RECURRENT FATAL HYDROPS-FETALIS ASSOCIATED WITH A NUCLEOTIDE SUBSTITUTION IN THE ERYTHROCYTE BETA-SPECTRIN GENE

We studied a kindred in which four third-trimester fetal losses occurr ed, associated with severe Coombs-negative hemolytic anemia and hydrop s fetalis. Postmortem examination of two infants revealed extensive ex tramedullary erythropoiesis. Studies of erythrocytes and erythrocyte m embranes from the parents revealed abnormal erythrocyte membrane mecha nical 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 beta-spectrin gen e, S2019P, in a region of beta spectrin that is critical for normal sp ectrin function. Both parents and two living children were heterozygou s for this mutation; three infants dying of hydrops fetalis were homoz ygous for this mutation. In an in vitro assay using recombinant peptid es, the mutant beta-spectrin peptide demonstrated a significant abnorm ality in its ability to interact with alpha spectrin. This is the firs t description of a molecular defect of the erythrocyte membrane associ ated with hydrops fetalis.