History
Hereditary elliptocytosis (HE) is a heterogeneous group of disorders that shares the common feature of generally having more than 25% elliptical red blood cells (RBCs). Because specific molecular lesions do not necessarily correlate with clinical manifestations, a morphologic classification has been devised. The three commonly identified morphologic variants are common HE, spherocytic elliptocytosis, and Southeast Asian ovalocytosis (SAO, also known as stomatocytic elliptocytosis). Common HE can be further subcategorized on the basis of clinical features.
Common HE
Common HE is the most prevalent form of HE and includes the following subcategories:
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Typical HE (mild HE)
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A silent carrier state
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Hereditary pyropoikilocytosis (HPP)
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Neonatal poikilocytosis
In general, symptoms are rare because even when hemolysis is present, most patients have compensated hemolysis. However, patients with clinically significant hemolysis may have symptoms related to anemia; that is particularly true of homozygotes and those with HPP.
In otherwise asymptomatic patients, hemolysis may occasionally increase because of intercurrent infections (eg, hepatitis, infectious mononucleosis, malaria), renal transplant rejection, vitamin B-12 deficiency, or even normal pregnancy. Transfusion support may be necessary during hemolysis.
The most common clinical form of HE is typical HE, also known as mild HE or heterozygous common HE. Patients are asymptomatic, and the disease is incidentally diagnosed because of abnormal results on laboratory tests (ie, peripheral smears). Patients do not have anemia, though all of the peripheral smear may show prominent elliptocytosis.
The silent carrier state in HE is associated with normal peripheral smear and no anemia. Patients are asymptomatic, and the condition is detected by laboratory testing of membrane cytoskeletal properties that is performed during pedigree analysis.
HPP is considered the most severe type of HE and manifests during infancy. Most patients are of African origin, though cases have been reported in individuals of Arabian or Caucasian descent. The name is derived from similarities in the morphology of blood smears of HPP and in those of patients with thermal burns; that is, spherocytes are more abundant than elliptocytes. As opposed to neonatal poikilocytosis, the hemolytic anemia in HPP is lifelong. Parents of patients with HPP may have typical HE, but in general, all first-degree relatives including parents are clinically and hematologically healthy.
In neonatal poikilocytosis, which occurs almost exclusively in African-American families, newborns and infants have severe hemolytic anemia that typically resolves after the first year of life. Transfusions and phototherapy may be required during severe hemolytic anemia and jaundice. The resolution of symptoms after a year helps distinguish neonatal poikilocytosis from HPP.
Spherocytic elliptocytosis
Spherocytic elliptocytosis is also known as spherocytic HE, HE with spherocytosis, or hereditary hemolytic ovalocytosis. Unlike HPP, which is generally an autosomal recessive disorder, spherocytic elliptocytosis is an autosomal dominant disorder. This form is most commonly observed in individuals of European descent, particularly Italians. It is often associated with clinically apparent mild to moderate hemolysis.
Southeast Asian ovalocytosis
Also known as stomatocytic elliptocytosis, SAO is a variant that commonly occurs in malaria-endemic Southeast Asia—namely, Indonesia, Malaysia, Melanesia, New Guinea, and the Philippines. [2] The mode of transmission is autosomal dominant. Only heterozygous conditions are reported, and the homozygous state is thought to be lethal in utero. Of note, SAO confers resistance against Plasmodium falciparum infection, likely because of alterations in band 3, which is one of the malaria receptors. SAO is usually associated with mild or no hemolysis but is associated with renal tubular acidosis.
Physical Examination
Most patients are asymptomatic and do not have any obvious physical signs. findings in patients with clinically significant hemolysis include the following:
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Splenomegaly
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Pallor
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Scleral icterus
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Leg ulcers (rare)
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Hereditary elliptocytosis: Peripheral blood smear reveals cigar-shaped erythrocytes (elliptocytes). 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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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.
Tables
| Phenotype | Gene | Inheritance |
|---|---|---|
| Disorders with RBC membrane structural defect | ||
| HE Type 1 | EPB41 | AD |
| HE Type 2 | SPTA1 | AD |
| HE Type 3 | SPTB | AD |
| HPP | SPTA1 | AR |
| SAO | SLC4A1 | AD |
| HS Type 1 | ANK1 | AD/AR |
| HS Type 2 | SPTB | AD |
| HS Type 3 | SPTA1 | AR |
| HS Type 4 | SLC4A1 | AD |
| HS Type 5 | EPB42 | AR |
| Disorders with altered RBC membrane permeability | ||
| DHS 1 | PIEZO1 | AD |
| DHS 2 | KCNN4 | AD |
| OHS | RHAG | AD |
| CHC | ABCB6 | AD |
| FP | SLC4A1 | AD |
AD: autosomal dominant; AR: autosomal recessive; CHC: cryohydrocytosis; DHS: dehydrated hereditary stomatocytosis; FP: familial pseudohyperkalemia; HE: hereditary elliptocytosis; HPP: hereditary pyropoikilocytosis; HS: hereditary spherocytosis; OHS: overhydrated hereditary stomatocytosis; SAO: Southeast Asian ovalocytosis
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