GATA1 Mutation and Transient Myeloproliferative Disorder in Association With Down Syndrome: A Case Report and Review of the Literature

Abstract

The present study is a rare case of Down syndrome-related in-utero death associated with transient myeloproliferative disorder (TMD) and a GATA1 mutation diagnosed during fetal autopsy examination. The study attempts to evaluate factors associated with progression of the TMD to leukemia along with assessing leukemia as a cause of death in fetuses with Down syndrome. The implication for appropriate genetic counseling and treatment of mothers carrying fetuses with the aforementioned abnormality is stressed. A 43-year-old woman experienced intrauterine fetal demise. The male fetus was a product of a 31-week, 3-day gestation by ultrasound. Fetal autopsy was performed that revealed high weight for gestational age, short neck, large protruding tongue, extra folds of skin on the ear lobes, fused eyelids, protuberant abdomen, and a single palmar crease on the right palm. Internal examination revealed enlarged liver, spleen, pancreas, brain, and thymus. The placenta was large for gestational age with adequate villous histology. The distended fetal blood vessels in the placenta and fetal organs revealed a large population of immature myeloid cells, which stained positively for CD56 immunostain. Cytogenetic analysis of fetal tissues revealed a male karyotype and trisomy of chromosome 21, 47XY+21. Down syndrome is a common chromosomal disorder, with an occurrence of 1 in every 700 births. Children with Down syndrome have a 10- to 20- fold increased risk of developing leukemia, including acute lymphoid leukemia (ALL) and acute myeloid leukemia (AML). In 5% to 10% of patients with Down syndrome, a preleukemic condition known as TMD is present. Of fetuses with Down syndrome, 15% to 20% Down syndrome are stillborn, and the incidence of TMD and AML in them is unknown. In 20% to 30% of newborns with Down syndrome and transient abnormal myelopoiesis, myeloid leukemia develops before the age of 4 years. Of TMD cases, 25% are asymptomatic and a diagnosis is suspected from laboratory tests ordered for other reasons. GATA1 mutation analysis by the WAVE technique was performed at the Weatherall Institute of Molecular Medicine. The technique is a DNA fragment analysis system determined by WAVEMAKER software. GATA1 mutation analysis revealed a deletion of 87 base paairs of the transcript sequence, consistent with transient abnormal myeloproliferative disorder. GATA1 is a transcription factor that is crucial for the development of erythroid and megakaryocytic cells. Its reduced expression leads to deficient maturation and increased proliferation of megakaryocytic cells and subsequent development of a TMD. The altered expression is also observed in neonatal and congenital leukemia in Down syndrome. The development of this mutation and its downstream genotypic and phenotypic manifestations may serve as a model to elucidate the pathogenesis of leukemia. TMD and leukemia are underrecognised causes of fetal death in Down syndrome because of infrequent and inadequate histologic examination of the fetus and placenta. Fetopsies and placentas from Down syndrome stillbirths must be scrupulously examined for evidence of infiltrates of immature myeloid cells.