Hereditary Elliptocytosis

Updated: Feb 09, 2016
  • Author: Daniel J Kim, MD, MS; Chief Editor: Emmanuel C Besa, MD  more...
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Overview

Background

Hereditary elliptocytosis (HE) encompasses inherited disorders of erythrocytes that have the common feature of elliptical RBCs on morphologic examination and shortened RBC survival. These disorders are clinically, genetically, and biochemically heterogeneous. [1]

HE is due to defects in either the structure or quantity of the cytoskeletal proteins responsible for maintaining the biconcave morphology of RBCs. Mutations in either alpha- and beta-spectrin are most commonly responsible, but mutations in other cytoskeletal proteins (band 4.1 and glycophorin) are also described. [2] Most of these disorders are clinically silent, with only some forms associated with clinically significant hemolysis.

The mode of inheritance is autosomal dominant, except for hereditary pyropoikilocytosis (HPP) which is autosomal recessive. Instances of spontaneous mutations are rare.

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Pathophysiology

HE results from defects in the protein scaffolding of the erythrocyte membrane, which decrease the deformability and resilience of the RBCs. Normal RBCs are 7 microns and assume the shape of a biconcave disk with central pallor. They are rugged cells and can survive in the circulation for 120 days as they repeatedly and momentarily assume an elliptical shape to negotiate through capillaries as small as 2-3 microns in diameter.

Although normal RBCs can regain their discoid shape because of their elastic recoil after they pass through the microcirculation, the RBCs in HE fail to regain their normal discoid shape. This failure eventually produces the fixed characteristic morphology of elliptocytes with a decreased surface-to-volume ratio. These elliptocytes are not as deformable as normal RBCs and are eventually trapped and removed by the spleen. This process of premature destruction (ie, cells surviving <120 d) is the basis of the extravascular hemolysis that clinically defines these disorders.

The RBC membrane is composed of a fragile lipid bilayer stretched over a flexible protein cytoskeleton. Spectrin is the major component of this scaffold and consists of 2 chains, alpha and beta, which are encoded by separate genes and which are twisted together to form an elongated heterodimer. At the head region, the heterodimers associate to form tetramers. At the distal end, they bind to other cytoskeletal proteins, namely actin and protein 4.1. These proteins, in turn, anchor the scaffold to the lipid bilayer by linking to the transmembrane proteins band 3, glycophorin A, and glycophorin C.

Mutations in either of the spectrins, glycophorin C, or band 4.1 account for most cases of HE. Different point mutations are described in various families and account for some the clinical variability of this disorder. Mutations affecting the level (but not the structure) of glycophorin C (Leach phenotype) are also described. These mutations collectively result in defective assembly of the protein scaffolding on the inner aspect of the RBC membrane. The most common group of mutations affect alpha- or beta-spectrin and result in defects in the formation of the spectrin heterodimer or in the association of the heterodimer with the lipid anchoring complex (formed by actin, band 3, protein 4.1 and glycophorin C). [3]

Taken together, all of these defects result in defects in membrane stability and deformability as the RBCs pass through the microcirculation. The spleen removes the damaged erythrocytes, diminishing erythrocyte survival. Therefore, as with other chronic hemolytic disorders, clinical sequelae of HE may include splenomegaly and a propensity to develop gallstones, along with a variable degree of anemia.

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Epidemiology

Frequency

United States

HE has a prevalence of 250-500 cases per million population.

International

HE has worldwide distribution, but the incidence is considerably higher in areas endemic for malaria than in nonendemic areas because of relative resistance of elliptocytes against malaria. In equatorial Africa, the incidence is approximately 0.6%; in Malayan aborigines, the incidence is as high as 30%. However, the true incidence is unknown because many patients do not have any symptoms. [4]

Mortality/Morbidity

Most patients with the common form of HE are asymptomatic. Only 5-20% develop uncompensated hemolysis with anemia. Other findings consistent with chronic hemolysis are splenomegaly, pigmented gallstones, leg ulcers, and elevated reticulocyte counts.

Race-, Sex-, and Age-related Demographics

Although no racial or ethnic group is spared, some variants of HE occur more frequently in certain ethnic populations than in others. For example, the incidence of stomatocytic elliptocytosis among Malayan aborigines is 30%. HE with neonatal poikilocytosis occurs almost exclusively in African American families, but spherocytic elliptocytosis most commonly affects individuals of European descent.

Because HE is an autosomal disorder, the distribution between the sexes is equal.

HE is a congenital disease. However, other acquired disorders, such as myelofibrosis and myelophthisic anemias, may affect the degree of hemolysis.

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