eMedicine Specialties > Pediatrics: General Medicine > Hematology

Hereditary Elliptocytosis and Related Disorders

Author: Richard H Sills, MD, Professor of Pediatrics, Upstate Medical University
Coauthor(s): Mandy Meck, MD, Assistant Professor, Department of Pediatrics, University of Virginia School of Medicine; Consulting Staff, Department of Pediatrics, Division of Hematology/Oncology, Carilion Roanoke Community Hospital
Contributor Information and Disclosures

Updated: Sep 26, 2008

Introduction

Background

Hereditary elliptocytosis (HE) and its variants are congenital hemolytic disorders in which erythrocytes are either elongated into a cigar or oval shape or are poikilocytic and bizarrely shaped.¹ Its transmission has usually been described as autosomal dominant. Rare de novo mutations have been described.

These disorders are characterized by clinical, biochemical, and genetic heterogeneity. At least 4 genetic loci have been implicated in the pathogenesis of these disorders. Clinical manifestations range from an asymptomatic carrier state to severe hemolytic anemia. Members of the same family may exhibit different clinical courses, and an individual's frequency and severity of hemolysis may change with time. Most patients with hereditary elliptocytosis or its variants lead healthy lives.

Pathophysiology

Hereditary elliptocytosis and its related disorders are caused by mutations that disrupt the RBC cytoskeleton, a multiprotein complex responsible for the elasticity and durability of the circulating erythrocytes. Media file 1 depicts the complexity of the RBC membrane. Spectrin tetramers form a large part of the cytoskeletal framework and are composed of heterodimers of alpha and beta subunits. These are tethered to the plasma membrane proteins AE1 (band 3) and glycophorin C through the ankyrin/protein 4.2 complex and through protein 4.1R and its associated actin filaments.

Mutations that disrupt the formation of spectrin tetramers result in hereditary elliptocytosis. The circulating erythrocytes undergo a progressive transformation from a normal discocyte to an elliptocyte. Approximately 65% of cases of hereditary elliptocytosis are the result of mutations of alpha spectrin, 30% are the result of mutations of beta spectrin, and 5% are the result of mutations of protein 4.1R.² The result of these mutations is a mechanically unstable membrane less tolerant of shear stress that is susceptible to permanent deformation. 

RBC precursors in common hereditary elliptocytosis are round but become more elliptical as they age. Elliptocytes and poikilocytes are postulated to be permanently stabilized in their abnormal shape because the weakened skeletal interactions facilitate skeletal reorganization after prolonged or repetitive cellular deformation. This may result in hemolytic anemia with RBC fragmentation. Splenic sequestration is the dominant cause of the decreased survival of these abnormal red cells. 

Some of the more severe forms of hereditary elliptocytosis are associated with poikilocytosis. Hereditary elliptocytosis represents a spectrum of disorders with asymptomatic carriers and mild hereditary elliptocytosis at one end and with severe hereditary elliptocytosis and hereditary pyropoikilocytosis (HPP) at the other. More severe cases likely result from coinheritance of a typical hereditary elliptocytosis mutation and a relatively common but weak alpha gene allele that results in clinically apparent hemolytic anemia.

HPP is a subset of hereditary elliptocytosis due to homozygous or compound heterozygous mutations in spectrum that result in severe abnormalities of spectrin.³  HPP is characterized by bizarre RBC morphology similar to that seen in thermal burns. Notable blood smear findings include fragmented erythrocytes, microspherocytes, and elliptocytes. The RBCs demonstrate features of decreased deformability and increased membrane fragmentation.

Southeast Asian ovalocytosis is very common in areas where malaria is endemic. It is unique because a single mutation of band 3 is responsible for the defect. Hemolysis is absent or minimal.

Frequency

United States

The frequency of this disorder ranges from 1 case per 5000 population to 1 case per 10,000 population among whites.

International

Worldwide, the incidence is estimated to be 1 case per 2000-4000 individuals. It is more common in regions where malaria is endemic; the prevalence in West Africa approaches 2%. The true incidence is unknown because the clinical severity of hereditary elliptocytosis is heterogeneous, and many patients are asymptomatic.

The incidence of Southeast Asian ovalocytosis ranges from 5-25% in Melanesia, Philippines, Indonesia, and southern Thailand.

Mortality/Morbidity

Morbidity in these disorders depends on the frequency and degree of hemolytic anemia. The clinical phenotype ranges from asymptomatic carrier status to severe transfusion-dependent, and even fatal, hemolytic anemia. Individuals with chronic hemolysis may have complications such as jaundice, splenomegaly, and early gallbladder disease. Mortality is rare.

Race

Hereditary elliptocytosis and HPP are more common in individuals of African, Mediterranean, and Southeast Asian descent, presumably because elliptocytes confer some resistance to malaria.

Sex

No sex predilection is reported.

Clinical

History

Hereditary elliptocytosis clinical presentation widely varies. Most patients are asymptomatic, and the diagnosis is usually made incidentally when a blood smear is examined. Asymptomatic patients are heterozygous for the disease and are classified as having mild or common hereditary elliptocytosis (HE). Approximately 10% of patients have moderate-to-severe anemia, with intermittent episodes of acute hemolysis with jaundice and splenomegaly. Patients with severe hereditary elliptocytosis or hereditary pyropoikilocytosis (HPP) are almost always homozygotes or are compound heterozygotes. These patients are usually transfusion dependent and often require palliative splenectomy.

• Common or mild hereditary elliptocytosis
  • Common hereditary elliptocytosis is rarely symptomatic in the neonatal period. Severe hemolytic anemia with poikilocytosis and jaundice almost never occur.
  • Typically, elliptocytes do not appear in the blood until the patient is aged 4-6 months.
  • Even when neonatal hemolysis is severe, the symptoms typically resolve by the time the patient is aged 6-12 months, and the anemia improves.
  • In children and adults, common hereditary elliptocytosis is usually asymptomatic or associated with mild hemolytic anemia, although moderate or even severe hemolysis occasionally occurs.
  • The degree of hemolysis does not correlate with the percentage of elliptocytes seen in the blood.
  • The severity of hemolysis in common hereditary elliptocytosis varies not only among different kindreds but also within given families.
• Severe hereditary elliptocytosis and HPP
  • In general, patients with homozygous hereditary elliptocytosis or HPP have symptomatic hemolytic anemia that requires transfusion support and eventual splenectomy.
  • Patients with HPP typically present in the early newborn period with severe hemolytic anemia with RBC fragmentation, poikilocytosis, elliptocytosis, and microspherocytosis, as evident on peripheral blood smears.
  • Neonatal hyperbilirubinemia and severe anemia in the first few months of life are the typical presenting signs.
  • Complications of severe anemia, including splenomegaly, growth retardation, frontal bossing, and early gallbladder disease, are common.
  • HPP in infants is likely to gradually evolve into more typical mild hereditary elliptocytosis with concomitant improvement of symptoms and anemia.
• Southeast Asian ovalocytosis
  • Southeast Asian ovalocytosis (stomatocytic elliptocytosis) is a benign disorder in which erythrocytes have a broad oval shape. Stomatocytes are occasionally present.
  • Hemolysis is minimal or absent. However, the disorder appears to decrease the risk of malaria parasitemia and the clinical severity of malaria.
  • This condition occurs in as many as 15% of the indigenous populations of Malaysia and Papua, New Guinea.

Physical

Most patients have normal physical examination findings. In patients with illnesses, evaluate for signs of cardiovascular compromise, and monitor growth parameters on a yearly basis. Patients undergoing hemolysis may have pallor, jaundice, or splenomegaly. Patients with severe neonatal hereditary elliptocytosis or HPP may exhibit signs of chronic anemia, such as frontal bossing, failure to thrive, and splenomegaly.

Causes

Hereditary elliptocytosis and its variants are predominantly inherited in an autosomal dominant fashion. Spontaneous mutations have also been reported.

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