Hereditary Nonspherocytic Hemolytic Disease: A Study of a Singular Familial Hemolytic Syndrome

Abstract

Abstract Extensive studies were performed on four cases from three unrelated kindreds with a familial hemolytic syndrome not associated with any significant red cell anomaly (hereditary nonspherocytic hemolytic disease). These cases were compared with similar ones already reported in the literature. 1. Hereditary nonspherocytic hemolytic disease appears to be transmitted as a Mendelian dominant. Frequently the gene responsible for the condition seems to have low expressivity. In some cases, the hereditary mechanism may be due to inheritance of a recessive gene from each parent. The basic erythrocytic defect responsible for the condition is unknown. In view of various clinical and hematologic findings, it is likely that hereditary nonspherocytic hemolytic disease may be a group of diseases involving more than one mechanism. 2. All criteria of hemolytic anemia (erythroid hyperplasia of the bone marrow, reticulocytosis, hyperbilirubinemia, increased fecal urobilinogen, rapid turnover of tracer iron in the plasma) were satisfied. 3. Red cell survival time studies revealed an intraerythrocytic defect with a mean life span of twelve to seventeen days. Normal red cells transfused into the patients under study survived normally. Anemia was normochromic and normocytic or macrocytic; it varied from mild to severe. 4. Osmotic and mechanical fragility of the red cells was normal. Osmotic and mechanical fragility tests after incubation at 37 C. for 24 hours in some showed a mild increase compared with normal controls. Autohemolysis of incubated oxalated blood was not marked and varied from case to case. 5. The electrophoretic mobility of hemoglobin from the patients was that of normal adult hemoglobin. Small increases of fetal hemoglobin were seen in several cases. 6. In contrast to the histologic findings in hereditary spherocytosis the splenic pulp was not congested, but hemosiderin deposits were heavy. Liver biopsy specimens showed deposits of hemosiderin in parenchymal and Kupffer cells. 7. Splenectomy did not arrest the hemolytic process. Mild improvement was seen in one case. In most cases the operation is of no value. 8. Diagnostic difficulties may be encountered with mild cases of hereditary spherocytosis. Examination of rouleaux in fresh blood and an osmotic fragility test in 0.65 per cent sodium chloride after incubation usually establishes the differential diagnosis. The condition may present clinically as hemolytic disease of the newborn and must be differentiated from erythroblastosis due to Rh or other blood group incompatibilities. Other hereditary hemolytic diseases such as sickle cell anemia, Cooley’s anemia, hereditary spherocytosis, and hereditary hemolytic elliptocytosis are easily ruled out by their typical clinical and hematologic manifestations. When a family study is negative or cannot be done, a red cell survival time determination may be necessary to rule out acquired hemolytic anemia with a negative Coombs test. Some cases that have been diagnosed as constitutional hyperbilirubinemia (familial nonhemolytic jaundice) may actually represent mild hereditary nonspherocytic hemolytic disease.