Recurrent Fatal Hydrops Fetalis Associated with a Nucleotide Substitution in the Erythrocyte , 8 - Spectrin Gene

We studied a kindred in which four third-trimester fetal losses occurred, associated with severe Coombs-negative hemolytic anemia and hydrops fetalis. Postmortem examination of two infants revealed extensive extramedullary erythropoiesis. Studies of erythrocytes and erythrocyte membranes from the parents revealed abnormal erythrocyte membrane mechanical stability as well as structural and functional abnormalities in spectrin, the principal structural protein of the erythrocyte membrane. Genetic studies identified a point mutation of the p-spectrin gene, S2019P, in a region of ,B spectrin that is critical for normal spectrin function. Both parents and two living children were heterozygous for this mutation; three infants dying of hydrops fetalis were homozygous for this mutation. In an in vitro assay using recombinant peptides, the mutant 8-spectrin peptide demonstrated a significant abnormality in its ability to interact with a spectrin. This is the first description of a molecular defect of the erythrocyte membrane associated with hydrops fetalis. (J. Clin. Invest. 1995. 95:1174-1182.)