Severe Fetal and Neonatal Anemia Due to Heterozygosity for a 198 Kb Deletion Removing the Entire β-Globin Gene Cluster

Abstract 5171

Infants who are heterozygous for a number of (γδβ)⁰-thalassemia deletions are known to present with neonatal hemolytic anemia (Koenig et al, Am J Hematol 84:603, 2009). The breakpoints for most of these large deletions have not been identified. Molecular diagnoses of these deletions therefore can be challenging. We now report an infant girl of Irish/Scottish descent with self-limited fetal and neonatal hemolytic anemia, in whom we have defined the extent of the large deletion removing the entire β-globin gene cluster. At 32-week of gestation, fetal tachycardia prompted percutaneous umbilical cord blood sampling, which revealed a hematocrit of 14%. Umbilical cord transfusion was undertaken followed by Caesarean section delivery. Brisk hemolysis continued in the first few days of life (reticulocyte count of 22 – 24%), with no other causes of hemolysis identified. In the following weeks, the infant was transfused on three occasions. After 2-month of age, she became transfusion-independent with a stable microcytic anemia. The infant's mother also had a history of hemolytic anemia requiring transfusion in the neonatal period, and subsequently became transfusion independent with a microcytic anemia. The mother and several of her family members were extensively investigated, and shown to have a novel (γδβ)⁰-thalassemia deletion of over 100 kb (Pirastu et al, J Clin Invest 72:602, 1983). Multiplex ligation-dependent probe amplification (MLPA) was carried out in the genomic DNA from the present neonate. The infant was heterozygous for a large deletion spanning at least from 5′ to the HS 5 of the LCR to 3′ of the β-globin gene. Sequential gap-PCR reactions and nucleotide sequencing were done. The deletion was characterized with its 5` breakpoint at nt 5,376,341 and 3` breakpoint at nt 5,178,572 (GenBank NT_009237). The deletion measures 197,770 bp, removing the β-globin LCR, all of the β-like globin genes, and several olfactory receptor genes. A diagnostic gap-PCR test was established for detection of this deletion. This case illustrates the syndrome of neonatal hemolytic anemia caused by large deletions removing the entire β-globin gene cluster. MLPA is a useful tool to screen for these deletions. The pathophysiology of these self-limited and sometimes severe fetal and neonatal hemolytic anemias is presently not understood. We speculate that expression of α-hemoglobin stabilizing protein (AHSP) and/or the proteolytic capacity to degrade excess α-globin chains within erythroid cells might be diminished during fetal and neonatal development, accounting for increased red cell membrane damage and hemolysis in affected fetuses and neonates.