AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Dresbach first described hereditary elliptocytosis (HE) in 1904. HE and its variants are rare congenital hemolytic disorders in which erythrocytes are either elongated into a cigar or oval shape or poikilocytic and bizarrely shaped.

The disorder is transmitted as an autosomal dominant trait and 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 HE or its variants lead healthy lives.

Pathophysiology

HE and its related disorders are caused by mutations that disrupt the red blood cell cytoskeleton, a multiprotein complex responsible for the elasticity and durability of the circulating erythrocytes. The diagram in Image 1 depicts the complexity of the red blood cell membrane. Spectrin tetramers form a large part of the skeletal 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 HE. These qualitative defects create a red blood cell membrane that is less tolerant of shear stress and more susceptible to permanent deformation. A few mutations of the alpha-spectrin subunit are responsible for most cases of HE. HE also occurs with deficiencies in protein 4.1 or glycophorin C or when defects of band 3 protein or beta-spectrin impair ankyrin binding.

The principal functional consequence of the spectrin mutations is a weakening or disruption of the 2-dimensional integrity of the membrane skeleton. These horizontal membrane defects lead to mechanical instability, which can be sufficient to cause hemolytic anemia with red blood cell fragmentation. How elliptocytes are formed is unclear. Red blood cell precursors in common HE 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.

Hereditary pyropoikilocytosis (HPP) is thought to result from co-inheritance of a mutation that impairs self-association of spectrin and causes HE and a second mutation that results in quantitative spectrin deficiency. HPP is characterized by bizarre red blood cell morphology similar to that seen in thermal burns. Notable blood smear findings include fragmented erythrocytes, microspherocytes, and elliptocytes. The red blood cells demonstrate features of decreased deformability and increased membrane fragmentation.

Some of the more severe forms of HE are associated with poikilocytosis, and approximately one third of family members of patients with HPP have mild HE. Many of these patients have identical genetic defects in spectrin. Perhaps HE represents a spectrum of disorders with asymptomatic carriers and mild HE at one end and with severe HE and HPP at the other. All involve elliptogenic mutations, but the amounts of spectrin production vary.

Frequency

International

Worldwide, the incidence of HE is estimated to be 1 case per 2000-4000 individuals. The true incidence is unknown because the clinical severity of HE is heterogeneous, and many patients are asymptomatic.

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

HE and HPP are more common in individuals of African and Mediterranean descent, presumably because elliptocytes confer some resistance to malaria. In some parts of Africa, HE is as common as 1 case per 100 individuals. One of the HE variants, Southeast Asian ovalocytosis (stomatocytic elliptocytosis), is present in as many as 15% of the indigenous populations of Malaysia and Papua, New Guinea.

Sex

HE and HPP have no reported sex predilection.

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

The clinical presentation of patients with HE is highly variable. Most patients are asymptomatic, and the diagnosis is made incidentally when a blood smear is examined. Asymptomatic patients are heterozygous for the disease and are classified as having mild or common HE. Less often, patients with otherwise mild symptomatology experience intermittent episodes of acute hemolysis with anemia, jaundice, and splenomegaly. Patients with severe HE or HPP are almost always homozygotes, or they have the HE mutation or this mutation plus deficient spectrin, respectively. These patients are usually transfusion dependent, and they often require palliative splenectomy.

• Common or mild HE
• • Common HE 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 HE 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 HE varies not only among different kindreds but also within given families.
• Severe HE and HPP
• • In general, patients with homozygous HE or HPP have symptomatic hemolytic anemia requiring transfusion support and eventual splenectomy.
  • Patients with HPP typically present in the early newborn period with severe hemolytic anemia with red blood cell 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 HE 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.
  • This condition occurs in as many as 15% of the indigenous populations of Malaysia and of 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 HE or HPP may exhibit signs of chronic anemia, such as frontal bossing, failure to thrive, and splenomegaly.

Causes

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

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Other Problems to be Considered

Pseudoelliptocytosis can be an artifact of blood film preparation. Pseudoelliptocytes would be seen primarily at the tapered edge of a smear instead of uniformly distributed. A wet preparation can be used to discern the true elliptical shape of HE versus the discoid shape of a normal erythrocyte.

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• Peripheral blood smear
• • The hallmark of HE is the presence of cigar-shaped elliptocytes on the peripheral blood smear. Elliptocytes are normochromic and normocytic and range from few to 100% of erythrocytes. Spherocytes, ovalocytes, stomatocytes, and fragmented cells may also be observed.
  • HPP erythrocytes are bizarrely shaped with fragmentation or budding. Morphology is similar to that seen in patients who have sustained severe thermal burns. Microspherocytosis is commonly found. Pyknocytes are prominent in blood smears of neonates with HPP.
• Controlled thermal stress test
• • Thermal instability of erythrocytes occurs in the severe variants of HE, including HPP.
  • These tests are generally not required to establish the diagnosis.
• CBC with reticulocyte count
• • A CBC reveals the degree of anemia if present. Most patients with HE are not anemic. A CBC is determined to evaluate the other cell lines. Their numbers are generally within the reference ranges, but they can be elevated if acute hemolysis is present.
  • The reticulocyte count in mild HE is typically less than 5%. In the severe forms of HE and in HPP, reticulocyte counts as high as 30% have been reported.
• Osmotic fragility tests: Osmotic fragility testing is not typically required, although results are within reference ranges in common HE and are increased in severe HE and HPP.
• DNA testing: Although a review of family history and the red blood cell morphology can usually confirm the diagnosis of HE or HPP, specialized testing is available. Testing includes cDNA and genomic DNA analyses and analysis of membrane proteins by using gel electrophoresis and spectrin-dimer self-association assays.
• Other laboratory tests: Measures of increased erythrocyte production and destruction could be evaluated, as in any hemolytic process. These include serum bilirubin and urinary urobilinogen levels, which are increased during hemolysis, and the serum haptoglobin level, which is decreased.

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical Care

Treatment is rarely indicated for patients with mild HE or its variants. In severe cases, occasional erythrocyte transfusions may be required.

• Daily folate is recommended for patients with significant hemolysis.
• The detection of gallstones is important, and patients older than 6 years should undergo abdominal ultrasonography if they are symptomatic.
• Observe patients with sporadic hemolysis for signs of decompensation during serious illnesses or conditions that exacerbate hemolysis.
• Pay special attention to viral illnesses such as parvovirus, which can cause transient red blood cell aplasia and sudden precipitous decreases in hemoglobin levels.
• Care for neonates as for any patient with hemolytic anemia.
• Phototherapy and exchange transfusion are warranted in cases of severe anemia and hyperbilirubinemia.

Surgical Care

Splenectomy has been palliative in severe cases of HE and HPP, and indications are the same as those for hereditary spherocytosis. Consider splenectomy in patients who have moderate-to-severe anemia with significant symptoms (eg, growth failure, skeletal changes, leg ulcers) and in older patients with vascular compromise to vital organs.

Splenectomy is rarely necessary in the first 2 years of life; if possible, avoid it in patients younger than 5 years because of the risk of pneumococcal disease. In most neonates with HE and HPP, even those with severe hemolytic anemia in the perinatal period, the disease evolves to mild HE. For this reason and because of the substantial risk of overwhelming bacterial septicemia (especially in the first 5 years of life), postpone splenectomy until it is strictly indicated.

After splenectomy, most patients with HE or HPP have increased hemoglobin levels, decreased reticulocyte counts, and improved symptoms.

Administer pneumococcal vaccines before the procedure; both conjugated and polysaccharide vaccines may be indicated and ensure that the Haemophilus influenzae vaccine has also been administered. Patients who undergo splenectomy need lifelong antibiotic prophylaxis to prevent postoperative infections caused by encapsulated bacteria.

Consultations

Because these disorders are rare, consult a pediatric hematologist for the evaluation and management of hematologic manifestations.

Diet

No dietary restrictions are indicated.

Activity

No restrictions on activity are indicated, unless a substantial splenomegaly is present. A risk of splenic rupture is associated with contact sports.

MEDICATION

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

The only medication routinely used in the treatment of HE in patients with significant hemolysis is folic acid. Patients undergoing splenectomy require pneumococcal (nonconjugated vaccine, as well as conjugated vaccine, if not already given, and H influenzae vaccine, if not already given) before the procedure and lifelong prophylactic antibiotics. Details of presplenectomy and postsplenectomy care are beyond the scope of this article.

Drug Category: Vitamins

Vitamins are essential for normal DNA synthesis, and they are consumed during times of increased red blood cell turnover.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Further Inpatient Care

• Inpatient care is rarely required.

Further Outpatient Care

• The frequency of outpatient visits depends on the clinical picture and the severity of hemolytic disease. In general, annual examinations with an evaluation of CBC and reticulocyte count suffice. See patients on an as-needed basis to evaluate for signs of increased hemolysis such as pallor or jaundice.

In/Out Patient Meds

• Patients who have significant hemolytic anemia should take 1 mg of folic acid daily to replenish their stores and to support red blood cell production.

Deterrence/Prevention

• Offer genetic counseling to all patients with HE or its variants.

Complications

• Hemolytic anemia is the primary complication of HE and HPP. The severity is extremely variable, but some patients require erythrocyte transfusions.
• Transient pure red blood cell aplasia has been reported in patients with sporadic hemolysis. The causes seem to be identical to those of other hemolytic diseases, with parvovirus being the most common cause.
• Patients requiring blood transfusions are at risk for transfusion reactions and the transmission of viral or other infections.
• Patients who have significant hemolytic disease are also at risk for gallstones secondary to chronic hyperbilirubinemia. If symptomatic, patients older than 6 years should undergo ultrasonographic evaluations to assess the gallbladder.
• Splenic rupture is a potential but rare event, if substantial splenomegaly is present.

Prognosis

• The prognosis for patients with HE and related disorders is good; patients should have a normal life expectancy.

Patient Education

• Educate patients and their parents about the genetic factors of the disease.
• Educate patients and their parents about the signs and symptoms of hemolysis and anemia and about when they should call their physician. Education should include training about how to recognize signs of splenic sequestration and how to palpate the size of the spleen.
• Educate patients requiring splenectomy about the risks of infection and about the indications for prophylactic antibiotic therapy and vaccinations. Patients should know when to seek medical attention for fever if they have significant hemolysis or have undergone splenectomy.
• Patients should know the signs and symptoms associated with gallstones, and they should understand that they are at increased risk if significant hemolysis is present.
• Patients with hereditary elliptocytosis should be counseled that their offspring could have severe hemolytic anemia in the newborn period that requires exchange transfusion of red blood cells.
• If splenomegaly is substantial, patients should be counseled concerning the risk of abdominal trauma and potential splenic rupture or subcapsular hematoma.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Failure to educate patients and their families about the infectious complications of splenectomy
• Failure to provide genetic counseling
• Failure to warn patients about the risk of splenic rupture in association with splenomegaly

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Schematic diagram of the red blood cell membrane showing the interactions of various proteins involved in the pathogenesis of hereditary elliptocytosis.
	View Full Size Image
Media type:  Image

Media file 2:  Cigar-shaped erythrocytes seen in hereditary elliptocytosis. Courtesy of Jean A. Shafer, BS, MA, Assistant Professor of Hematology and Pathology at the University of Rochester School of Medicine and Dentistry.
	View Full Size Image
Media type:  Image

Media file 3:  Bizarre red blood cell morphology seen in hereditary pyropoikilocytosis. Courtesy of Jean A. Shafer, BS, MA, Assistant Professor of Hematology and Pathology at the University of Rochester School of Medicine and Dentistry.
	View Full Size Image
Media type:  Image

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

• Christensen RD. Hematologic Problems of the Neonate. 2000;231-233.
• Floyd PB, Gallagher PG, Valentino LA, et al. Heterogeneity of the molecular basis of hereditary pyropoikilocytosis and hereditary elliptocytosis associated with increased levels of the spectrin alpha I/74-kilodalton tryptic peptide. Blood. Sep 1 1991;78(5):1364-72. [Medline]. [Full Text].
• Gallagher PG. Hereditary elliptocytosis: spectrin and protein 4.1R. Semin Hematol. Apr 2004;41(2):142-64.
• Gallagher PG, Lux SE. Disorders of the Erythrocyte Membrane. Nathan and Oski's Hematology of Infancy and Childhood. 2003;617-632.
• Lanzkowsky P. Manual of Pediatric Hematology and Oncology. 2nd ed. 1995;108-109.
• Lilleyman JS, Hann IM, Blanchette VS. Pediatric Hematology. 2nd ed. 1999;266-271.
• Miraglia del Giudice E, Perrotta S, Sannino E, et al. Molecular heterogeneity of hereditary elliptocytosis in Italy. Haematologica. Sep-Oct 1994;79(5):400-5. [Medline].
• Stamatoyannopoulos G, Majerus PW, Perlmutter RM. The Molecular Basis of Blood Diseases. 3rd ed. 2001;297-298.

Article Last Updated: Jun 22, 2006