Hereditary spherocytosis refers to a group of heterogeneous disorders that are characterized by the presence of spherical-shaped erythrocytes (spherocytes) on the peripheral blood smear. The disorders are characterized clinically by anemia, jaundice, and splenomegaly, with variable severity. Common ... Hereditary spherocytosis refers to a group of heterogeneous disorders that are characterized by the presence of spherical-shaped erythrocytes (spherocytes) on the peripheral blood smear. The disorders are characterized clinically by anemia, jaundice, and splenomegaly, with variable severity. Common complications include cholelithiasis, hemolytic episodes, and aplastic crises (review by Perrotta et al., 2008). Elgsaeter et al. (1986) gave an extensive review of the molecular basis of erythrocyte shape with a discussion of the role of spectrin and other proteins such as ankyrin, actin (102630), band 4.1 (130500), and band 3 (109270), all of which is relevant to the understanding of spherocytosis and elliptocytosis (see 611904). See Delaunay (2007) for a discussion of the molecular basis of hereditary red cell membrane disorders. - Genetic Heterogeneity of Hereditary Spherocytosis Also see spherocytosis type 2 (see 182870), caused by mutation in the SPTB gene (182870) on chromosome 14q22-q23; spherocytosis type 3 (270970), caused by mutation in the SPTBA gene (182860) on chromosome 1q21; spherocytosis type 4 (see 109270), caused by mutation in the SLC4A1 gene (109270) on chromosome 17q21-q22; and spherocytosis type 5 (612690), caused by mutation in the EPB42 gene (177070) on chromosome 15q15.
MacKinney et al. (1962) and Morton et al. (1962) studied 26 families. They concluded that after the initial case in a family has been identified, 4 tests suffice for the diagnosis in other family members: smear, reticulocyte count, ... MacKinney et al. (1962) and Morton et al. (1962) studied 26 families. They concluded that after the initial case in a family has been identified, 4 tests suffice for the diagnosis in other family members: smear, reticulocyte count, hemoglobin, and bilirubin. The fragility test (increased osmotic fragility characterizes the disease) is unnecessary after the diagnosis has been made in the proband. It was estimated that the prevalence is 2.2 per 10,000, that the mutation rate is 0.000022 and that about one-fourth of cases are sporadic. No evidence of reproductive compensation or of increased prenatal and infant mortality was found. No enzyme defect was identified (Miwa et al., 1962). Several observations suggest that more than one type of hereditary spherocytosis exists in man (review by Zail et al., 1967). Barry et al. (1968) pointed out that hemochromatosis is a serious complication of untreated spherocytosis. Fargion et al. (1986) described 2 brothers who were thought to be heterozygous for the hemochromatosis gene and who also were affected with hereditary spherocytosis. Both had severe iron overload whereas all relatives without hereditary spherocytosis, including those with HLA haplotypes identical to those of the 2 brothers, had normal iron stores. Montes-Cano et al. (2003) reported a similar situation in a Spanish family: 3 members of different generations were diagnosed with hereditary spherocytosis and 1 of them, 44 years of age, presented iron overload with hepatic deposit and required treatment with periodic phlebotomies. Other members of the family showed normal values in iron metabolism. The patient with iron overload was a compound heterozygote for the H63D (235200.0002) and C282Y (235200.0001) mutations in the HFE gene. In a family with 6 persons affected in 3 generations, Wiley and Firkin (1970) found a form of hereditary spherocytosis with unusual features; other reports of atypical disease were reviewed. Aksoy et al. (1974) described severe hemolytic anemia in a patient seemingly with both elliptocytosis (inherited probably from the father) and spherocytosis (inherited from the mother). This finding raises a question of possible allelism of spherocytosis and one form of elliptocytosis. A genetic compound is more likely to show summation of effects than is a double heterozygote. Epidemic aplastic crisis in congenital chronic hemolytic anemias has been attributed to the human parvovirus (HPV) which also causes erythema infectiosum, or fifth disease (Tsukada et al., 1985; Rao et al., 1983). Lefrere et al. (1986) showed that in both children and adults the human parvovirus can precipitate aplastic crisis in hereditary spherocytosis just as it does in other forms of hereditary hemolytic anemia, particularly sickle cell disease. Healthy persons probably develop an erythroblastopenia when experiencing their first contact with HPV, but this escapes notice when the normal red cell life span allows maintenance of hemoglobin level throughout the interruption of red cell production. Ng et al. (1987) described a father and a son in whom aplastic crisis in hereditary spherocytosis was precipitated by parvovirus infection. Moiseyev et al. (1987) described a kindred in which hereditary spherocytosis occurred in combination with hypertrophic cardiomyopathy in 5 individuals in 4 successive generations. In another branch of the family, 4 individuals in 3 successive generations had either hereditary spherocytosis or hypertrophic cardiomyopathy (192600), but not both. Coetzer et al. (1988) described a 41-year-old man and an unrelated 49-year-old woman who had atypical, severe spherocytosis with partial response to splenectomy. No information on the family aided in evaluating inheritance in the second case; in the first case, the deceased father had had chronic anemia and a sib had died at age 3 months of unknown cause. In these 2 patients, the authors found a partial deficiency of ankyrin and spectrin in red cells. Coetzer et al. (1988) concluded that a defect in synthesis of ankyrin was the primary abnormality. In the offspring of first-cousin parents, both of whom had hereditary spherocytosis, Duru et al. (1992) observed a 6-month-old male infant with severe anemia. The infant required red blood cell transfusions starting at the age of 1 month and continuing until splenectomy was performed at the age of 1 year to produce a complete hematologic remission. Duru et al. (1992) concluded that this represented an example of homozygosity for the spherocytosis gene, presumably an ankyrin mutant, and that splenectomy can cure the anemia, even in the homozygote. Both sickle cell anemia and hereditary spherocytosis are known causes of leg ulcers. Peretz et al. (1997) reported the case of an 18-year-old Bedouin with leg ulcers of 12-months duration; past history revealed HS since childhood. Treatment for 6 months with various conservative modalities had no effect on the ulcers. However, complete clearance was achieved 2 months after splenectomy. The precocious formation of bilirubinate gallstones is the most common complication of hereditary spherocytosis, and the prevention of this problem represents a major impetus for splenectomy in many patients with compensated hemolysis. Because Gilbert syndrome (143500) had been considered a risk factor for gallstone formation, Miraglia del Giudice et al. (1999) postulated that the association of this common inherited disorder of hepatic bilirubin metabolism with hereditary spherocytosis could increase cholelithiasis. To test this hypothesis, 103 children with mild to moderate hereditary spherocytosis who, from age 1 year, had undergone a liver and biliary tree ultrasonography every year, were retrospectively examined. The 2-bp TA insertion within the promoter of the UGT1A1 gene (191740.0011), which is associated with Gilbert syndrome, was screened. The risk of developing gallstones was statistically different among the 3 groups of patients (homozygotes for the normal UGT1A1 allele, heterozygotes, and homozygotes for the allele with the TA insertion). Miraglia del Giudice et al. (1999) concluded that although patients with hereditary spherocytosis were the only ones studied, extrapolating these findings to patients who have different forms of inherited (e.g., thalassemia, intraerythrocytic enzymatic deficiency) or acquired (e.g., autoimmune hemolytic anemia, hemolysis from mechanical heart valve replacement) chronic hemolysis may be warranted. - Reviews Davies and Lux (1989) gave a useful review of hereditary disorders of the red cell membrane skeleton. They referred to a form of spherocytosis due to a defect in ankyrin as spherocytosis-1 and a form due to a defect in beta-spectrin as spherocytosis-2. Perrotta et al. (2008) reviewed the several forms of hereditary spherocytosis.
Davies and Lux (1989) stated that dosage analysis in 2 hereditary spherocytosis patients with chromosome 8p11 deletions showed them to be hemizygous for the ankyrin gene. A corresponding reduction of approximately 50% in the amount of ankyrin protein ... Davies and Lux (1989) stated that dosage analysis in 2 hereditary spherocytosis patients with chromosome 8p11 deletions showed them to be hemizygous for the ankyrin gene. A corresponding reduction of approximately 50% in the amount of ankyrin protein was also seen in these patients, who had mental retardation in addition to the red cell defect. In both normoblastosis mice and hereditary spherocytosis humans, spectrin is also reduced as a secondary phenomenon. Iolascon et al. (1991) described 2 Italian families with ankyrin deficiency spherocytosis. In both, the disorder was a new mutation in the proband; 1 proband transmitted it to an offspring. Eber et al. (1996) screened all 42 coding exons plus the 5-prime untranslated/promoter region of ankyrin-1 and the 19 coding exons of band 3 (SLC4A1; 109270) in 46 hereditary spherocytosis families. They identified 12 ankyrin-1 mutations and 5 band-3 mutations. Missense mutations and a mutation in the putative ankyrin-1 promoter were common in recessive HS (see 612641.0002). In contrast, ankyrin-1 and band 3 frameshift and nonsense null mutations prevailed in dominant HS. Increased accumulation of the normal protein product partially compensated for the ankyrin-1 or band 3 defects in some of these null mutations. The findings indicated to Eber et al. (1996) that ankyrin-1 mutations are a major cause of dominant and recessive HS (between 35 and 65%), that band 3 mutations are less common (between 15 and 25%), and that the severity of HS is modified by factors other than the primary gene defect. Gallagher and Forget (1998) tabulated a total of 34 mutations in the ANK1 gene that have been associated with hereditary spherocytosis, as contrasted with 2 mutations in the alpha-spectrin gene and 19 in the beta-spectrin gene. In the proband reported by Duru et al. (1992), Edelman et al. (2007) identified a homozygous splice site mutation in the ANK1 gene (612641.0007). Each parent was heterozygous for the mutation.