Pediatric Hereditary Elliptocytosis and Related Disorders

Hereditary elliptocytosis and hereditary pyropoikilocytosis are congenital hemolytic disorders in which erythrocytes either are elongated into an oval form or are irregularly shaped (see images below).[1] Transmission is primarily via an autosomal dominant pattern, but de novo mutations, recessive inheritance, and X-linkage have also been described,[2] with next-generation sequencing (NGS) permitting a wider variety of mutations to be identified.[3]

These disorders are characterized by clinical, biochemical, and genetic heterogeneity. Numerous molecular defects have been implicated in the pathogenesis of these disorders. Clinical manifestations range from an asymptomatic carrier state to severe hemolytic anemia. Expressivity is variable, with members of the same family with the same genetic defect exhibiting different clinical courses. Additionally, an individual's frequency and severity of hemolysis may change with time.

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. RBCs must be adequately resilient and sufficiently flexible to withstand shearing forces as they pass through the microcirculation.

The normal RBC membrane consists of a lipid bilayer, which contains proteins and glycans.

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. Defects in horizontal interactions result in hereditary elliptocytosis.

The image seen below depicts the complexity of the RBC membrane.

A crystal structure of the spectrin tetramerization domain complex has been determined, and information gleaned from studying it is expected to further elucidate the molecular basis of hereditary hemolytic anemias.

In hereditary elliptocytosis, circulating erythrocytes undergo a progressive transformation from a normal discocyte to an elliptocyte. Most cases of hereditary elliptocytosis are the result of mutations of alpha spectrin or beta spectrin. A minority of cases are due mutations of protein 4.1R, ankyrin, or glycophorin C. The result of these mutations is a mechanically unstable membrane that is less tolerant of shear stress and susceptible to permanent deformation.

RBC precursors in common hereditary elliptocytosis are round but become more elliptical as they age. Normal RBCs also undergo repeated elliptical deformation during circulation. Normal erythrocytes, however, regain their discoid shape. Erythrocytes in hereditary elliptocytosis lack elasticity and remain elliptical. Elliptocytes and poikilocytes are postulated to be permanently fixed in their abnormal shape because the weakened membrane interactions facilitate skeletal reorganization after prolonged or repetitive cellular deformation. This results in mechanical instability and susceptibility to fragmentation and lysis. Splenic sequestration of these abnormal RBCs is the dominant cause of decreased erythrocyte survival in hereditary elliptocytosis.

Some of the more severe forms of hereditary elliptocytosis are associated with marked poikilocytosis or variation in RBC shape. This is deemed hereditary pyropoikilocytosis. Hereditary pyropoikilocytosis is characterized by bizarre RBC morphology similar to that seen in thermal burns. Blood smear findings are most notable for fragmented erythrocytes and microspherocytes. Elliptocytes are present but in fewer numbers. The RBCs demonstrate features of decreased deformability and increased membrane fragmentation.

Hereditary pyropoikilocytosis and more severe cases of hereditary elliptocytosis likely result from coinheritance of a typical hereditary elliptocytosis mutation and a relatively common but clinically silent alpha-spectrin gene allele alpha-LELY. This is homozygous or compound heterozygous inheritance.[2]

An acquired form of elliptocytosis has been identified in several bone marrow disorders, including fibrosis, myelophthisis, and myelodysplasia.[4]

Southeast Asian ovalocytosis is form of elliptocytosis. This condition is unique because a single mutation of band 3 (anion exchanger 1) is responsible for the defect. All individuals with Southeast Asian ovalocytosis are heterozygotes for band 3 gene mutations because the homozygous form is lethal in utero.

Frequency

United States

The true number of cases is unknown because the clinical severity of this group of disorders is heterogeneous and many patients are asymptomatic and without anemia. There is a strong association between hereditary elliptocytosis and hereditary pyropoikilocytosis in families. Patients with hereditary pyropoikilocytosis may have relatives with undiagnosed hereditary elliptocytosis.

Clinically apparent elliptocytic disorders are present in approximately 1 in 2000-4000 individuals.

International

Worldwide, the incidence varies widely. The conditions are seen in increased frequency in Southeast Asia, Africa, and the Mediterranean. It is most common in malaria-endemic regions. The prevalence of hereditary elliptocytosis in West Africa, for example, approaches 2%.[5] The prevalence of Southeast Asian ovalocytosis may be as high as 25% in several Southeast Asian ethnic groups. These groups are primarily found in the Philippines, southern Thailand, Malaysia, Papua New Guinea, Indonesia, Borneo, Brunei, Cambodia, and in native Australians and certain native South Africans.[6]

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 or hydrops fetalis. Individuals with chronic hemolysis may have complications such as jaundice, splenomegaly, aplastic crises, and early gallbladder disease. Southeast Asian ovalocytosis is homozygous lethal to fetuses. Otherwise, mortality is rare.

Race

Hereditary elliptocytosis and hereditary pyropoikilocytosis are more common in individuals of West African, Central African, Mediterranean, and Southeast Asian descent. This distribution parallels the geographic distribution of malaria.

Sex

No sex predilection is observed.

Age

This condition may present at any age with hemolytic anemia and the characteristic morphological abnormalities. In anemic pregnant women, it is important to diagnose hereditary elliptocytosis because neonates of affected women are at risk of clinically significant perinatal hemolysis with severe anemia and hyperbilirubinemia.[7] Hydrops fetalis may also occur.

The clinical presentation of hereditary elliptocytosis 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 condition and are classified as having mild or common hereditary elliptocytosis.

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 with hereditary pyropoikilocytosis are almost always homozygotes or compound heterozygotes. These patients are often transfusion dependent. Differences in clinical severity reflect manifestations of different mutations and are closely related to the extent of membrane surface area loss.[8]

All patients with conditions predisposing them hemolytic anemia are expected to be at risk of aplastic crisis during infection with parvovirus B-19.

Common or mild hereditary elliptocytosis

In neonates with common hereditary elliptocytosis, a precise diagnosis often cannot be established. The classic morphological findings may not be present.

Common hereditary elliptocytosis is rarely symptomatic in the neonatal period. Severe hemolytic anemia with poikilocytosis and jaundice may occasionally occur. Blood smear evaluation may reveal pyknocytes instead of elliptocytes. Pyknocytes are irregular, dense, distorted, spiculated RBCs similar to acanthocytes. Typically, elliptocytes do not appear in the blood until several months after birth.

Red blood cell survival is shorter than 120 days in neonates, particularly in premature neonates, so anemia may be severe. Anemia may be absent, however, if a persistent increase in reticulocyte production is able to compensate for hemolysis.[9]

Even when neonatal hemolysis is severe, this typically resolves by the time the patient is aged 12 months, and the anemia gradually improves.

Some neonates who present with moderate hemolysis and blood smear findings consistent with hereditary pyropoikilocytosis may have a course that gradually evolves into mild anemia with little or no hemolysis.

In children and adults, common hereditary elliptocytosis is usually asymptomatic or associated with mild sporadic hemolytic anemia.

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.

Spherocytic elliptocytosis

Spherocytic hereditary elliptocytosis is rare. The exact prevalence is unknown. Most patients have mild or moderate hemolysis. Blood smears show spherocytes, microspherocytes, and microelliptocytes. The elliptocyte percentage may be low.

Severe hereditary elliptocytosis and hereditary pyropoikilocytosis

Often, patients with homozygous hereditary elliptocytosis or hereditary pyropoikilocytosis have symptomatic hemolytic anemia that requires transfusion support and eventual splenectomy.

Many patients with hereditary pyropoikilocytosis present in the early newborn period with severe hemolytic anemia. Blood smears reveal RBC fragmentation, poikilocytosis, elliptocytosis, and microspherocytosis.

Neonatal hyperbilirubinemia and severe anemia in the first few months of life are typical.

Complications of severe anemia, including splenomegaly, growth retardation, frontal bossing, and early gallbladder disease, are common.

Southeast Asian ovalocytosis

Southeast Asian ovalocytosis is a mild form of elliptocytosis. Although this is a considered a benign disorder, neonates may experience hemolysis. The RBC membrane is rigid and hyperstable. Stomatocytes are RBCs with broad oval shapes and one or more stoma in a variety of orientations.[6] Hemolysis is minimal or absent outside of the newborn period.

Southeast Asian ovalocytosis confers some protection against Plasmodium falciparum and Plasmodium vivax infection. Individuals with Southeast Asian ovalocytosis have a significant reduction in the frequency and severity of cerebral malaria.[10]

Most patients have normal physical examination findings. Patients undergoing hemolysis may have signs of cardiovascular compromise, pallor, jaundice, and/or acute splenomegaly. Patients with severe forms may exhibit signs of chronic anemia, such as frontal bossing, failure to thrive, and chronic splenomegaly.

Adults may have skin ulcers.[11]

Hereditary elliptocytoses are inherited disorders. Some patients with bone marrow dysfunction have developed acquired hereditary elliptocytosis.[4]

Peripheral blood smear

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

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.

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.[13]

Genetic analysis can explain clinical severity and inheritance patterns.[14] 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.[15]

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.[2]

Ektacytometry

Ektacytometry measures RBC deformability.[16] 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.[8] Ektacytometry used in combination with gene sequencing, although not readily available, can help to clarify unusual variants.[17]

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.[18]

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.

Treatment is rarely indicated for patients with mild variants of hereditary elliptocytosis. In severe cases, occasional erythrocyte transfusions may be required.

Daily folic acid supplementation is recommended for patients with hemolysis.

Observe patients with sporadic hemolysis for signs of decompensation during serious illnesses or when known to have conditions that exacerbate hemolysis.

Pay special attention to viral illnesses such as parvovirus B-19 infection, which can cause transient RBC aplasia and sudden precipitous decreases in hemoglobin levels. Reticulocytopenia will be present.

Care for neonates as for any patient with hemolytic anemia. The diagnosis is rarely made in the neonatal period.

Phototherapy and exchange transfusion are warranted in cases of severe anemia and hyperbilirubinemia.

Anticipate symptomatic hemolysis in previously asymptomatic patients who undergo prosthetic heart valve replacement.[19]

The spleen removes abnormal RBCs from circulation. Splenectomy reduces the severity of anemia by increasing the circulatory life span of fragmented RBCs.

Splenectomy has been helpful in severe cases of hereditary elliptocytosis and hereditary pyropoikilocytosis. The 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. Subtotal splenectomy is only moderately and transiently effective and does not eliminate the need for total splenectomy in patients with severe symptoms.

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 severe hereditary elliptocytosis or hereditary pyropoikilocytosis, the condition evolves to a milder form. For this reason, and because of the substantial risk of infection, splenectomy should be postponed in children younger than 5 years.

After splenectomy, most patients with hereditary elliptocytosis or hereditary pyropoikilocytosis have increased hemoglobin levels, decreased reticulocyte counts, and improved signs and symptoms. Hemolysis is not, however, eliminated.

Administer pneumococcal vaccines prior to the procedure; both conjugated and polysaccharide vaccines may be indicated depending on the patient's age. PCV13 should be administered to those who have not received it. Ensure that the Haemophilus influenzae type B vaccine series has also been administered. Conjugated meningococcal vaccine (MCV4) should also be given if the child is aged 2 years 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.

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

Consult a surgeon early in the course of severe disease for counseling regarding cholecystectomy or splenectomy.

No dietary restrictions are indicated for hereditary elliptocytosis or hereditary pyropoikilocytosis.

Identify and treat and concomitant conditions such as iron-deficiency or folate deficiency.

If the patient with hereditary elliptocytosis/hereditary pyropoikilocytosis also has glucose-6-phosphatase deficiency, appropriate dietary restrictions should be implemented.

No restrictions on activity are indicated, unless substantial splenomegaly is present. A relatively small risk of splenic rupture is associated with contact sports in patients with splenomegaly. However, this is not an absolute contraindication to participation in athletics. Some patients may be offered a spleen guard.

The only medication routinely used in the treatment of symptomatic hereditary elliptocytosis is folic acid. If not already given, patients undergoing splenectomy require the pneumococcal vaccine (nonconjugated as well as conjugated), meningococcal vaccine, and H influenzae vaccine before the procedure. They may also require prophylactic antibiotics after removal of the spleen. Details of presplenectomy and postsplenectomy care are beyond the scope of this article. Consult age-appropriate recommendations from the Centers for Disease Control and Prevention.

Class Summary

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

Folic acid (Folvite)

Folic acid is an important cofactor for enzymes used in the production of RBCs.

The frequency of outpatient visits depends on the clinical picture and the severity of hemolytic disease. In general, annual physical examinations to assess growth and spleen size are appropriate. At each visit, a CBC count and reticulocyte count should be obtained. Patients should be seen as needed to evaluate for signs of increased hemolysis such as pallor or jaundice. Severely symptomatic children should be monitored for failure to thrive. Patients who have undergone splenectomy should be evaluated when febrile.

Inpatient care is rarely required but is indicated for severe complications.

Patients who have hemolytic anemia should take folic acid daily to replenish their folate stores and to support RBC production.

Offer genetic counseling to all patients with hereditary elliptocytosis or its variants. Inform patients that asymptomatic relatives including parents and siblings may be affected.

Hemolytic anemia is the primary complication of hereditary elliptocytosis and hereditary pyropoikilocytosis. The severity widely varies, but some patients require RBC transfusions.

Transient pure RBC aplasia with acute anemia has been reported in patients with sporadic hemolysis. As in 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 cholelithiasis secondary to chronic hemolysis. If symptomatic, patients should undergo ultrasonographic evaluations to assess the gallbladder.

Albeit rare, splenic rupture is possible if substantial splenomegaly is present.

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

Educate patients and their parents about the inheritance pattern of the disease. They should understand that asymptomatic family members may have affected offspring.

Patients with hereditary elliptocytosis should be counseled that their offspring could have severe hemolytic anemia in the newborn period.

Educate patients and their parents about the signs and symptoms of hemolysis and anemia with instructions on when to access medical care. Patients and/or parents should become skilled in palpation of the size of the spleen.

Educate patients requiring splenectomy about the risks of infection. Educate patients about the need for preoperative vaccinations. Educate patients about the appropriate timing of immunization in relation to splenectomy.

Educate patients about when to seek medical attention for fever if they have undergone splenectomy.

Patients should know the signs and symptoms that indicate the presence of gallstones, and they should understand that they are at increased risk if significant hemolysis is present.

If splenomegaly is substantial, patients should be counseled concerning the risk of abdominal trauma and potential splenic rupture or subcapsular hematoma.