eMedicine Specialties > Pediatrics: General Medicine > Hematology

Hereditary Elliptocytosis and Related Disorders

Richard H Sills, MD, Professor of Pediatrics, Upstate Medical University
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

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.

Differential Diagnoses

Other Problems to Be Considered

Elliptocytosis can be seen in a wide variety of disorders as noted above. However, the number of elliptocytes seen is usually considerably less than that seen in hereditary elliptocytosis (HE).

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 hereditary elliptocytosis versus the discoid shape of a normal erythrocyte.

Workup

Laboratory Studies

• Peripheral blood smear
  • The hallmark of hereditary elliptocytosis (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.
  • Poikilocytosis (variation in cell shape) and erythrocyte fragmentation in addition to elliptocytosis are a feature of patients with severe anemia.
  • Hereditary pyropoikilocytosis (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 hereditary elliptocytosis, including HPP.
  • These tests are not generally required to establish the diagnosis.
• CBC count with reticulocyte count
  • A CBC count reveals the degree of anemia if present. Only 10% of patients are anemic. A CBC count is determined to evaluate the other cell lines. Their numbers are generally within the reference ranges but can be elevated if acute hemolysis is present.
  • The reticulocyte count in mild hereditary elliptocytosis is typically less than 5%. In the severe forms of hereditary elliptocytosis 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 hereditary elliptocytosis and are increased in severe hereditary elliptocytosis and HPP.
• DNA testing: Although a review of family history and the RBC morphology can usually confirm the diagnosis of hereditary elliptocytosis or HPP, specialized testing is available. Testing includes complementary DNA 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

Medical Care

Treatment is rarely indicated for patients with mild hereditary elliptocytosis (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 RBC 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 hereditary elliptocytosis and hereditary pyropoikilocytosis (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 overwhelming bacterial septicemia. In most neonates with hereditary elliptocytosis and HPP, even those with severe hemolytic anemia in the perinatal period, the disease evolves to mild hereditary elliptocytosis. 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 hereditary elliptocytosis 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 depending on the patient's age. Ensure that the Haemophilus influenzae vaccine has also been administered. Conjugated meningococcal vaccine (MCV4) should also be given if the child is 2 years of age or older. Patients who undergo splenectomy should be placed on antibiotic prophylaxis to prevent postoperative infections caused by encapsulated bacteria. The duration of such therapy remains controversial but should last until at least age 5 years and should be no less than one year in duration. In children, the duration is typically considerably longer.

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

The only medication routinely used in the treatment of hereditary elliptocytosis (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.

Vitamins

Vitamins are essential for normal DNA synthesis and are consumed during times of increased RBC turnover.

Folic acid (Folvite)

Important cofactor for enzymes used in production of RBCs.

Dosing

Adult

1 mg PO qd

Pediatric

Administer as in adults

Interactions

Increase in seizure frequency and subtherapeutic levels of phenytoin reported when used concurrently

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Some products may contain benzyl alcohol as a preservative (associated with a fatal gasping syndrome in premature infants); resistance to treatment may occur in alcoholism and deficiencies of other vitamins

Follow-up

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 count and reticulocyte count suffice. See patients on an as-needed basis to evaluate for signs of increased hemolysis such as pallor or jaundice.

Inpatient & Outpatient Medications

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

Deterrence/Prevention

• Offer genetic counseling to all patients with hereditary elliptocytosis (HE) or its variants.

Complications

• Hemolytic anemia is the primary complication of hereditary elliptocytosis and hereditary pyropoikilocytosis (HPP). The severity widely varies, but some patients require erythrocyte transfusions.
• Transient pure RBC aplasia has been reported in patients with sporadic hemolysis. The causes seem to be identical to those of other hemolytic diseases; parvovirus is 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 hereditary elliptocytosis 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 RBCs.
• If splenomegaly is substantial, patients should be counseled concerning the risk of abdominal trauma and potential splenic rupture or subcapsular hematoma.

Miscellaneous

Medicolegal 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

Media file 1: Schematic diagram of the components of the red cell membrane. Hereditary elliptocytosis can result from defects of alpha or beta spectrin or from a defective spectrin-actin-protein 4.1R junctional complex.

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.

Media file 3: Bizarre RBC 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.

References

1. Delaunay J. The molecular basis of hereditary red cell membrane disorders. Blood Rev. Jan 2007;21(1):1-20. [Medline].

2. Gallagher PG. Hereditary elliptocytosis: spectrin and protein 4.1R. Semin Hematol. Apr 2004;41(2):142-64. [Medline].

3. 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].

4. Christensen RD. Hematologic Problems of the Neonate. 2000:231-233.

5. Gallagher PG, Lux SE. Disorders of the erythrocyte membrane. In: Nathan and Oski's Hematology of Infancy and Childhood. 2003:617-32.

6. Lanzkowsky P. Manual of Pediatric Hematology and Oncology. 2^nd ed. 1995:108-9.

7. Lilleyman JS, Hann IM, Blanchette VS. Pediatric Hematology. 2^nd ed. 1999:266-71.

8. 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].

9. Quigley M, Linfesty RL, Bethel K, Sharpe R. Stubby elliptocytes are an invariable feature of leukoerythroblastosis. Blood. Mar 15 2007;109(6):2666. [Medline].

10. Stamatoyannopoulos G, Majerus PW, Perlmutter RM. The Molecular Basis of Blood Diseases. 3^rd ed. 2001:297-8.

Keywords

hereditary elliptocytosis, HE, hereditary pyropoikilocytosis, HPP, hemolytic anemia, Southeast Asian ovalocytosis, stomatocytic elliptocytosis, malaria, jaundice, splenomegaly, early gallbladder disease, neonatal hyperbilirubinemia, growth retardation, chronic anemia, frontal bossing, failure to thrive

Contributor Information and Disclosures

Author

Richard H Sills, MD, Professor of Pediatrics, Upstate Medical University
Richard H Sills, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American Society of Hematology, and American Society of Pediatric Hematology/Oncology
Disclosure: Nothing to disclose.

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
Mandy Meck, MD is a member of the following medical societies: American Academy of Pediatrics and American Society of Hematology
Disclosure: Nothing to disclose.

Medical Editor

Sharada A Sarnaik, MB, BS, Professor of Pediatrics, Wayne State University School of Medicine; Director, Sickle Cell Center, Attending Hematologist/Oncologist, Children's Hospital of Michigan
Sharada A Sarnaik, MB, BS is a member of the following medical societies: American Association of Blood Banks, American Association of University Professors, American Society of Hematology, American Society of Pediatric Hematology/Oncology, New York Academy of Sciences, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from broker recommendation; Avanir Pharma Stock Investment from broker recommendation

Managing Editor

Gary D Crouch, MD, Program Director of Pediatric Hematology-Oncology Fellowship, Department of Pediatrics, Associate Professor, Uniformed Services University of the Health Sciences
Gary D Crouch, MD is a member of the following medical societies: American Academy of Pediatrics and American Society of Hematology
Disclosure: Nothing to disclose.

CME Editor

Helen SL Chan, MBBS, FRCP(C), FAAP, Senior Scientist, Research Institute; Professor, Division of Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Canada
Helen SL Chan, MBBS, FRCP(C), FAAP is a member of the following medical societies: American Academy of Pediatrics, American Association for Cancer Research, American Society of Hematology, and Royal College of Physicians and Surgeons of Canada
Disclosure: Nothing to disclose.

Chief Editor

Max J Coppes, MD, PhD, MBA, Executive Director, Center for Cancer and Blood Disorders, Children's National Medical Center, Washington, DC; Professor of Medicine, Oncology, and Pediatrics, Georgetown University
Max J Coppes, MD, PhD, MBA is a member of the following medical societies: American Association for Cancer Research, American Society of Pediatric Hematology/Oncology, and Society for Pediatric Research
Disclosure: Nothing to disclose.

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