hereditary elliptocytosis

Hereditary elliptocytosis

Hereditary elliptocytosis refers to a group of rare inherited blood conditions where the red blood cells are elliptically shaped 1). The presence of elliptically shaped red cells on peripheral blood smear is a characteristic feature of hereditary elliptocytosis 2). Hereditary elliptocytosis is clinically and genetically heterogeneous disorder of the red cell membrane characterized by manifestations ranging from mild to severe transfusion-dependent hemolytic anemia but with the majority of patients being asymptomatic. While hereditary elliptocytosis has been described worldwide, it is more common in malaria‐endemic regions of West Africa with a prevalence approximately 2%  3). Hereditary elliptocytosis has a prevalence of 250-500 cases per million population in the US. However, the true incidence is unknown because many patients do not have any symptoms 4).

Hereditary elliptocytosis is typically inherited as an autosomal dominant disorder and the de novo mutations are rare 5). Hereditary elliptocytosis is caused by a genetic change in either the EPB41, SPTA1, or SPTB gene, and is inherited in an autosomal dominant pattern. Hereditary pyropoikilocytosis is a related condition with more serious symptoms, and is inherited in an autosomal recessive pattern. Most hereditary elliptocytosis is due to heterozygous mutations of genes that encode the α-spectrin (encoded by SPTA1), β-spectrin (encoded by SPTB), or protein 4.1 6). Hereditary elliptocytosis occurs in about 1 per 3000 individuals worldwide and presents heterogeneously ranging from asymptomatic carries to severe, life-threatening hemolytic anemia and splenomegaly 7). Hydrops fetalis in association with hereditary elliptocytosis has been reported in a few families. While an overwhelming majority of hereditary elliptocytosis cases are asymptomatic, 10% of patients present with moderate‐to‐severe anemia 8). Poikilocytes and fragmented red cells in addition to elliptocytes are a feature of red cell morphology in hereditary elliptocytosis individuals with moderate–to‐severe anemia. Typically, individuals heterozygous for an elliptocytic variant have asymptomatic elliptocytosis, while individuals with homozygous or compound heterozygous for hereditary elliptocytosis variants experience mild–to‐severe anemia.

Hereditary elliptocytosis symptoms vary from very mild to severe and can include fatigue, shortness of breath, gallstones, and yellowing of the skin and eyes (jaundice). Some people with this condition have an enlarged spleen. Diagnosis of hereditary elliptocytosis is made by looking at the shape of the red blood cells under a microscope. Treatment is usually not necessary unless severe anemia occurs. In severe cases, surgery to remove the spleen may decrease the rate of red blood cell damage. Hereditary elliptocytosis is generally not life-threatening.

Hereditary elliptocytosis causes

Hereditary elliptocytosis is caused by a genetic change in either the EPB41, SPTA1, or SPTB gene, and is inherited in an autosomal dominant pattern, with the exception of hereditary pyropoikilocytosis, which is generally autosomal recessive. With discovered mutation increasing, there may be still many unknown mutations can result in hereditary elliptocytosis 9). The mutated proteins in hereditary elliptocytosis increase the fragility of the erythrocytic membrane skeleton. The erythrocyte spectrin is a scaffold protein composed of 2 subunits, α-spectrin (encoded by SPTA1) and β-spectrin (encoded by SPTB), maintains the cellular shape, regulates the lateral mobility of integral membrane proteins, and provides structural support for the lipid bilayer 10). Mutations in SPTA1 are the most common pathogenesis of hereditary elliptocytosis, occurring in 65% of cases, followed by mutations in β-spectrin (30%) and protein 4.1R (5%) 11). In all these cases, the defects in spectrin or in protein 4.1R lead to a weakened lateral interactions of the spectrin‐based membrane skeleton.

When hereditary pyropoikilocytosis was originally described in 1975, it was thought to be a distinct entity due to the increased thermal sensitivity of the red cells and the unusual morphological features of red cells in these patients that mimicked those seen in blood smears of individuals with severe thermal burns 12). However, subsequent detailed molecular studies have shown that hereditary pyropoikilocytosis is a subset of hereditary elliptocytosis due to either homozygous or compound heterozygous mutations in the α‐spectrin gene leading to very severe disruption of spectrin self‐association 13).

Decreased membrane mechanical stability is a common feature of all forms of hereditary elliptocytosis. A modest decrease in membrane mechanically results in progressive transformation of discoid red cells to elliptocytes during red cell life span in circulation. More severe decrease in membrane mechanical stability leads to membrane fragmentation and generation of fragmented red cells with reduced membrane surface area. The fragmented red cells with decreased membrane surface area and increased sphericity are sequestered from circulation by the spleen leading to anemia. The extent of decrease in membrane mechanical stability is directly related to the severity of anemia. Splenectomy significantly decreases the severity of the anemia by increasing the life span of fragmented red cells.

Hereditary elliptocytosis symptoms

Hereditary elliptocytosis 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 are not necessarily correlated with clinical manifestations, a morphologic classification has been devised. The three commonly identified morphologic variants include common hereditary elliptocytosis, spherocytic elliptocytosis, and Southeast Asian ovalocytosis (also known as stomatocytic elliptocytosis). Common hereditary elliptocytosis can be further subcategorized on the basis of clinical features.

Most patients are asymptomatic and do not have any obvious physical signs. findings in patients with clinically significant hemolysis include the following:

  • Splenomegaly
  • Pallor
  • Scleral icterus
  • Leg ulcers (rare)

Common hereditary elliptocytosis

Common hereditary elliptocytosis is the most prevalent form of hereditary elliptocytosis and includes subcategories of typical hereditary elliptocytosis (mild hereditary elliptocytosis), a silent carrier state, hereditary pyropoikilocytosis, and neonatal poikilocytosis. Most patients with the common form of hereditary elliptocytosis are asymptomatic. Only 5-20% develop uncompensated hemolysis with anemia. 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, particularly among homozygotes and those with hereditary pyropoikilocytosis.

Other findings consistent with chronic hemolysis are splenomegaly, pigmented gallstones, leg ulcers, and elevated reticulocyte counts.

In otherwise asymptomatic patients, hemolysis may occasionally increase because of intercurrent infections (eg, hepatitis, infectious mononucleosis, and 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 hereditary elliptocytosis is typical hereditary elliptocytosis, also known as mild hereditary elliptocytosis or heterozygous common hereditary elliptocytosis. 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 hereditary elliptocytosis 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.

Hereditary pyropoikilocytosis is considered the most severe type of hereditary elliptocytosis and manifests during infancy. Most patients are of African origin, though cases have been reported in people of Arabian or Caucasian descent. The name is derived from similarities in the morphology of blood smears of hereditary pyropoikilocytosis 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 hereditary pyropoikilocytosis is lifelong. Parents of patients with hereditary pyropoikilocytosis may have typical hereditary elliptocytosis, 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 hereditary pyropoikilocytosis.

Spherocytic elliptocytosis

Spherocytic elliptocytosis is also known as spherocytic hereditary elliptocytosis, hereditary elliptocytosis with spherocytosis, or hereditary hemolytic ovalocytosis. This form is most commonly observed in individuals of European descent, particularly Italians.

It is often associated with clinically apparent mild to moderate hemolysis, with a peripheral smear showing both spherocytes and elliptocytes but no poikilocytes.

Unlike hereditary pyropoikilocytosis, which is generally an autosomal recessive disorder, spherocytic elliptocytosis is an autosomal dominant disorder.

Southeast Asian ovalocytosis

Also known as stomatocytic elliptocytosis, Southeast Asian ovalocytosis is a variant that commonly occurs in malaria-endemic Southeast Asia, namely, Indonesia, Malaysia, Melanesia, New Guinea, and the Philippines.

Features include the following:

  • Southeast Asian ovalocytosis is usually associated with mild or no hemolysis
  • On peripheral smears, red blood cells show a characteristic morphology with one or two transverse slits across the body of oval-shaped red blood cells.
  • Southeast Asian ovalocytosis is unique among elliptocytoses in that the membrane structure of the red blood cells is characterized by rigid stability rather than instability
  • Southeast Asian ovalocytosis is associated with renal tubular acidosis

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, Southeast Asian ovalocytosis confers resistance against Plasmodium falciparum infection, likely because of alterations in band 3, which is one of the malaria receptors.

Hereditary elliptocytosis diagnosis

Hereditary elliptocytosis can be diagnosed by looking at the shape of the red blood cells under the microscope (blood smear). Genetic testing can help as well 14). Hereditary elliptocytosis is sometimes diagnosed by chance when other conditions are suspected.

Hereditary elliptocytosis treatment

Treatment for hereditary elliptocytosis is often not necessary. A diet rich in folic acid or folic acid supplementation is recommended to avoid consequences of folate deficiency in a hemolytic state 15). Other supportive measures, such as blood transfusions, may be indicated if the anemia is severe. When symptoms are severe enough, some people with hereditary elliptocytosis will be treated with transfusion or even removal of the spleen (splenectomy) 16).

Hereditary elliptocytosis prognosis

Hereditary elliptocytosis is generally mild and very rarely life threatening 17).

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