Myelodisplastic Syndrome with Trysomy 21 IN A Patient with Constitutional Submicroscopic 21Q22 Deletion.
Authors: Caliendo Irene , Di Concilio Rosanna , Danise Paolo , Guerriero Anna , Aurino Anna Maria , Amendolara Maria , d'Urzo Giovanna , Luciano Luigia , Ingenito Marcello , Amendola Giovanni 
Published: October 2019

Abstract
Abstract 4831

Introduction
Previous studies showed that chromosomal and genomic aberrations leading to activation of oncogenes or haploisufficiency of tumor suppressor genes are well-known pathogenic mechanisms in cancer. Additional copies of chromosme 21 are frequently found in Myelodisplastic Syndrome (MDS) and in Acute Myeloid Leukemia (AML); the presence of these chromosomal abnormalities and the high incidence of acute leukemias in subjects with constitutional trisomy 21, suggest that genes on chromosome 21, including RUNX1/AML1, play a particular role in leukemogenesis and hematopoiesis. We describe a patient with syndromic trombocytopenia ( average platelet count= 70000/mm3), psychomothor delay, microcephaly and low stature, that developed a progressive anemia and became transfusion-dependent at seventeen years of age.

Materials and methods
Cytogenetic analysis was performed on bone marrow cells and on peripheral blood lymphocytes, with standard techniques and evaluated with Giemsa-trypsin-Giemsa banding according to International System for Human Cytogenetic Nomenclature (ISCN 2005). Fluorescent In Situ Hybridization (FISH) experiments was performed on bone marrow samples with LSI AML1/ETO Dual Color, Dual Fusion Translocation and, at the same time, the High-resolution oligo array-CGH (Agilent Human Genome CGH Microarray 44B) was performed on the DNA of the patient.

Results
The bone marrow cells showed marked dysplastic morphology and the following abnormal karyotype: 46,XX[14]/47,XX,+21[6]; the peripheral blood karyotype was normal. The High-resolution oligo array-CGH demonstrated a constitutional de novo microdeletion of one chromosome 21. The interstitial deletion was found to be approximately 4,4Mb (Megabases), extending from 32,29 Mb to 36,51 Mb on band 21q22.11-12, involving MRAP, IFNAR2, IFNGRR2, KCNE2, KCNE1 and RUNX1 genes. The FISH performed on bone marrow cells, revealed two orange signals representing normal copies of ETO and one green signal for AML1 in 60% interphase cells and two orange signals and two green signals in the remaining 40% cells. The first pattern of signals, for AML1, is related to cells with karyotype 46,XX, while the second pattern of signals is related to cells with karyotype 47,XX,+21. These results indicate that in the myelodisplastic clone the third chromosome 21 are not deleted on band 21q22.

Conclusion
Three cases were recently published of syndromic thrombocytopenia with 21q22 constitutional deletion, including RUNX1, and variable degree of dysmorphic features and mental delay. One of the three patients developed LMA at the age of six years. Our results further support the fundamental role, in the pathogenetic mechanism of syndromic trombocytopenia and MDS/AML, of the numerical abnormalities of chromosome 21 associated with submicroscopic rearrangement of RUNX1 and other dosage-sensitive unknown genes on chromosome 21.

Disclosures
No relevant conflicts of interest to declare.