Hereditary Spherocytosis 

Hereditary spherocytosis (HS) is a familial hemolytic disorder with marked heterogeneity of clinical features, ranging from an asymptomatic condition to fulminant hemolytic anemia. The morphologic hallmark of HS is the microspherocyte, which is caused by loss of membrane surface area, and an abnormal osmotic fragility in vitro. Investigation of HS has afforded important insights into the structure and function of cell membranes and into the role of the spleen in maintaining red blood cell (RBC) integrity. An intrinsic genetic defect causes defects in membrane proteins.

The major complications are aplastic or megaloblastic crisis, hemolytic crisis, cholecystitis and cholelithiasis, and severe neonatal hemolysis.

Hemolysis in HS results from the interplay of an intact spleen and an intrinsic membrane protein defect that leads to abnormal RBC morphology.

HS erythrocytes are caused by membrane protein defects resulting in cytoskeleton instability. Spectrin deficiency leads to loss of erythrocyte surface area, which produces spherical RBCs. Spherocytic RBCs are culled rapidly from the circulation by the spleen. Patients with HS develop splenomegaly. Biochemical spectrin deficiency and the degree of spectrin deficiency are reported to correlate with the extent of spherocytosis, the degree of abnormality on osmotic fragility test results, and the severity of hemolysis. Hemolysis primarily is confined to the spleen and, therefore, is extravascular. Spectrin deficiency is the result of impaired synthesis, whereas in other instances, it is caused by quantitative or qualitative deficiencies of other proteins that integrate spectrin into the cell membrane. In the absence of these binding proteins, free spectrin is degraded, leading to spectrin deficiency.

Four abnormalities in red cell membrane proteins have been identified and include (1) spectrin deficiency alone, (2) combined spectrin and ankyrin deficiency, (3) band 3 deficiency, and (4) protein 4.2 defects. Spectrin deficiency is the most common defect. Each is associated with a variety of mutations that result in different protein abnormalities and varied clinical expression. Most cases of HS are heterozygous because homozygous states are lethal.

Spectrin deficiency

Mutations of alpha-spectrin are associated with recessive forms of HS, whereas mutations of beta-spectrin occur in families with autosomal dominant forms of HS.^{[1, 2]} Synthesis of alpha-spectrin is 3-fold greater than that of beta-spectrin. The excess alpha chains normally are degraded. Heterozygotes for alpha-spectrin defects produce sufficient normal alpha-spectrin to balance normal beta-spectrin production. Defects of beta-spectrin are more likely to be expressed in the heterozygous state because synthesis of beta-spectrin is the rate-limiting factor. Red cell membranes isolated from individuals with autosomal recessive HS have only 40-50% of the normal amount of spectrin (relative to band protein 3), whereas red cell spectrin levels range from 60-80% of normal in the autosomal dominant form of HS.

Identification of an alpha-spectrin mutation involves a point mutation at codon (969), resulting in an amino acid substitution (alanine [Ala]/aspartic acid [Asp]) at the corresponding site of alpha-spectrin in 50% of patients with severe recessive HS. Mutations involving the alpha-spectrin beta-spectrin gene also occur, each resulting in spectrin deficiency. The first identified point mutation leads to a defective binding of spectrin to protein 4.1. Several other beta-spectrin mutations have been identified. Some of these mutations result in impaired beta-spectrin synthesis. Others produce unstable beta-spectrins or abnormal beta-spectrins that do not bind to ankyrin and undergo proteolytic degradation.

Ankyrin defects

HS is described in patients with translocation of chromosome 8 or deletion of the short arm of chromosome 8 where the ankyrin gene is located, and patients with HS and deletion of chromosome 8 are shown to have a decrease in red cell ankyrin content. Ankyrin is the principal binding site for spectrin on the red cell membrane. Studies of cytoskeletal protein assembly in reticulocytes indicate that ankyrin deficiency leads to decreased incorporation of spectrin. In HS caused by ankyrin deficiency, a proportional decrease in spectrin content occurs, although spectrin synthesis is normal. Of particular interest, 75-80% of patients with autosomal dominant HS have combined spectrin and ankyrin deficiency and the 2 proteins are diminished equally.

Band 3 deficiency

Band 3 deficiency has been recognized in 10-20% of patients with mild-to-moderate autosomal dominant HS. These patients also have a proportionate decrease in protein 4.2 content on the membrane. In some people with HS who are deficient in band 3, the deficiency is considerably greater in older RBCs. This suggests that band 3 protein is unstable.

Protein 4.2 (pallidin) deficiency

Hereditary hemolytic anemia has been described in patients with a complete deficiency of protein 4.2. Spherocytes, elliptocytes, or sphero-ovalocytes have characterized RBC morphology. Deficiency of protein 4.2 in HS is relatively common in Japan. One that appears to be common in the Japanese population (protein 4.2 Nippon) is associated in the homozygous state with a red cell morphology described as spherocytic, ovalocytic, and elliptocytic. Another mutant protein 4.2 (protein 4.2 Lisboa) is caused by a deletion that results in a complete absence of protein 4.2. This is associated with a typical HS phenotype.

Frequency

United States

HS is the most common of the hereditary hemolytic anemias among people of Northern European descent.^[3] In the United States, the incidence of the disorder is approximately 1 case in 5000 people. However, this figure probably is an underestimate. Given that the incidence of HS in the United States is 1 case in 5000 people and that approximately 25% of all HS is autosomal recessive, calculations indicate that the HS silent carrier state might exist in 1.4% of the population.

• HS usually is transmitted as an autosomal dominant trait, and the identification of the disorder in multiple generations of affected families is the rule. Homozygosity for this dominantly transmitted HS gene has not been identified. This suggests that the homozygous state is incompatible with life. Twenty-five percent of all newly diagnosed patients do not demonstrate a dominant inheritance pattern. Parents of these patients do not have clinical or hematological abnormalities. New mutations have been implicated that may explain some of these sporadic cases.
• An autosomal recessive mode of inheritance also occurs. This is supported by the descriptions of families in which apparently healthy parents have had more than one affected child. This recessive pattern may account for 20-25% of all HS cases. It manifests only in individuals who are homozygous or compound heterozygous and often is associated with severe hemolytic anemia.

International

The disease is encountered worldwide, but its incidence and prevalence in other groups are not established clearly.

Mortality/Morbidity

• Anemia or hyperbilirubinemia may be of such magnitude as to require exchange transfusion in the neonatal period. Anemia usually is mild to moderate; however, sometimes it is very severe and sometimes it is not present. Splenomegaly is the rule, and palpable spleens have been detected in more than 75% of affected subjects. Severe hemolytic anemia requires red cell transfusions.
• In chronic congenital hemolytic anemia (ie, HS), long periods of asymptomatic disease depend on a fragile equilibrium in which the excessive destruction of cells is balanced by accelerated erythropoiesis. Disruption of this equilibrium can lead to rapid and dramatic falls in blood hemoglobin levels, producing an aplastic crisis. Most, if not all, aplastic crises are caused by infection with type B19 human parvovirus (HPV). In some cases, an abrupt increase in the rate of red cell destruction may occur, possibly because of increased splenic activity (hemolytic crisis). Another type of crisis develops because of complicating folate deficiency (megaloblastic crisis), to which patients with chronic hemolysis appear to be particularly prone. The onset of megaloblastic crises tends to be more gradual than that of aplastic or hemolytic crises and is unrelated to complicating infections.
• In patients with mild HS, cholelithiasis may be the first sign of an underlying red cell disorder. Cholelithiasis is common in HS. Gallstones of the pigment type (caused by bilirubin) may be found in very young children, but the incidence of gallstones increases markedly with age. A history of family members with cholelithiasis in the second or third decade of life is a clue to the possible presence of HS.

Race

• HS is the most common hereditary hemolytic anemia among people of Northern European descent. Its incidence and prevalence in other ethnic groups are not clearly established.