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Pediatric Hereditary Elliptocytosis and Related Disorders Workup

  • Author: Trisha Simone Tavares, MD, FAAP; Chief Editor: Max J Coppes, MD, PhD, MBA  more...
 
Updated: Oct 16, 2013
 

Laboratory Studies

Peripheral blood smear

The hallmark of hereditary elliptocytosis is the presence of elliptocytes on the peripheral blood smear (see image below).

Cigar-shaped erythrocytes seen in hereditary ellip 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.

Elliptocytes are normochromic and normocytic and may constitute few or all of the patient’s erythrocytes. Spherocytes, ovalocytes, stomatocytes, and fragmented cells may also be observed.

Poikilocytosis (variation in cell shape) and erythrocyte fragmentation are seen in addition to elliptocytosis in patients with severe variants of hereditary elliptocytosis.

Hereditary pyropoikilocytosis erythrocytes are bizarrely shaped (see image below) with fragmentation or budding. The mean cell volume is low, owing to the presence of cell fragments.

Bizarre RBC morphology seen in hereditary pyropoik 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.

Morphology is similar to that seen in patients who have sustained severe thermal burns. Microspherocytosis is commonly found. Distorted, contracted erythrocytes, known as pyknocytes, are prominent in blood smears of neonates with hereditary pyropoikilocytosis.

Parents of infants with signs of hereditary elliptocytosis/hereditary pyropoikilocytosis should undergo examination of their peripheral blood smears to aid in the diagnosis of their child.

CBC count with reticulocyte count

Hemoglobin assay reveals the degree of anemia, if present. A minority of patients with mild hereditary elliptocytosis are anemic.

The reticulocyte count in mild hereditary elliptocytosis is typically less than 5%. In the severe forms of hereditary elliptocytosis and in hereditary pyropoikilocytosis, reticulocyte counts as high as 30% have been reported. High levels of reticulocytosis may compensate for mild anemia.

Markers of hemolysis

Nonspecific markers of increased erythrocyte production and destruction could be evaluated, as in any hemolytic process. These include increased serum indirect bilirubin, increased urinary urobilinogen, increased serum lactate dehydrogenase, and decreased serum haptoglobin.

Osmotic fragility test

Osmotic fragility testing is not typically required. When performed, the results are normal in common hereditary elliptocytosis but reveal abnormal curves in severe hereditary elliptocytosis and in hereditary pyropoikilocytosis. Patients with spherocytic elliptocytosis also have abnormal results.

Controlled thermal stress test

Thermal instability of erythrocytes occurs in hereditary elliptocytosis. Cells fragment at a lower temperature than normal RBCs, and this fragmentation occurs after a shorter period of heating than expected. These tests may be used if membrane protein analysis is unavailable.

DNA testing

Genetic analysis can characterize the molecular defect that results in the clinical and laboratory findings. This is not readily available in all laboratories.

Multiple mutations have been identified. Description of the structure of the erythrocyte spectrin tetramerization domain complex has been accomplished and will further elucidate the structural abnormalities that result in clinically relevant mutations.[11]

Genetic analysis can explain clinical severity and inheritance patterns. For example, in patients with spectrin mutations, differences in clinical expression are partially related to the spectrin alpha-LELY polymorphism. If this mutation is present on the otherwise unaffected spectrin allele, the disease may be more severe because the concentration of the mutant allele is increased.

Demonstration of a deletion in the SLC4A1 gene is characteristic of Southeast Asian ovalocytosis.[12]

Spectrin oligomerization assay

The fraction of spectrin dimers in patients with alpha-spectrin defects correlates well with clinical severity. In individuals with hereditary pyropoikilocytosis and severe hereditary elliptocytosis, spectrin dimers are not converted to tetramers and high percentages of dimers are detected during this assay.[1]

Ektacytometry

Ektacytometry measures RBC deformability. An ektacytometer is a laser-diffraction viscometer in which deformability is measured as a continuous function of the osmolality of the suspending medium. The Omin point is the osmolality at which the minimum deformability index is reached and is related to the surface area–to-volume ratio of the cell. The Hyper point is the osmolality at which the minimum deformability index reaches half of its maximum value. The Hyper point is related to the internal viscosity of the cell and to its mechanical properties.

In hereditary elliptocytosis, ektacytometry shows decreased maximum deformability characterized by a trapezoidal curve with normal Omin and Hyper points. In hereditary pyropoikilocytosis, the maximum deformability is decreased and the Omin and Hyper points are shifted towards the left. In Southeast Asian ovalocytosis, the key finding is lack of deformability of the erythrocytes.[6]

Cation leak testing

Identification of the cation leak in patients who are thought to have hereditary stomatocytosis may be accomplished by comparing the concentration of potassium in the serum of fresh blood with the concentration of potassium in stored refrigerated blood.[13]

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Imaging Studies

In patients who are at risk for gallstones, gallbladder ultrasonography should be performed. In patients with severe anemia and congestive heart failure, cardiac echocardiography should be used.

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Contributor Information and Disclosures
Author

Trisha Simone Tavares, MD, FAAP Attending Physician, Department of Pediatrics, Section of Hematology/Oncology, Cardon Children's Medical Center

Trisha Simone Tavares, MD, FAAP is a member of the following medical societies: Children's Oncology Group

Disclosure: Nothing to disclose.

Coauthor(s)

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, American Society of Pediatric Hematology/Oncology

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Gary D Crouch, MD Associate Professor, Program Director of Pediatric Hematology-Oncology Fellowship, Department of Pediatrics, Uniformed Services University of the Health Sciences

Gary D Crouch, MD is a member of the following medical societies: American Academy of Pediatrics, American Society of Hematology

Disclosure: Nothing to disclose.

Chief Editor

Max J Coppes, MD, PhD, MBA Executive Vice President, Chief Medical and Academic Officer, Renown Heath

Max J Coppes, MD, PhD, MBA is a member of the following medical societies: American College of Healthcare Executives, American Society of Pediatric Hematology/Oncology, Society for Pediatric Research

Disclosure: Nothing to disclose.

Additional Contributors

Sharada A Sarnaik, MBBS Professor of Pediatrics, Wayne State University School of Medicine; Director, Sickle Cell Center, Associate Hematologist/Oncologist, Children's Hospital of Michigan

Sharada A Sarnaik, MBBS is a member of the following medical societies: American Society of Hematology, American Society of Pediatric Hematology/Oncology, New York Academy of Sciences, Society for Pediatric Research, Children's Oncology Group, American Academy of Pediatrics, Midwest Society for Pediatric Research

Disclosure: Nothing to disclose.

References
  1. Grace RF, Lux SE. Disorders of the Red Cell Membrane. Orkin SH, ed. Nathan and Oski's Hematology of Infancy and Childhood. 7th ed. Philadelphia, Pa: Saunders Elsevier; 2009. Chapter 15.

  2. Knight J, Czuchlewski DR. Acquired elliptocytosis of myelodysplastic syndrome. Blood. 2013 Jan 24. 121(4):572. [Medline].

  3. Barcellini W, Bianchi P, Fermo E, et al. Hereditary red cell membrane defects: diagnostic and clinical aspects. Blood Transfus. 2011 Jul. 9(3):274-7. [Medline]. [Full Text].

  4. Garnett C, Bain BJ. South-East Asian ovalocytosis. Am J Hematol. 2013 Apr. 88(4):328. [Medline].

  5. Soderquist C, Bagg A. Hereditary elliptocytosis. Blood. 2013 Apr 18. 121(16):3066. [Medline].

  6. Da Costa L, Galimand J, Fenneteau O, Mohandas N. Hereditary spherocytosis, elliptocytosis, and other red cell membrane disorders. Blood Rev. 2013 May 9. [Medline].

  7. Brugnara C, Platt OS. The Neonatal Erythrocyte and Its Disorders. Orkin SH, ed. Nathan and Oski's Hematology of Infancy and Childhood. 7th ed. Philadelphia, Pa: Saunders Elsevier; 2009.

  8. Rosanas-Urgell A, Lin E, Manning L, Rarau P, Laman M, Senn N. Reduced risk of Plasmodium vivax malaria in Papua New Guinean children with Southeast Asian ovalocytosis in two cohorts and a case-control study. PLoS Med. 2012. 9(9):e1001305. [Medline].

  9. Heeney M, Dover GJ. Orkin SH, ed. Nathan and Oski's Hematology of Infancy and Childhood. 7th ed. Philadelphia, Pa: Saunders Elsevier; 2009. Chapter 19.

  10. Luzzatoo L, Poggi V. Glucose-6-Phosphate Dehydrogenase Deficiency. Orkin SH, ed. Nathan and Oski's Hematology of Infancy and Childhood. 7th ed. Philadelphia, Pa: Saunders Elsevier; 2009. Chapter 17.

  11. Ipsaro JJ, Harper SL, Messick TE, Marmorstein R, Mondragon A, Speicher DW. Crystal structure and functional interpretation of the erythrocyte spectrin tetramerization domain complex. Blood. 2010 Jun 10. 115(23):4843-52. [Medline]. [Full Text].

  12. Wilder JA, Stone JA, Preston EG, Finn LE, Ratcliffe HL, Sudoyo H. Molecular population genetics of SLC4A1 and Southeast Asian ovalocytosis. J Hum Genet. 2009 Mar. 54(3):182-7. [Medline].

  13. King MJ, Bruce LJ, Dhermy D. Hemolytic Anemias Associated with Disorders of Erythrocyte Membrane and Cytoskeleton Proteins. Kottke-Marchant K, Davis BH, eds. Laboratory Hematology Practice. Oxford, UK: Wiley-Blackwell; 2012.

  14. Caprari P, Tarzia A, Mojoli G, Cianciulli P, Mannella E, Martorana MC. Hereditary spherocytosis and elliptocytosis associated with prosthetic heart valve replacement: rheological study of erythrocyte modifications. Int J Hematol. 2009 Apr. 89(3):285-93. [Medline].

 
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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.
Schematic diagram of the components of the RBC membrane. Hereditary elliptocytosis can result from defects of alpha or beta spectrin or from a defective spectrin-actin-protein 4.1R junctional complex.
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.
 
 
 
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