Fetal origin of the GATA1 mutation in identical twins with transient myeloproliferative disorder and acute megakaryoblastic leukemia accompanying Down syndrome

GATA1 mutations have been found in almost all cases of transient myeloproliferative disorder (TMD) and acute megakaryoblastic leukemia (AMKL) accompanying Down syndrome (DS).^1-6  The mutations of the GATA1 gene, which is located on chromosome X, may occur prenatally or perinatally in individuals with TMD. Recently, Rainis et al⁴  reported that the same GATA1 mutation was found in identical twins with AMKL and acquired trisomy 21. This suggested that the mutation occurred in one of the twins in utero, that this twin did not have DS, and that preleukemic cells migrated to the other twin through embryonic blood connections.^4,7  However, no unambiguous evidence has yet been presented for the prenatal timing of the GATA1 mutation in the patient with TMD and DS. We recently encountered identical twin females who had TMD with DS.

The 34-year-old mother was admitted to our hospital because of threatened premature delivery at 29 weeks of gestation. Because ultrasonography revealed hydrops fetalis in one of the twins, they were delivered by cesarean section at 32 weeks of gestation. Both of the twins showed leukocytosis from birth and were diagnosed as TMD. We analyzed the GATA1 mutation in peripheral blood samples from both patients. Written informed consent was obtained from their parents. Genomic DNA was extracted and cDNA was constructed, and then polymerase chain reaction (PCR) was performed and the products were sequenced directly, as described previously.⁶  Both patients had an identical mutation in the GATA1 gene. An insertion of 20 nucleotides corresponding to a sequence in exon 2 of the GATA1 gene was detected, resulting in the introduction of a premature stop codon in the gene sequence encoding the N-terminal activation domain (Figure 1). Both cases evolved to myelodysplastic syndrome after spontaneous resolution 13 months later, and the older twin sister died of pulmonary bleeding because of uncontrolled pulmonary hypertension. The other twin's disease evolved to AMKL at the age of 15 months. The identical mutation was also found in her AMKL blast cells. This unique GATA1 mutation found in identical twin females provides unequivocal evidence that cases of TMD in identical twins have a common clonal origin. The only plausible explanation is as follows: following initiation of TMD in one twin fetus, clonal progeny spread to the cotwin via vascular anastomoses within a single, monochorionic placenta, like those found in cases of leukemia in infantile identical twins.^8,9  Our results provide definitive evidence that GATA1 mutations occur in utero in cases of AMKL with DS.