Distinct GATA1 Point Mutations in Identical Twin Boys with Down Syndrome and Transient Abnormal Myelopoiesis from a Triplet Pregnancy
Liqun Yin, Mark A Lovell, Michael L Wilson, Qi Wei, Xiayuan Liang. University of Colorado School of Medicine, Aurora, CO; Denver Health Medical Center, Denver, CO; Children's Hospital Colorado, Aurora, CO
Background: Transient abnormal myelopoiesis (TAM) is a unique clonal hematologic abnormality manifested by a proliferation of myeloid blasts in peripheral blood (PB) and bone marrow (BM) in newborns with Down syndrome (DS), which is indistinguishable from acute megakaryoblastic leukemia. The hematopoietic cells in TAM are characterized by mutations in the key megakaryocyte-erythroid transcription factor, GATA1. The identification and characterization of DS newborns with TAM from a multiple pregnancy has not been previously described. We evaluated the clinical and pathological features of 34-week gestational age identical twin boys with DS and TAM from a triplet pregnancy.
Design: PB smears, BM aspirate smears (Triplets A and B), and placentas were evaluated. Flow cytometric immunophenotyping of PB (Triplets A and B) and immunohistochemical (IHC) stains for all placentas were performed. Karyotype was performed on triplets A, B, and C. Molecular analysis of short tandem repeat (STR) DNA profiling and DNA sequencing of GATA1 were performed on triplets A and B.
Results: 1) Triplets A and B had a 47,XY,+21 karyotype while Triplet C had a 46,XX karyotype. 2) Triplets A and B were monozygous twins by STR DNA profiling analysis. 3) Triplet A had a 49C>T GATA1 point mutation while Triplet B had a distinct 37G>T point mutation. Both point mutations result in a premature stop codon. 4) Triplets A and B showed blasts with megakaryocytic differentiation in both the postnatal PB and placentas (Figure below) by flow and IHC staining, while Triplet C had no blasts in either the PB or placenta.
|Birth weight (g)||WBC (10^3)||PB blasts (%)||BM blasts (%)||GATA1|
|Triplet A||2100||203||45||33||c. 49C>T||p.Q17X|
|Triplet B||1860||249||95||42||c. 37G>T||p.E13X|