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LETTER TO EDITOR
Year : 2012 | Volume : 55 | Issue : 3 | Page : 426-427

Transient myeloproliferative disorder in Down's syndrome

Vinayak Y Kshirsagar1, Minhajuddin Ahmed1, Sylvia M Colaco1, Manal Ahmed2

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

Kshirsagar VY
Ahmed M
Colaco SM
Ahmed M

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Date of Web Publication

29-Sep-2012
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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

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Kshirsagar VY, Ahmed M, Colaco SM, Ahmed M. Transient myeloproliferative disorder in Down's syndrome. Indian J
Pathol Microbiol [serial online] 2012 [cited 2015 Jul 29];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]

This pag

Down 'S Syndrome

What Causes Leukemia
Symptoms of Liver Cancer

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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Transient myeloproliferative disorder in Down's syndrome Kshirsagar VY,... Page 2 of 3

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On flow cytometry of the peripheral blood the findings were as follows: CD45-98%, CD7- 64%, CD33- 80%, CD11798%,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

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

References
1.
2.
3.
4.

5.

6.

Schunk GJ, Lehman WL. Mongolism and congenital leukemia. JAMA 1954;155:250-1.
[PUBMED]
Isaacs H Jr. Fetal and neonatal leukemia. J Pediatr Hematol Oncol 2003;25:348-61.
[PUBMED]
Choi JK. Hematopoietic disorders in down syndrome. Int J Clin Exp Pathol 2008;1:387-95.
[PUBMED]
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.
[PUBMED]
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.
[PUBMED]
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.
[PUBMED]

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Transient myeloproliferative disorder in Down's syndrome Kshirsagar VY,... Page 3 of 3

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

DOI: 10.4103/0377-4929.101773

Figures
[Figure 1], [Figure 2]

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