Hereditary elliptocytosis: Clinical features, diagnosis, and treatment
- William C Mentzer, MD
William C Mentzer, MD
- Section Editor — Red Cell Disorders
- Professor of Pediatrics
- University of California, San Francisco
- Section Editors
- Donald H Mahoney, Jr, MD
Donald H Mahoney, Jr, MD
- Section Editor — Pediatric Hematology
- Professor of Pediatrics
- Baylor College of Medicine
- Stanley L Schrier, MD
Stanley L Schrier, MD
- Editor-in-Chief — Hematology
- Section Editor — Myeloproliferative Disorders; Red Cell Disorders
- Professor of Medicine
- Stanford University School of Medicine
Hereditary elliptocytosis (HE), also called hereditary ovalocytosis, is a heterogeneous group of inherited erythrocyte disorders, most of which are autosomal dominant, that have in common the presence of elongated, oval, or elliptically shaped red blood cells (RBCs) on the peripheral blood smear. Hemolytic anemia in these disorders ranges from absent to life-threatening. Severe hemolysis is usually a consequence of homozygosity or compound heterozygosity for one or more of the various membrane protein mutations associated with this disorder.
●The clinical features, diagnosis, and treatment of HE will be reviewed here. The genetics, molecular biology, pathophysiology, and possible role in resistance to malaria in HE are discussed separately. (See "Hereditary elliptocytosis: Genetics and pathogenesis".)
The prevalence of HE in the United States is not greater than 2.5 to 5 per 10,000, although the true incidence is unknown since most patients with HE are either asymptomatic or undiagnosed. However, in regions of Africa and Southeast Asia in which malaria is endemic, HE may affect more than 30 percent of the population [1-3]. (See "Hereditary elliptocytosis: Genetics and pathogenesis", section on 'Resistance to malaria'.)
The hereditary pyropoikilocytosis variant of HE, although rare, is more frequent among African-American individuals, while the spherocytic elliptocytosis variant is seen only in Caucasians.
- Lux SE, Palek J. Disorders of the red cell membrane. In: Blood. Principles and Practice of Hematology, Handin RI, Lux SE, Stossel TP (Eds), Lippincott, Philadelphia 1995. p.1701.
- Glele-Kakai C, Garbarz M, Lecomte MC, et al. Epidemiological studies of spectrin mutations related to hereditary elliptocytosis and spectrin polymorphisms in Benin. Br J Haematol 1996; 95:57.
- Nagel RL. Red-cell cytoskeletal abnormalities--implications for malaria. N Engl J Med 1990; 323:1558.
- Tomaselli MB, John KM, Lux SE. Elliptical erythrocyte membrane skeletons and heat-sensitive spectrin in hereditary elliptocytosis. Proc Natl Acad Sci U S A 1981; 78:1911.
- Palek J, Jarolim P. Clinical expression and laboratory detection of red blood cell membrane protein mutations. Semin Hematol 1993; 30:249.
- Perrotta S, Iolascon A, De Angelis F, et al. Spectrin Anastasia (alpha I/78): a new spectrin variant (alpha 45 Arg-->Thr) with moderate elliptocytogenic potential. Br J Haematol 1995; 89:933.
- Parquet N, Devaux I, Boulanger L, et al. Identification of three novel spectrin alpha I/74 mutations in hereditary elliptocytosis: further support for a triple-stranded folding unit model of the spectrin heterodimer contact site. Blood 1994; 84:303.
- Tchernia G, Mohandas N, Shohet SB. Deficiency of skeletal membrane protein band 4.1 in homozygous hereditary elliptocytosis. Implications for erythrocyte membrane stability. J Clin Invest 1981; 68:454.
- Garbarz M, Lecomte MC, Dhermy D, et al. Double inheritance of an alpha I/65 spectrin variant in a child with homozygous elliptocytosis. Blood 1986; 67:1661.
- Alloisio N, Morlé L, Pothier B, et al. Spectrin Oran (alpha II/21), a new spectrin variant concerning the alpha II domain and causing severe elliptocytosis in the homozygous state. Blood 1988; 71:1039.
- Coetzer T, Palek J, Lawler J, et al. Structural and functional heterogeneity of alpha spectrin mutations involving the spectrin heterodimer self-association site: relationships to hematologic expression of homozygous hereditary elliptocytosis and hereditary pyropoikilocytosis. Blood 1990; 75:2235.
- Iarocci TA, Wagner GM, Mohandas N, et al. Hereditary poikilocytic anemia associated with the co-inheritance of two alpha spectrin abnormalities. Blood 1988; 71:1390.
- Gallagher PG, Petruzzi MJ, Weed SA, et al. Mutation of a highly conserved residue of betaI spectrin associated with fatal and near-fatal neonatal hemolytic anemia. J Clin Invest 1997; 99:267.
- Austin RF, Desforges JF. Hereditary elliptocytosis: an unusual presentation of hemolysis in the newborn associated with transient morphologic abnormalities. Pediatrics 1969; 44:196.
- Mentzer WC Jr, Iarocci TA, Mohandas N, et al. Modulation of erythrocyte membrane mechanical stability by 2,3-diphosphoglycerate in the neonatal poikilocytosis/elliptocytosis syndrome. J Clin Invest 1987; 79:943.
- Jarolim P, Palek J, Coetzer TL, et al. Severe hemolysis and red cell fragmentation caused by the combination of a spectrin mutation with a thrombotic microangiopathy. Am J Hematol 1989; 32:50.
- Caprari P, Tarzia A, Mojoli G, et al. Hereditary spherocytosis and elliptocytosis associated with prosthetic heart valve replacement: rheological study of erythrocyte modifications. Int J Hematol 2009; 89:285.
- Pui CH, Wang W, Wilimas J. Hereditary elliptocytosis: morphologic abnormalities during acute hepatitis. Clin Pediatr (Phila) 1982; 21:188.
- Nkrumah FK. Hereditary elliptocytosis associated with severe haemolytic anaemia and malaria. Afr J Med Sci 1972; 3:131.
- Schoomaker EB, Butler WM, Diehl LF. Increased heat sensitivity of red blood cells in hereditary elliptocytosis with acquired cobalamin (vitamin B12) deficiency. Blood 1982; 59:1213.
- Jensson O, Jónasson T, Olafsson O. Hereditary elliptocytosis in Iceland. Br J Haematol 1967; 13:844.
- Horiguchi-Yamada J, Fujikawa T, Ideguchi H, et al. Hemolysis caused by CMV infection in a pregnant woman with silent elliptocytosis. Int J Hematol 1998; 68:311.
- Pajor A, Lehoczky D. Hemolytic anemia precipitated by pregnancy in a patient with hereditary elliptocytosis. Am J Hematol 1996; 52:240.
- Zarkowsky HS, Mohandas N, Speaker CB, Shohet SB. A congenital haemolytic anaemia with thermal sensitivity of the erythrocyte membrane. Br J Haematol 1975; 29:537.
- Bock I, Perrin J, Braun F, et al. [A case of hereditary pyropoikilocytosis with mild expression and delayed onset]. Ann Biol Clin (Paris) 2012; 70:483.
- Eng LI. Hereditary ovalocytosis and haemoglobin E-ovalocytosis in Malayan aborigines. Nature 1965; 208:1329.
- Genton B, al-Yaman F, Mgone CS, et al. Ovalocytosis and cerebral malaria. Nature 1995; 378:564.
- Garnett C, Bain BJ. South-East Asian ovalocytosis. Am J Hematol 2013; 88:328.
- Laosombat V, Dissaneevate S, Wongchanchailert M, Satayasevanaa B. Neonatal anemia associated with Southeast Asian ovalocytosis. Int J Hematol 2005; 82:201.
- Laosombat V, Viprakasit V, Dissaneevate S, et al. Natural history of Southeast Asian Ovalocytosis during the first 3 years of life. Blood Cells Mol Dis 2010; 45:29.
- Fucharoen G, Fucharoen S, Singsanan S, Sanchaisuriya K. Coexistence of Southeast Asian ovalocytosis and beta-thalassemia: a molecular and hematological analysis. Am J Hematol 2007; 82:381.
- Liu SC, Jarolim P, Rubin HL, et al. The homozygous state for the band 3 protein mutation in Southeast Asian Ovalocytosis may be lethal. Blood 1994; 84:3590.
- Picard V, Proust A, Eveillard M, et al. Homozygous Southeast Asian ovalocytosis is a severe dyserythropoietic anemia associated with distal renal tubular acidosis. Blood 2014; 123:1963.
- Bruce LJ, Wrong O, Toye AM, et al. Band 3 mutations, renal tubular acidosis and South-East Asian ovalocytosis in Malaysia and Papua New Guinea: loss of up to 95% band 3 transport in red cells. Biochem J 2000; 350 Pt 1:41.
- King MJ, Telfer P, MacKinnon H, et al. Using the eosin-5-maleimide binding test in the differential diagnosis of hereditary spherocytosis and hereditary pyropoikilocytosis. Cytometry B Clin Cytom 2008; 74:244.
- Wilmotte R, Maréchal J, Morlé L, et al. Low expression allele alpha LELY of red cell spectrin is associated with mutations in exon 40 (alpha V/41 polymorphism) and intron 45 and with partial skipping of exon 46. J Clin Invest 1993; 91:2091.
- Mohandas N, Winardi R, Knowles D, et al. Molecular basis for membrane rigidity of hereditary ovalocytosis. A novel mechanism involving the cytoplasmic domain of band 3. J Clin Invest 1992; 89:686.
- Dhermy D, Feo C, Garbarz M, et al. Prenatal diagnosis of hereditary elliptocytosis with molecular defect of spectrin. Prenat Diagn 1987; 7:471.
- Knight J, Czuchlewski DR. Acquired elliptocytosis of myelodysplastic syndrome. Blood 2013; 121:572.
- Greenberg LH, Tanaka KR. Hereditary elliptocytosis with hemolytic anemia--a family study of five affected members. Calif Med 1969; 110:389.
- Medejel N, Garçon L, Guitton C, et al. Effect of subtotal splenectomy for management of hereditary pyropoikilocytosis. Br J Haematol 2008; 142:315.
- CLINICAL SYNDROMES
- Silent carrier
- Common hereditary elliptocytosis
- - Influence of extrinsic factors
- Neonatal period
- Disease-related alterations
- Hereditary pyropoikilocytosis
- Spherocytic elliptocytosis
- Southeast Asian ovalocytosis
- MAKING THE DIAGNOSIS
- When to suspect the diagnosis of HE
- Initial laboratory testing
- Ancillary laboratory testing
- Molecular diagnosis
- DIFFERENTIAL DIAGNOSIS
- Routine and supportive care
- FAMILY TESTING AND PRENATAL COUNSELING
- SUMMARY AND RECOMMENDATIONS