mutations in GATA1 lead to a proliferation of multiple cell types that are responsible for this syndrome. Documented cases of TMD reflect this proliferation with a predominance of blasts in the peripheral blood.
Transient Myeloproliferative Disorder: Whats Eosinophilia Got to Do With It?
Wade L. Schulz, PhD
1 , Malini B. DeSilva, MD 2 and R. Scott Velders, MD 3
University of Minnesota 1 Medical Scientist Training Program and 2 Departments of Internal Medicine and Pediatrics; 3 Hennepin County Medical Center Pediatrics
References 1. Gamis, A. S., & Smith, F. O. (2012). Transient myeloproliferative disorder in children with Down syndrome: clarity to this enigmatic disorder. British journal of haematology, 159(3), 27787. 2. Ishigaki, H., Miyauchi, J., Yokoe, A., Nakayama, M., et al. (2011). Expression of megakaryocytic and myeloid markers in blasts of transient abnormal myelopoiesis in a stillbirth with Down syndrome: report of histopathological findings of an autopsy case. Human pathology, 42(1), 1415. 3. Kawase, K., Azuma, E., Ohshita, H., Tanaka, T.,et al. (2012). Risk factors for early death in transient myeloproliferative disorder without phenotypic features of Down syndrome: a case report and literature review. Journal of pediatric hematology/oncology, 34(6), 4759. 4. Moiz, B., & Shafiq, M. (2012). Transient myeloproliferative disorder. Blood, 120(24), 46724672. 5. Seewald, L., Taub, J. W., Maloney, K. W., & McCabe, E. R. B. (2012). Acute leukemias in children with Down syndrome. Molecular genetics and metabolism, 107(1-2), 2530. 6. Shimizu, R., & Yamamoto, M. (2012). Contribution of GATA1 dysfunction to multi-step leukemogenesis. Cancer science, 103(12), 203944. 7. Suda, J., Eguchi, M., Akiyama, Y., Iwama, Y., et al. (1987). Differentiation of blast cells from a Downs syndrome patient with transient myeloproliferative disorder. Blood, 69(2), 50812. 8. Webb, D., Roberts, I., & Vyas, P. (2007). Haematology of Down syndrome. Archives of disease in childhood. Fetal and neonatal edition, 92(6), F5037. 9. Zon, L. I., Yamaguchi, Y., Yee, K., Albee, E. a, Kimura, a, Bennett, J. C., Orkin, S. H., et al. (1993). Expression of mRNA for the GATA-binding proteins in human eosinophils and basophils: potential role in gene transcription. Blood, 81(12), 323441.
Transient Myeloproliferative Disorder Occurs in 10% of newborns with Down syndrome Often asymptomatic and found incidentally In severe cases, TMD can cause respiratory distress, cardiovascular compromise, and liver failure Peripheral blood characterized by circulating blasts Case reports have also described basophilia Typical peripheral blood smear in a patient with transient myeloproliferative disorder. Note the predominance of blasts with a deeply basophilic cytoplasm. Genetics and Differentiation Proliferation due to mutation in GATA-1 that accompanies trisomy 21 No documented cases of eosinophilia Monocytes, eosinophils, and megakaryocytes derived from common myeloid progenitor Recent studies have shown GATA-1 also regulates eosinophil differentiation
Case Follow Up and Discussion Patient remained asymptomatic over hospital course Patients white cell count continued to decrease spontaneously Discharged on 6 th day of life with close follow-up by PCP at outside facility Documented cases of TMD have shown circulating blasts or basophils in the peripheral blood; however, this case had an unusual presentation. Recent evidence has shown that the GATA-1 gene product implicated in the development of TMD also controls eosinophil differentiation. In patients with suspected TMD, the presence of eosinophilia is likely consistent and may not require additional workup for an infectious cause. While initially concerning to providers and parents, TMD is normally asymptomatic and spontaneously resolves, but demands close follow-up due to the increased risk of leukemia. Initial Presentation Full-term female infant born to mother of advanced maternal age by C-section Physical characteristics of Down syndrome, karyotype revealed 47,XX,+21 By 30 hours of life, patient developed hyperbilirubinemia and hepatosplenomegaly which prompted the need for phototherapy and further evaluation CBC revealed WBC count of 35.2x10 9 cells/L with 44% eosinophils Management and Treatment Majority of cases resolve spontaneously within weeks Treatment with cytarabine (Ara-C) used for symptomatic cases Long-term follow-up with CBC every 3-6 months for the first few years of life due to increased risk of AML (30% of cases by 3 years of age) American Academy of Pediatrics recommends counseling parents on signs of leukemia, including easy bruising, petechiae, increased lethargy, and changes in feeding
Learning Objectives Understand the presentation of transient myeloproliferative disorder (TMD) Demonstrate variations in the presentation of TMD Understand the genetic basis of TMD and cell differentiation Recognize findings of TMD that require treatment and potential long-term effects of TMD Peripheral Morphology Anisopoikilocytosis with evidence of increased red cell regeneration Moderate absolute eosinophilia with a subset of immature neutrophils Immature subset lacked nuclear segmentation Characterized by basophilic and eosinophilic granules Platelet count normal with rare circulating megakaryocyte nuclei Hospital Course Infant was afebrile, but due to a failed hearing screen she was evaluated for infectious causes of eosinophilia; CMV and toxoplasma found to be negative WBC count declined to 22.5x10 9 cells/L and eosinophilia resolved by day five of life Hyperbilirubinemia resolved, thought to be physiologic jaundice of the newborn Final pathology diagnosis of transient myeloproliferative disorder (TMD)