502 TRANSIENT MYELOPROLIFERATIVE DISORDER IN A NON-DOWN SYNDROME INFANT WITH BLAST CELL MOSAICISM FOR TRISOMY 21: WHAT IS THE RISK FOR LEUKEMIA AND PATHOGENESIS?

Transient myeloproliferative disorder (“TMD”) with or without progression to acute megakaryocytic leukemia (“AMKL”) has been reported in association with Down syndrome (“DS”) for the past 40 years. To date, 29 cases of TMD have been reported to occur in phenotypically normal children with mosaicism for trisomy 21. Fourteen percent of them developed AMKL. Therefore, both non-DS and DS patients with TMD have a high predicted predisposition to develop leukemia. We report a new non-DS infant with TMD and blast cell mosaicism for trisomy 21 to raise awareness of the risk for leukemia and discuss a hypothetical role of GATA1 mutations in the pathogenesis of trisomy 21-associated TMD and AMKL. The patient is now a 12 month-old male who, at 2 days of age, presented with a white blood cell count of 54,000 cells per microliter with 34% blasts. TMD was confirmed and a peripheral blood karyotype showed 47, XY, +21[10]/46, XY [10] mosaic trisomy 21. Dysmorphologic exams at 5 weeks and 6 months of age showed no signs of DS. TMD resolved and blood karyotype was normal at 6 months. At 12 months, karyotype of fibroblasts cultured from a duplicate thumb was normal. The cytomorphological and karyotypic findings are consistent with a diagnosis of resolved TMD in a child with blast clone mosaicism for trisomy 21, without constitutional trisomy 21. The pathogenesis of TMD/AMKL in infants with full or mosaic trisomy 21 is not understood; however, it has recently been shown that virtually all DS infants with TMD/AMKL have in utero acquired GATA1 mutations, which disappear with resolution of the blasts. GATA1 is a key regulator of megakaryocyte and other hematopoietic cell differentiation. It has been hypothesized that GATA1 mutations block megakaryocytic differentiation in hematopoietic cells having trisomy 21-associated survival advantages, ultimately leading to the development of TMD/AMKL (Ahmed, 2004). As a candidate for further study, RUNX-1 is located on chromosome 21 and is often dysregulated in leukemogenesis. To date, GATA1 has not been studied in non-DS children with TMD, such as our patient, and mutation analysis is being pursued using archival slides