Prenatal diagnosis of transient abnormal myelopoiesis in three fetuses with Down syndrome: heterogeneous ultrasonographic findings and outcomes

Transient abnormal myelopoiesis (TAM) is diagnosed in approximately 10% of neonates with Down syndrome (DS) and progresses to life-threatening illness in 20% of cases. We describe here three cases of TAM which showed heterogeneous ultrasonographic findings and outcomes. The first case was of a 27-year-old woman at 32 + 5 weeks' gestation with severe fetal hepatosplenomegaly (liver longitudinal diameter 78 mm and spleen longitudinal diameter 60 mm (> 2 SDs above reference values1, 2)) (Figure 1). At 34 weeks' gestation, signs of fetal heart failure and increased middle cerebral artery velocity (> 1.5 SDs3) were noted. In addition, liver and spleen dimensions increased to 85 mm and 65 mm, respectively. Given these findings, we opted to administer corticosteroids and deliver by Cesarean section. The neonate weighed 2110 g, fetal hemoglobin was 9.7 g/dL and the karyotype was 46XX,+21. Blood tests showed severe leukocytosis, with white blood cell (WBC) count 118.100/μL with 56% myeloblasts, anemia and coagulopathy. Treatment with cytarabine (1 mg/kg for 3 days) was started. After a brief period of clinical stabilization, the neonate died on the 11th day postpartum. Placental histology revealed placentomegaly and extravasated fetal myeloblasts in the perivillous space, representing involvement of the maternal compartment of the placenta (Figure 2). Maternal flow cytometry performed the day before delivery showed fetal cells in the maternal blood. The second case was of a 24-year-old woman with a fetus with cytogenetically confirmed trisomy 21 presenting at 33 weeks' gestation with severe isolated hepatosplenomegaly (hepatic diameter 72 mm and spleen diameter 53 mm (> 2 SDs1, 2)). Spleen and liver dimensions remained stable for the whole pregnancy. At 35 weeks' gestation, due to a fetal Doppler indicating worsening condition, labor was induced and a male neonate weighing 2850 g was delivered. Placental histology did not reveal any noteworthy findings. Maternal flow cytometry performed before and after delivery was negative. The neonatal period was uneventful. The third case was of a 47-year-old woman with a fetus with cytogenetically confirmed trisomy 21 and an uncomplicated pregnancy with no fetal abnormalities noted on the monthly scans. A male neonate weighing 2925 g was delivered at 39 weeks' gestation. During the first days postpartum, the WBC count increased to 97.03/μL and neonatal ultrasound showed mild hepatosplenomegaly. Treatment with cytarabine (1 mg/kg for 3 days) was started. At 2 months postpartum, the neonate was stable and WBC count was 10.32/μL. Placental histology revealed presence of myelodysplastic congenital disorder on the fetal side of the placenta only. All newborns carried the mutation of the GATA-1 gene. As stated in the literature and encountered in our first case, poor prognostic factors in fetal TAM are hepatosplenomegaly, hypoechoic hepatomegaly and non-immune fetal hydrops4. In addition, the presence of fetal abnormal myeloblasts in the maternal space of the placenta in the first case may also represent a poor prognostic factor for the neonate5. This finding is likely to reflect the higher burden of circulating immature cells, as confirmed by maternal flow cytometry, and therefore a more aggressive fetal disease.