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Congenital Microspherocytosis
*
CONGENITAL MICROSPHEROCYTOSIS ARTHUR E. Me ELFRESH, M.D.
Congenital microspherocytosis (familial acholuric jaundice, Minkowsky-Chauffard disease) is the most common hereditary hemolytic disease of people of English or northern European descent. Since many patients are asymptomatic and since there is no simple test to determine the presence of the condition, the exact incidence of the disease is not known. Although limited primarily to Caucasians, congenital microspherocytosis does occur in Negroes; Kline and Holman l l have reviewed 42 cases among 13 Negro families reported in the literature. Congenital microspherocytosis is transmitted as a dominant characteristic; thus either parent may transmit it to children of either sex. Nevertheless cases in which there is no evidence of the disease in eitheI parent do occur. In addition, among families with the disease there is less than the expected 1: 1 ratio of affected to nonaffected persons. These discrepancies from the expected pattern of inheritance may be the result of an increased incidence of fetal or neonatal deaths of involved infants or may indicate failure to detect mildly affected persons. 15 Determination of the osmotic fragility of the red blood cells by the standard methods may give normal results in almost one quarter of affected persons; determination of the osmotic fragility of erythrocytes which have been incubated sterilely for 24 hours will detect the condition in almost all affected persons.
PATHOGENESIS
The anemia of hereditary spherocytosis results from a defect in the From St. Christopher's Hospital for Children and the Department of Pediatrics, Temple University School of Medicine, Philadelphia.
666
CONGENITAL MICROSPHEROCYTOSIS
patient's erythrocytes, which have a life span shorter than normal, as short as 15 days in some instances. A portion of the erythrocytes are spheroidal rather than biconcave; only mature erythrocytes have the spheroidal shape, which is not seen in the erythroid precursors of the bone marrow. When normal biconcave erythrocytes are exposed to increasingly dilute concentrations of saline, they behave as osmometers; i.e. they absorb greater amounts of water as the solutions become more dilute. The cells become progressively more spheroidal and finally rupture when they have swollen to approximately 175 per cent of their original volume. The erythrocytes of congenital microspherocytosis are already spheroidal and can only swell to approximately 150 per cent of their original volume before hemolysis occurS.lO The spheroidal shape and the abnormal osmotic behavior, however, are probably not the cause of the increased rate of hemolysis, but in all likelihood are merely reflections of abnormal cellular metabolism. Selwyn and Dacie17 showed that when spherocytes were incubated under sterile conditions, they were less spheroidal after 48 hours than after 24 hours of incubation, but that the rate of hemolysis was greater at 48 hours. In erythrocytes from patients with this disorder Prankerd et aI.14 found abnormalities related to incorporation of phosphorus into adenosine-triphosphate, and Allison, Kates and James 1 have suggested that there is an abnormality of lipid metabolism. These studies indicate the presence of a metabolic abnormality, the exact nature of which is still not clear. Although the abnormal erythrocytes represent the principal abnormality in congenital microspherocytosis, the spleen is the organ principally responsible for the excessive destruction of these abnormal cells. When spherocytes have been transfused into normal recipients before splenectomy performed with gastrectomy, blood from the excised spleens has been found to contain a greater percentage of spherocytes than was present in the general circulation. s The spleen thus acts to some degree solely as a filter. "Crises," during which the usually mild anemia becomes severe, occur intermittently in many patients and may be the first indication of the disease. Crises were formerly thought to result from an increase in the rate of erythrocytic destruction, but it is now apparent that the crisis is most frequently the result of a reduction in the production of erythrocytes. If the peripheral blood is examined early in the course of a crisis, one finds reticulocytopenia and frequently leukopenia and thrombocytopenia. These findings are a reflection of a hypoplastic bone marrow. Since the life span of the spherocytic erythrocyte is only 14 to 19 days, cessation of red cell production rapidly results in severe anemia. The hypoplastic period persists from 6 to 10 days, after which the reticulocytes again increase in number; there is frequently leukocytosis during the period of recovery.2, 6, 13
ARTHUR E. Me ELFRESH
667
MANIFESTATIONS
The signs and symptoms of congenital microspherocytosis are extremely variable; manifestations of the disease may begin immediately after birth, or the disease may remain entirely unsuspected through life. One may encounter many degrees of severity among the members of a family. When symptoms begin at birth, the appearance of anemia with jaundice and splenomegaly may simulate erythroblastosis; exchange transfusions may be required to reduce the concentration of bilirubin, since kernicterus has occasionally resulted from hyperbilirubinemia during the first week of life. 12 , 16, 18, 21 The appearance of symptoms in the newborn period, however, is a rare event. The degree of anemia is variable, but is rarely severe enough to cause symptoms except during crises. The hemoglobin concentration is often maintained at normal or near normal levels by an increased rate of erythropoiesis, and the patient is not aware of his disease until jaundice is noted, his spleen or liver is palpated, or a crisis occurs. Frequently the illness is completely asymptomatic and the diagnosis is made only because the condition is detected in another member of the family and family studies are carried out. Jaundice is absent in many patients. In others, icterus may appear intermittently and may suggest infectious hepatitis. In one of our patients there were only 3 periods of jaundice, each lasting 2 to 3 weeks, between the ages of 3 and 11 years. He was otherwise completely well. In many children, however, mild to moderate jaundice is present constantly and the serum bilirubin concentration is often slightly elevated even when no jaundice is apparent. Gallstones are common as a result of the increased bilirubin production. They have been seen in a child as young as three years of age and are not uncommon in adolescents; cholecystography should always be performed in older children when this disease is diagnosed. The severe anemia which occurs during a hypoplastic crisis may result in tachycardia, hyperpnea, cardiac failure or loss of consciousness. The crisis is often the first sign of the illness. I recently saw a 13-year-old boy who was admitted with a hemoglobin concentration of less than 3 Gm. per 100 m!. and a hematocrit level of 8 per cent. He had previously been entirely well and had recently completed a two-week canoe trip. It should be re-emphasized that many patients exhibit no manifestations of the disorder whatsoever; the discovery of one involved member in a family is reason to institute hematologic investigation of the entire family in order to detect asymptomatic cases. The father of the boy mentioned above was 46 years old, he had never been anemic or jaundiced and had served 4 years in the army. His only evidence of the dis-
668
CONGENITAL MICROSPHEROCYTOSIS
ease was a slight increase in his reticulocyte count and abnormal osmotic fragilities of his erythrocytes. LABORATORY STUDIES
The degree of anemia is variable; in the absence of a crisis the hemo· globin concentration is rarely less than 8 Gm. per 100 ml. and is often normal. The anemia is normochromic with a mean corpuscular volume which is often increased as a result of the spheroidal shape of the red cells. Spherocytes on a stained blood smear appear as small, densely stained cells, the most intense staining appearing in the center of the cell (the thickest portion) rather than around the periphery as in normal red cells (see Fig. 18). Spherocytes may be few in number and are
Fig. 18. Peripheral blood from a five-year-old girl with congenital microspherocytosis. The dark-staining spherocytes stand out in contrast to the more numerous normal cells.
best appreciated when a saline suspension of red cells is examined microscopically under reduced illumination; as the cells tumble about, the spherocytes are easily distinguished from normally shaped cells. The reticulocyte count is almost always elevated, but is usually not above 3 to 5 per cent. After a hypoplastic crisis, however, reticulocytes may constitute 50 per cent or more of the cells present. The determination of the osmotic fragility of erythrocytes in hypotonic saline is the one test most frequently done to detect or confirm the presence of spherocytes. Hemolysis of spherocytes usually begins at concentrations above 0.48 per cent saline, the concentration below which normal cells begin to hemolyze. But in 10 to 20 per cent of patients with congenital microspherocytosis no increase in susceptibility to hypotonic saline is seen with the conventional test; the osmotic fra-
r ARTHUR E. Me ELFRESH
66<)
gility must always be determined with erythrocytes which have been incubated sterilely for 24 hours before one can be sure that the osmotic fragility test is truly normaJ.17,24 Although incubation in this fashion will increase the osmotic fragility of normal red cells slightly, the increase with cells from persons with congenital microspherocytosis is much greater than with cells from normal persons. Normal cells after incubation have initial hemolysis below 0.60 per cent saline, but spherocytes after incubation hemolyze at concentrations well above this. The mechanical fragility of the erythrocytes is also increased, but facilities for this test are not usually available. 19 Patients with acquired hemolytic anemia may also have spherocytes, and these cells also have an abnormal osmotic fragility. The antihuman globulin antibody test (Coombs test) should be performed in all patients in whom there is no family history of the disease to rule out acquired hemolytic anemia of the Coombs-positive variety. TREATMENT
In few hematologic disorders does therapy produce as rewarding a response as does splenectomy for the patient with congenital microspherocytosis. The operation should be performed even if anemia and jaundice are absent, for the incidence of gallstones increases with age, and the first crisis may constitute a threat to life. We currently modify this dictum with children younger than five years of age, in whom splenectomy apparently results in a decreased resistance to infection. Although there is some controversy in this regard, our experience confirms the hazard from subsequent infection which splenectomy entails for the young child.20 For this reason we have adopted a policy of careful watchfulness until the age of five years, when splenectomy is performed. The parents are carefully informed of the signs of anemia, and transfusions are given if required during this period. It is essential to have reliable parents; if the parents appear uncooperative or grossly disinterested, we may recommend splenectomy at an earlier age. Splenectomy is rarely an emergency. Transfusions will carry the patient through a crisis, and an elective splenectomy may be performed when the patient is in optimum physical condition. In older children cholecystography should be performed before operation, and the gallbladder should be palpated during the splenectomy. Cholecystectomy should be carried out if stones are present. After splenectomy the number of spherocytes often increases, and the increased osmotic and mechanical fragility of the red cells persists. Increased hemolysis ceases, however, there is no anemia, and the number of reticulocytes becomes normal or only slightly increased. The platelet count increases in the immediate postsplenectomy period, but
670
CONGENIT AL MICROSPHEROCYTOSIS
only rarely to levels above one million per cubic millimeter, as may occur after splenectomy for idiopathic thrombocytopenia. The spleen is particularly easy to remove during childhood, since adhesions are usually absent. The results are so favorable that one may unhesitatingly recommend the procedure after the age of five years. Since most infections in splenectomized infants and children have occurred in the first year after the operation and have been due to pneumococci, we currently prescribe prophylactic doses of oral penicillin for one year after operation. The value of this is yet to be proved. SUMMARY
Congenital spherocytosis may be manifest shortly after birth or may remain asymptomatic throughout life. Determination of the osmotic fragility of incubated erythrocytes will invariably detect the disorder. Splenectomy should be performed whenever the disease is diagnosed in order to avoid the severe anemia which may occur during aplastic crises and the development of cholelithiasis, which is extremely common in adults with this disorder. REFERENCES 1. Allison, A. C., Kates, M., and James, A. T.: An Abnonnality of Blood Lipids in Hereditary Spherocytosis. Brit. M.f. 2:1766, 1960. 2. Battle, J. D.: Hereditary Spherocytosis (Congenital Hemolytic Jaundice). Patho· genesis of the "Hemolytic" Crisis. Am. ,. M.Sc., 224: 82, 1952. 3. Conrad, E., and Schmidt, R. E.: Congenital Hemolytic Anemia-A Case Requiring Early Splenectomy. Am. 1. Dis. Child., 72:731, 1946. 4. Dacie, J. V.: Observations on Autohemolysis in Familial Acholuric Jaundice. 1. Path. 6 Bact., 52:331, 1941. 5. Idem: Familial Hemolytic Anemia (Acholuric Jaundice), with Particular Reference to Changes in Fragility Produced by Splenectomy. Quart. ,. Med., 12:101, 1943. 6. Dameschek, W., and Bloom, M. L.: The Events in the Hemolytic Crisis of Hereditary Spherocytosis, with Particular Reference to Reticulocytopenia, Pancyto· penia and an Abnonnal Splenic Mechanism. Blood, 3: 1381, 1948. 7. Diamond, L. K.: Indications for Splenectomy in Childhood. Am. 1. Surg., 39:400, 1938. 8. Emerson, C. P., Shen,S. C., Harne, T. H. H., and Castle, W. B.: The Mechanism of Blood Destruction in Congenital Hemolytic Jaundice. (Abstract) 1. Clin. Invest., 26:1180, 1947. 9. Gofstein, R., and Gellis, S. S.: Splenectomy in Infancy and Childhood. Am. J. Dis. Child., 91:566,1956. 10. Guest, G. M.: Osmotic Behavior of Normal and Abnonnal Human Erythrocytes. 1. Clin. Invest., 29:1180, 1947. 11. Kline, A. H., and Holman, G. H.: Hereditary Spherocytosis in the Negro. Am. 1. Dis. Child., 94:616,1957. 12. Macaulay, D.: Acholuric Jaundice in a Newborn Infant. Arch. Dis. Childhood, 26:241,1951. 13. Owren, P. A.: Congenital Hemolytic Jaundice. The Pathogenesis of the "Hemo· lytic Crisis." Blood, 3:231, 1948. 14. Prankerd, F. A. J., Altman, K. I., and Young, L. E.: Abnormalities of Carbohy·
ARTHUR E. Me ELFRESH
15. 16. 17. 18. 19. 20. 21. 22. 23. 24.
671
drate Metabolism of Red Cells in Hereditary Spherocytosis. (Abstract) J. Clin. Invest., 33:957, 1954. Race, R. R.: On the Inheritance and Linkage Relations of Acholuric Jaundice. Ann. Eugenics, 11:365, 1942. Roddy, R., ed.: Clinical Conferences at St. Christopher's Hospital for Children. ]. Pediat., 44:213,1954. Selwyn, J. G., and Dacie, J. V.: Autohemolysis and Other Changes Resulting from the Incubation in Vitro of Red Cells from Patients with Congenital Hemolytic Anemia. Blood, 9:414,1954. Shapiro, C. M., Josephson, A. M., Rozengvaig, S., and Kauffman, A.: Hereditary Spherocytosis in the Neonatal Period.]. Pediat., 50:308, 1957. Shen, S. C., Castle, W. B., and Fleming, E. M.: Experimental and Clinical Observations on Increased Mechanical Fragility of Erythrocytes. Science, 100:387, 1944. Smith, C. H., Erlandson, M. E., Schulman, I., and Stern, G.: Hazard of Severe Infections in Splenectomized Infants and Children. Am. ]. Med., 22: 390, 1957. Stamey, C. C., and Diamond, L. K.: Congenital Hemolytic Anemia in the Newborn. Am.]. Dis. Child., 94:616,1957. Wise, W. D., and Loker, F. F.: Hereditary Spherocytic Anemia. South. MI, 53:709,1960. Wolman, I. J.: Congenital Hemolytic Anemia: A Review of Progress. Am. J. M. Sc., 210:798,1945. Young, L. E.: Hereditary Spherocytosis. Am. J. Med., 18:486, 1955.
St. Christopher's Hospital for Children 2600 N. Lawrence St. Philadelphia 33, Pa.
CONGENITAL MICROSPHEROCYTOSIS ARTHUR E. Me ELFRESH, M.D.
Congenital microspherocytosis (familial acholuric jaundice, Minkowsky-Chauffard disease) is the most common hereditary hemolytic disease of people of English or northern European descent. Since many patients are asymptomatic and since there is no simple test to determine the presence of the condition, the exact incidence of the disease is not known. Although limited primarily to Caucasians, congenital microspherocytosis does occur in Negroes; Kline and Holman l l have reviewed 42 cases among 13 Negro families reported in the literature. Congenital microspherocytosis is transmitted as a dominant characteristic; thus either parent may transmit it to children of either sex. Nevertheless cases in which there is no evidence of the disease in eitheI parent do occur. In addition, among families with the disease there is less than the expected 1: 1 ratio of affected to nonaffected persons. These discrepancies from the expected pattern of inheritance may be the result of an increased incidence of fetal or neonatal deaths of involved infants or may indicate failure to detect mildly affected persons. 15 Determination of the osmotic fragility of the red blood cells by the standard methods may give normal results in almost one quarter of affected persons; determination of the osmotic fragility of erythrocytes which have been incubated sterilely for 24 hours will detect the condition in almost all affected persons.
PATHOGENESIS
The anemia of hereditary spherocytosis results from a defect in the From St. Christopher's Hospital for Children and the Department of Pediatrics, Temple University School of Medicine, Philadelphia.
666
CONGENITAL MICROSPHEROCYTOSIS
patient's erythrocytes, which have a life span shorter than normal, as short as 15 days in some instances. A portion of the erythrocytes are spheroidal rather than biconcave; only mature erythrocytes have the spheroidal shape, which is not seen in the erythroid precursors of the bone marrow. When normal biconcave erythrocytes are exposed to increasingly dilute concentrations of saline, they behave as osmometers; i.e. they absorb greater amounts of water as the solutions become more dilute. The cells become progressively more spheroidal and finally rupture when they have swollen to approximately 175 per cent of their original volume. The erythrocytes of congenital microspherocytosis are already spheroidal and can only swell to approximately 150 per cent of their original volume before hemolysis occurS.lO The spheroidal shape and the abnormal osmotic behavior, however, are probably not the cause of the increased rate of hemolysis, but in all likelihood are merely reflections of abnormal cellular metabolism. Selwyn and Dacie17 showed that when spherocytes were incubated under sterile conditions, they were less spheroidal after 48 hours than after 24 hours of incubation, but that the rate of hemolysis was greater at 48 hours. In erythrocytes from patients with this disorder Prankerd et aI.14 found abnormalities related to incorporation of phosphorus into adenosine-triphosphate, and Allison, Kates and James 1 have suggested that there is an abnormality of lipid metabolism. These studies indicate the presence of a metabolic abnormality, the exact nature of which is still not clear. Although the abnormal erythrocytes represent the principal abnormality in congenital microspherocytosis, the spleen is the organ principally responsible for the excessive destruction of these abnormal cells. When spherocytes have been transfused into normal recipients before splenectomy performed with gastrectomy, blood from the excised spleens has been found to contain a greater percentage of spherocytes than was present in the general circulation. s The spleen thus acts to some degree solely as a filter. "Crises," during which the usually mild anemia becomes severe, occur intermittently in many patients and may be the first indication of the disease. Crises were formerly thought to result from an increase in the rate of erythrocytic destruction, but it is now apparent that the crisis is most frequently the result of a reduction in the production of erythrocytes. If the peripheral blood is examined early in the course of a crisis, one finds reticulocytopenia and frequently leukopenia and thrombocytopenia. These findings are a reflection of a hypoplastic bone marrow. Since the life span of the spherocytic erythrocyte is only 14 to 19 days, cessation of red cell production rapidly results in severe anemia. The hypoplastic period persists from 6 to 10 days, after which the reticulocytes again increase in number; there is frequently leukocytosis during the period of recovery.2, 6, 13
ARTHUR E. Me ELFRESH
667
MANIFESTATIONS
The signs and symptoms of congenital microspherocytosis are extremely variable; manifestations of the disease may begin immediately after birth, or the disease may remain entirely unsuspected through life. One may encounter many degrees of severity among the members of a family. When symptoms begin at birth, the appearance of anemia with jaundice and splenomegaly may simulate erythroblastosis; exchange transfusions may be required to reduce the concentration of bilirubin, since kernicterus has occasionally resulted from hyperbilirubinemia during the first week of life. 12 , 16, 18, 21 The appearance of symptoms in the newborn period, however, is a rare event. The degree of anemia is variable, but is rarely severe enough to cause symptoms except during crises. The hemoglobin concentration is often maintained at normal or near normal levels by an increased rate of erythropoiesis, and the patient is not aware of his disease until jaundice is noted, his spleen or liver is palpated, or a crisis occurs. Frequently the illness is completely asymptomatic and the diagnosis is made only because the condition is detected in another member of the family and family studies are carried out. Jaundice is absent in many patients. In others, icterus may appear intermittently and may suggest infectious hepatitis. In one of our patients there were only 3 periods of jaundice, each lasting 2 to 3 weeks, between the ages of 3 and 11 years. He was otherwise completely well. In many children, however, mild to moderate jaundice is present constantly and the serum bilirubin concentration is often slightly elevated even when no jaundice is apparent. Gallstones are common as a result of the increased bilirubin production. They have been seen in a child as young as three years of age and are not uncommon in adolescents; cholecystography should always be performed in older children when this disease is diagnosed. The severe anemia which occurs during a hypoplastic crisis may result in tachycardia, hyperpnea, cardiac failure or loss of consciousness. The crisis is often the first sign of the illness. I recently saw a 13-year-old boy who was admitted with a hemoglobin concentration of less than 3 Gm. per 100 m!. and a hematocrit level of 8 per cent. He had previously been entirely well and had recently completed a two-week canoe trip. It should be re-emphasized that many patients exhibit no manifestations of the disorder whatsoever; the discovery of one involved member in a family is reason to institute hematologic investigation of the entire family in order to detect asymptomatic cases. The father of the boy mentioned above was 46 years old, he had never been anemic or jaundiced and had served 4 years in the army. His only evidence of the dis-
668
CONGENITAL MICROSPHEROCYTOSIS
ease was a slight increase in his reticulocyte count and abnormal osmotic fragilities of his erythrocytes. LABORATORY STUDIES
The degree of anemia is variable; in the absence of a crisis the hemo· globin concentration is rarely less than 8 Gm. per 100 ml. and is often normal. The anemia is normochromic with a mean corpuscular volume which is often increased as a result of the spheroidal shape of the red cells. Spherocytes on a stained blood smear appear as small, densely stained cells, the most intense staining appearing in the center of the cell (the thickest portion) rather than around the periphery as in normal red cells (see Fig. 18). Spherocytes may be few in number and are
Fig. 18. Peripheral blood from a five-year-old girl with congenital microspherocytosis. The dark-staining spherocytes stand out in contrast to the more numerous normal cells.
best appreciated when a saline suspension of red cells is examined microscopically under reduced illumination; as the cells tumble about, the spherocytes are easily distinguished from normally shaped cells. The reticulocyte count is almost always elevated, but is usually not above 3 to 5 per cent. After a hypoplastic crisis, however, reticulocytes may constitute 50 per cent or more of the cells present. The determination of the osmotic fragility of erythrocytes in hypotonic saline is the one test most frequently done to detect or confirm the presence of spherocytes. Hemolysis of spherocytes usually begins at concentrations above 0.48 per cent saline, the concentration below which normal cells begin to hemolyze. But in 10 to 20 per cent of patients with congenital microspherocytosis no increase in susceptibility to hypotonic saline is seen with the conventional test; the osmotic fra-
r ARTHUR E. Me ELFRESH
66<)
gility must always be determined with erythrocytes which have been incubated sterilely for 24 hours before one can be sure that the osmotic fragility test is truly normaJ.17,24 Although incubation in this fashion will increase the osmotic fragility of normal red cells slightly, the increase with cells from persons with congenital microspherocytosis is much greater than with cells from normal persons. Normal cells after incubation have initial hemolysis below 0.60 per cent saline, but spherocytes after incubation hemolyze at concentrations well above this. The mechanical fragility of the erythrocytes is also increased, but facilities for this test are not usually available. 19 Patients with acquired hemolytic anemia may also have spherocytes, and these cells also have an abnormal osmotic fragility. The antihuman globulin antibody test (Coombs test) should be performed in all patients in whom there is no family history of the disease to rule out acquired hemolytic anemia of the Coombs-positive variety. TREATMENT
In few hematologic disorders does therapy produce as rewarding a response as does splenectomy for the patient with congenital microspherocytosis. The operation should be performed even if anemia and jaundice are absent, for the incidence of gallstones increases with age, and the first crisis may constitute a threat to life. We currently modify this dictum with children younger than five years of age, in whom splenectomy apparently results in a decreased resistance to infection. Although there is some controversy in this regard, our experience confirms the hazard from subsequent infection which splenectomy entails for the young child.20 For this reason we have adopted a policy of careful watchfulness until the age of five years, when splenectomy is performed. The parents are carefully informed of the signs of anemia, and transfusions are given if required during this period. It is essential to have reliable parents; if the parents appear uncooperative or grossly disinterested, we may recommend splenectomy at an earlier age. Splenectomy is rarely an emergency. Transfusions will carry the patient through a crisis, and an elective splenectomy may be performed when the patient is in optimum physical condition. In older children cholecystography should be performed before operation, and the gallbladder should be palpated during the splenectomy. Cholecystectomy should be carried out if stones are present. After splenectomy the number of spherocytes often increases, and the increased osmotic and mechanical fragility of the red cells persists. Increased hemolysis ceases, however, there is no anemia, and the number of reticulocytes becomes normal or only slightly increased. The platelet count increases in the immediate postsplenectomy period, but
670
CONGENIT AL MICROSPHEROCYTOSIS
only rarely to levels above one million per cubic millimeter, as may occur after splenectomy for idiopathic thrombocytopenia. The spleen is particularly easy to remove during childhood, since adhesions are usually absent. The results are so favorable that one may unhesitatingly recommend the procedure after the age of five years. Since most infections in splenectomized infants and children have occurred in the first year after the operation and have been due to pneumococci, we currently prescribe prophylactic doses of oral penicillin for one year after operation. The value of this is yet to be proved. SUMMARY
Congenital spherocytosis may be manifest shortly after birth or may remain asymptomatic throughout life. Determination of the osmotic fragility of incubated erythrocytes will invariably detect the disorder. Splenectomy should be performed whenever the disease is diagnosed in order to avoid the severe anemia which may occur during aplastic crises and the development of cholelithiasis, which is extremely common in adults with this disorder. REFERENCES 1. Allison, A. C., Kates, M., and James, A. T.: An Abnonnality of Blood Lipids in Hereditary Spherocytosis. Brit. M.f. 2:1766, 1960. 2. Battle, J. D.: Hereditary Spherocytosis (Congenital Hemolytic Jaundice). Patho· genesis of the "Hemolytic" Crisis. Am. ,. M.Sc., 224: 82, 1952. 3. Conrad, E., and Schmidt, R. E.: Congenital Hemolytic Anemia-A Case Requiring Early Splenectomy. Am. 1. Dis. Child., 72:731, 1946. 4. Dacie, J. V.: Observations on Autohemolysis in Familial Acholuric Jaundice. 1. Path. 6 Bact., 52:331, 1941. 5. Idem: Familial Hemolytic Anemia (Acholuric Jaundice), with Particular Reference to Changes in Fragility Produced by Splenectomy. Quart. ,. Med., 12:101, 1943. 6. Dameschek, W., and Bloom, M. L.: The Events in the Hemolytic Crisis of Hereditary Spherocytosis, with Particular Reference to Reticulocytopenia, Pancyto· penia and an Abnonnal Splenic Mechanism. Blood, 3: 1381, 1948. 7. Diamond, L. K.: Indications for Splenectomy in Childhood. Am. 1. Surg., 39:400, 1938. 8. Emerson, C. P., Shen,S. C., Harne, T. H. H., and Castle, W. B.: The Mechanism of Blood Destruction in Congenital Hemolytic Jaundice. (Abstract) 1. Clin. Invest., 26:1180, 1947. 9. Gofstein, R., and Gellis, S. S.: Splenectomy in Infancy and Childhood. Am. J. Dis. Child., 91:566,1956. 10. Guest, G. M.: Osmotic Behavior of Normal and Abnonnal Human Erythrocytes. 1. Clin. Invest., 29:1180, 1947. 11. Kline, A. H., and Holman, G. H.: Hereditary Spherocytosis in the Negro. Am. 1. Dis. Child., 94:616,1957. 12. Macaulay, D.: Acholuric Jaundice in a Newborn Infant. Arch. Dis. Childhood, 26:241,1951. 13. Owren, P. A.: Congenital Hemolytic Jaundice. The Pathogenesis of the "Hemo· lytic Crisis." Blood, 3:231, 1948. 14. Prankerd, F. A. J., Altman, K. I., and Young, L. E.: Abnormalities of Carbohy·
ARTHUR E. Me ELFRESH
15. 16. 17. 18. 19. 20. 21. 22. 23. 24.
671
drate Metabolism of Red Cells in Hereditary Spherocytosis. (Abstract) J. Clin. Invest., 33:957, 1954. Race, R. R.: On the Inheritance and Linkage Relations of Acholuric Jaundice. Ann. Eugenics, 11:365, 1942. Roddy, R., ed.: Clinical Conferences at St. Christopher's Hospital for Children. ]. Pediat., 44:213,1954. Selwyn, J. G., and Dacie, J. V.: Autohemolysis and Other Changes Resulting from the Incubation in Vitro of Red Cells from Patients with Congenital Hemolytic Anemia. Blood, 9:414,1954. Shapiro, C. M., Josephson, A. M., Rozengvaig, S., and Kauffman, A.: Hereditary Spherocytosis in the Neonatal Period.]. Pediat., 50:308, 1957. Shen, S. C., Castle, W. B., and Fleming, E. M.: Experimental and Clinical Observations on Increased Mechanical Fragility of Erythrocytes. Science, 100:387, 1944. Smith, C. H., Erlandson, M. E., Schulman, I., and Stern, G.: Hazard of Severe Infections in Splenectomized Infants and Children. Am. ]. Med., 22: 390, 1957. Stamey, C. C., and Diamond, L. K.: Congenital Hemolytic Anemia in the Newborn. Am.]. Dis. Child., 94:616,1957. Wise, W. D., and Loker, F. F.: Hereditary Spherocytic Anemia. South. MI, 53:709,1960. Wolman, I. J.: Congenital Hemolytic Anemia: A Review of Progress. Am. J. M. Sc., 210:798,1945. Young, L. E.: Hereditary Spherocytosis. Am. J. Med., 18:486, 1955.
St. Christopher's Hospital for Children 2600 N. Lawrence St. Philadelphia 33, Pa.