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LETTER TO EDITOR  
Year : 2012  |  Volume : 55  |  Issue : 3  |  Page : 426-427
Transient myeloproliferative disorder in Down's syndrome


1 Department of Pediatrics, Krishna Institute of Medical Sciences University, Karad, Maharashtra, India
2 Department of Patholgy, Apollo Hospitals, Hyderabad, Andhra Pradesh, India

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Date of Web Publication29-Sep-2012
 

How to cite this article:
Kshirsagar VY, Ahmed M, Colaco SM, Ahmed M. Transient myeloproliferative disorder in Down's syndrome. Indian J Pathol Microbiol 2012;55:426-7

How to cite this URL:
Kshirsagar VY, Ahmed M, Colaco SM, Ahmed M. Transient myeloproliferative disorder in Down's syndrome. Indian J Pathol Microbiol [serial online] 2012 [cited 2019 Jun 16];55:426-7. Available from: http://www.ijpmonline.org/text.asp?2012/55/3/426/101773


Sir,

Down's syndrome (DS) is the most common trisomy in humans, occurring in 1/600- 1/800 live births .A unique syndrome occurs only in newborn with DS or trisomy 21 mosaicism and is frequently associated with TMD, transient abnormal myelopoiesis (TAM) or transient leukaemia (TL). The first case was reported by Schunk and Lehman in 1954. [1] It is estimated that approximately 10% of DS infants will develop TMD; in which immature megakaryoblasts accumulate in liver, bone marrow and peripheral blood; this disorder undergoes spontaneous remission in most cases. Many infants may be clinically well at presentation with an incidental finding of circulating blasts in the blood. In some cases the disease is severe and potentially lethal, manifesting as hydrops fetalis, multiple effusions, and liver or multiorgan failure. [2]

A female neonate born by to an elderly primi with PIH with primary infertility and had features of DS. The hemogram on admission showed Hb-15.9 gm/dl; TC- 201,400/mm 3 ; Differential count- Atypical cells-90, Neutrophils-6, Lymphocytes-4; NRBCs 4-5/100WBC; Platelet count- 15,000/cumm; PCV-46.6% with normal blood sugar level. Peripheral smear report: RBC: Normocytic normochromic, WBC: 90% atypical cells with a high N/C ratio with moderate basophilic cytoplasm containing coarse basophilic granules and blebbing. The nucleoi were large with heterogenous chromatin and 3-5 nucleoli. Platelets: Reduced [Figure 1]. On MPO stain the blasts were negative for MPO, occasional neutrophils in the background were positive; thus the blasts were not of myeloid origin (barring M0, which morphology is against).
Figure 1: Peripheral smear showing large blast cells with abundant pale blue cytoplasm with cytoplasmic blebbing and protrusions reminiscent of cytoplasmic platelet budding of megakaryocytes and nuclues with condensed chromatin and distinct one to many nucleoli. Also seen are platelets of variable sizes. (Romanowsky, x1000)

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On flow cytometry of the peripheral blood the findings were as follows: CD45-98%, CD7- 64%, CD33- 80%, CD117-98%,CD34-88% and HLA DR-40%. CD41 and CD61 were unfortunately not done. Thus the flow cytometry report was 'AML with weak CD7 expression. Echocardiography revealed large size atrial septal defect measuring 20.7 mm with moderate size pericardial effusion, pericardiocentesis was done which revealed a TLC of 400/cumm and DC of P 75 L 25 with occasional mesothelial cell. EKG shows low voltage pattern. The FISH studies was performed to confirm DS on the nuclei using the Vysis Aneu vysion, DNA probe kit for chromosome 13,18,21,X and Y which revealed a Mosaic trisomy 21 (84%) [Figure 2]. Unfortunately before doing immune panel (CD41, CD61 and CD42a) the baby expired.
Figure 2: Cell showing two green and three orange signals for Chromosomes 13 and 21 respectively, indicating mosaic Trisomy 21 (84%). (Flourosence in situ hybridization)

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Down's syndrome is caused by an extra whole or partial copy of chromosome 21 and is the most common abnormality in the newborn. Upto 80%, 66% and 34% of DS newborns have neutrophilia, thrombocytopenia, and polycythemia, respectively. [3] These findings are usually referred collectively as hematological abnormalities in neonates with DS. [3]

Children with DS are at a higher risk of developing acute leukemias compared to the general pediatric population. [4] Neonates with DS also may develop TMD, an abnormal proliferation of myeloid blasts in the blood that resolves without therapeutic intervention. TMD and AMKL in DS show strikingly similar morphologic features. The main difference in the clinical presentation of these disorders is the age of onset, with TMD occurring during the first few days of life and spontaneously resolving by 3 months of age and AML usually manifesting after 1 year. TMD can present in the fetus [3] and can cause spontaneous fetal demise. Hence, the prevalence of TMD in DS may be even higher because most studies do not account for cases of spontaneous fetal demise secondary to TMD.

TMD blasts contain extra copies of chromosome 21 and occasionally additional karyotypic abnormalities. All TMD blasts have various somatic mutations in the X-linked gene GATA1 [5] that encodes a transcription factor critical for normal erythroid and mega-karyocytic development. Trisomy 21 and GATA1 mutations occur in TMDs that present in neonates who are mosaic for trisomy 21 and lack the clinical feature of DS. [6] Mutations in the tyrosine kinase JAK3 are present in a subset of TMD. [2] In our case only FISH for trisomy 21 was performed. Hence in the absence of karyotyping other additional mutations could not be documented. Despite the similarities between the blasts of TMD and DS-AMKL, their clinical courses differ, suggesting fundamental molecular differences. However, until these markers are validated, clinical history, cytogenetics, and mutational analysis of GATA1 remain the best studies that distinguish among the megakaryoblasts of TMD and DS-AMKL. The presence of Down syndrome/trisomy 21 and GATA1 mutations support TMD or DS-AMKL and these two diagnoses are best differentiated using the age of the patient.

In this case the morphology and age are highly suggestive of TMD as compared to AMKL, however the absence of complete immunotyping and genetic studies stops us from making a complete and final diagnosis. In retrospect this case brings to light the need for the clinician to be aware and to look for the haematological abnormalities associated with DS uncommon or clinically silent thus a simple base line blood count at birth may help.


   Acknowledgment Top


The authors are thankful to Dr Sandeep Kaulavkar for his support and Dr Kuldeep Shah for technical support.

 
   References Top

1.Schunk GJ, Lehman WL. Mongolism and congenital leukemia. JAMA 1954;155:250-1.  Back to cited text no. 1
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2.Isaacs H Jr. Fetal and neonatal leukemia. J Pediatr Hematol Oncol 2003;25:348-61.  Back to cited text no. 2
[PUBMED]    
3.Choi JK. Hematopoietic disorders in down syndrome. Int J Clin Exp Pathol 2008;1:387-95.  Back to cited text no. 3
[PUBMED]    
4.Karandikar NJ, Aquino DB, McKenna RW, Kroft SH. Transient myeloproliferative disorder and acute myeloid leukemia in Down syndrome. An immunophenotypic analysis. Am J Clin Pathol 2001;116:204-10.  Back to cited text no. 4
[PUBMED]    
5.Greene ME, Mundschau G, Wechsler J, McDevitt M, Gamis A, Karp J, et al. Mutations in GATA1 in both transient myeloproliferative disorder and acute megakaryoblastic leukemia of Down syndrome. Blood Cells Mol Dis 2003;31:351-6.  Back to cited text no. 5
[PUBMED]    
6.Cushing T, Clericuzio CL, Wilson CS, Taub JW, Ge Y, Reichard KK, et al. Risk for leukemia in infants without Down syndrome who have transient myeloproliferative disorder. J Pediatr 2006;148:687-9.  Back to cited text no. 6
[PUBMED]    

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Correspondence Address:
Vinayak Y Kshirsagar
Head of Department of Pediatrics, Krishna Institute of Medical Sciences University, Karad 415110, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0377-4929.101773

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