Cytogenetic and molecular analysis of a ring (21) in a patient with partial trisomy 21 and megakaryocytic leukemia

We describe a patient with an asymmetric double ring 21 in mosaic form, 45,XX, -21/46, XX, -21, +r(21), who has limited manifestations of Down syndrome and who developed acute myelofibrosis and megakaryocytic leukemia (AMKL), FAB M7, a hematologic disorder particularly common in Down syndrome patients. In situ hybridization studies, gene dosage, and DNA polymorphism analysis showed that the ring chromosome carries a duplicated region which extends from D21S406 on the centromeric side and includes marker D21S3 on the telomeric side. FISH studies indicate two sizes of ring 21 in the patient. The origin of the supernumerary chromosome 21 in the proband was paternal; furthermore, the r(21) probably was formed postzygotically. Included in the duplicated segment are the candidate genes for leukemia AML-1, ETS, and ERG. The potential significance of disomic homozygosity of loci on 21q in M7 megakaryocytic leukemia is discussed.