Prenatal Origin of Monosomy 7 in Very Young Children.

Abstract

Abstract 2557Monosomy 7 is a common chromosomal abnormality in adults with myelodysplasia (MDS) and AML, seen most frequently in older persons. It is believed to be one of a series of stochastically acquired genetic anomalies that accumulate over many years to complete the process of leukemogenesis. MDS in general and monosomy 7 in particular are rarely seen in children, although cases in very young children are reported. Monosomy 7 arising in very young children likely has a different etiology and may contribute differently to leukemogenesis, as the young age of the children does not allow sufficient time for stochastic acquisition of mutation in the same way as in elderly persons.A proportion of young children with monosomy 7 have an associated DNA instability disorder such as Fanconi anemia (FA) or Dyskeratosis Congenita, and this genetic background likely plays a key role in the evolution of malignancy. In a few reported cases, the occurrence of monosomy 7 is familial, and in a smaller number of cases yet, the clone may resolve spontaneously or wax and wane, as the associated pancytopenia waxes and wanes.We report 5 young children with monosomy 7 in whom we have explored the origins of monosomy 7. In case 1, who presented with MDS and monosomy 7 at 2 years of age, a stored cord blood was available for analysis. The sample was flow sorted and FISH for monosomy 7 was performed on different populations. The monosomy 7 clone was present in approximately 10% of the cord blood cells overall, and the same clone was found in the most primitive population, i.e. CD34+CD38- cells, suggesting in utero origin of this abnormal clone in a very early precursor or stem cell population (Table 1). Similar analyses done on BM or PB samples of 4 additional young patients with monosomy 7, with age range of 4 months to 42 months (3 ½ years)(median 22.5 months), also showed the abnormal clone to be present in CD34+ cells, supporting our hypothesis that monosomy 7 arises in early precursors or stem cells (Table 2, below). In fact, we were able to confirm the presence of monosomy 7 in the CD34+CD38- population in one of these additional cases for which sufficient material was available. Interestingly, in one patient (#4) where we had sequential samplings nine months apart, total BM showed a decrease in the percentage of cells with monosomy 7, from 2.6% to 1.1%. However, in sorted CD34+ cells, we detected a nearly 10 fold increase in cells with monosomy 7 (Table 2). Clinical significance of this finding remains to be determinedIn summary, our preliminary studies provide proof of concept that in children, the abnormal monosomy 7 clone is present in the hematopoietic stem cell compartment, and can arise in utero in the absence of any known genetic susceptibility syndrome.Table 1Patient 1 (UCB)FACS Analysis: % of Cord Blood Cells% Monosomy 7 by FISHCD3 (T cells)23.1%6/66 (9.1%)CD 19 (B cells)9.1%1/44 (0.02%)CD 14 (monocytes)4%1/8 (12.5%)CD 16 (granulocytes)21.5%0/20 (0%)CD341%70%CD34+CD38- (primitive progenitor)NA124/136 (91.2%)CD34+38+19-7- (myeloid progenitor)NA8/13 (61.5%)Table 2Patient # (BM or PB)% of total sample% Monosomy 7 by FISH% of total sample% Monosomy 7 by FISH% of total sample% Monosomy 7 by FISH% of total sample% Monosomy 7 by FISH% of total sample% Monosomy 7 by FISH% of total sample% Monosomy 7 by FISHCD3 (T cells)CD 19 (B cells)CD 14 (monocytes)CD 16 (granulocytes)CD34+38+ or CD34+ ( progenitor)CD34+CD38- (primitive progenitor)2 BM27.00.41.910.95.946.411.316.91.277 (34+)NANA3 BM40.32.56.61.72.49415.992.40.2478.3 (34+).01NA4-1 BM37.4013.303.75.915.03.83.91.31.72.84-2 BM13.029.540.4035.60.40.212.2 (34+)NANA5 PB21.81.53.4NA22.41009.1100NANANANA Disclosures:No relevant conflicts of interest to declare.