Elliptocytosis 3

A number sign (#) is used with this entry because of evidence that elliptocytosis-3 is caused by homozygous or heterozygous mutation in the SPTB gene (182870) on chromosome 14q23.

Description

Hereditary elliptocytosis-3 is a hemolytic disorder characterized by the presence of elliptical erythrocytes and resulting in some cases in hemolytic anemia (summary by Qualtieri et al., 1997).

For a general description and a discussion of genetic heterogeneity of hereditary elliptocytosis (HE), see EL1 (611804).

Clinical Features

Aksoy et al. (1974) described severe hemolytic anemia in a patient who seemingly had both elliptocytosis (inherited probably from the father) and spherocytosis (inherited from the mother). This finding raised 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 (McKusick, 1973). Now that separate mutations in the beta-spectrin gene are known to cause either spherocytosis or elliptocytosis, the genetic compound hypothesis is particularly plausible.

Pothier et al. (1987) described a 17-year-old white boy who presented with intermittent jaundice and spleen enlargement. He complained of asthenia and abdominal pains, which developed after meals or sports. Soon after birth he had presented with an acute hemolytic episode requiring a blood transfusion. Examination of erythrocytes at age 17 years on dried blood smears or after fixation with glutaraldehyde revealed 95% elliptocytosis. Both parents and a brother were clinically and hematologically normal.

Eber et al. (1988) described a large 5-generation German family in which 2 male members of the family suffered from recurrent hemolytic crises necessitating occasional transfusions. After splenectomy, both showed a persisting compensated microcytic hemolytic anemia. Their red cells displayed elliptocytosis and poikilocytosis. Three other members had anemia and recurring icterus but were otherwise well. A 75-year-old woman with relatively mild hemolytic anemia underwent cholecystectomy for pigment gallstones. One female member required an exchange transfusion shortly after birth because of severe hyperbilirubinemia and thereafter suffered from marked hemolytic anemia for which splenectomy was advised. Precocious and severe hemolytic anemia and hyperbilirubinemia was present in another neonate who later died from perinatal stress.

Kanzaki et al. (1992) studied an 8-month-old Japanese girl in whom moderate uncompensated hemolysis had been noted at 3 months of age. Neonatal jaundice had been successfully treated with light therapy for 48 hours. Elliptocytosis was present in nearly 90% of red blood cells. Neither hepatosplenomegaly nor lymphadenopathy was present. The patient's mother presented with slightly increased hemolysis and typical elliptocytosis identical to that of the proband. No other hematologic abnormalities were detected.

Anemia, Perinatal Hemolytic, Fatal or Near-Fatal

Gallagher et al. (1995) studied a Laotian kindred in which 4 third-trimester fetal losses occurred, associated with severe Coombs-negative hemolytic anemia and extensive extramedullary erythropoiesis. Postmortem examination of 2 infants revealed overt hydrops fetalis. Studies of erythrocytes and erythrocyte membranes from the parents revealed abnormal membrane mechanical stability as well as structural and functional abnormalities in spectrin. Both parents had mild elliptocytosis, and the father was heterozygous for both hemoglobin E trait and alpha-thalassemia trait. Blood smears from 1 infant revealed marked microcytosis, spherocytosis, polychomatophilia, poikilocytosis with red cell fragmentation, and the presence of numerous nucleated red blood cells.

Gallagher et al. (1997) described a Laotian family in which 2 sibs were born with severe nonimmune hemolytic anemia and hydrops fetalis. The first sib died on the second day of life. The neonatal course of the second sib was marked by ongoing hemolysis requiring repeated erythrocyte transfusions. He had remained transfusion-dependent for more than 2 years. His peripheral blood smear showed microspherocytes and nucleated red blood cells. Peripheral blood smears from both parents revealed rare elliptocytes. Examination of the patient erythrocyte membranes revealed abnormal mechanical stability, as well as structural and functional abnormalities in spectrin.

Molecular Genetics

Eber et al. (1988) found a truncated beta chain in affected members of a large German family in which several members suffered in varying degrees from a microcytic hemolytic anemia. The red cell morphology varied from smooth elliptocytes to predominantly poikilocytes. The abnormal spectrin made up about 30% of the total and was present almost entirely as the dimer.

Ohanian et al. (1985) described a case of hemolytic anemia with elliptocytosis in which a large part of the beta subunit of spectrin was truncated. Coetzer and Zail (1981) and Dhermy et al. (1982) found variants of the beta-subunit in patients with hereditary elliptocytosis.

In the patient studied by Pothier et al. (1987), Tse et al. (1991) detected heterozygosity for a 2-bp insertion after position 6231 in the beta-spectrin cDNA, resulting in frameshift and premature termination (182870.0005).

In an 8-month-old Japanese girl with hemolysis and elliptocytosis, Kanzaki et al. (1992) detected a 1-bp insertion in the SPTB gene (182870.0006).

In 3 members of a Calabrian family from southern Italy, Qualtieri et al. (1997) found heterozygosity for a single-base substitution changing the beta-spectrin codon 2064 from arginine to proline (R2064P; 182870.0012).

Gallagher and Forget (1996) cataloged 15 reported beta-spectrin mutations found in cases of hereditary elliptocytosis and hereditary pyropoikilocytosis. Three were splicing mutations, 3 were deletions, 1 was an insertion, and the remainder were missense mutations.

Anemia, Perinatal Hemolytic, Fatal or Near-Fatal

In a Laotian family with third-trimester fetal loss associated with hemolytic anemia and hydrops fetalis, Gallagher et al. (1995) detected a ser2019-to-pro substitution (S2019P; 182870.0009) in the C-terminal region of beta-spectrin that is critical for normal spectrin self-association. The parents and surviving children were heterozygous for the mutation, and the 3 deceased infants from whom material was available were homozygous.

In 2 sibs from a Laotian nonconsanguineous family with severe nonimmune hemolytic anemia and hydrops fetalis at birth, one who died on the second day of life and the other who was alive at 2 years of age, Gallagher et al. (1997) found homozygosity for a mutation in the SPTB gene resulting in a leu2025-to-arg substitution (L2025R; 182870.0011) in the region of beta-spectrin that participates in spectrin self-association. Each parent was heterozygous for the mutation, and the sibs homozygous.