Hereditary spherocytosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Zahir Ali Shaikh, MD[2]

Hereditary spherocytosis is a genetically transmitted form of hemolysis, characterized by hemolytic anemia, jaundice and splenomegaly. It was first described by Vanlair and Masius in 1871, where they described chronically icteric patients who had no bile in urine, no evidence of liver disease and often splenomegaly and family history of jaundice. Hereditary spherocytosis is classified in 05 subtypes on the basis of underlying protein defect including; ankyrin1, spectrin beta chain (erythrocytic), spectrin alpha chain (erythrocytic1), band 3 and protein 4.2. The defects in hereditary spherocytosis lie in the cell membrane. The cell membrane proteins essential for the integrity of cell membrane structure includes; spectrin, ankyrin, band 3 and protein 4.1 and 4.2, and their deficiency can produce varying degree of severity of the disease. it should be differentiated from autoimmune hemolysis, congenital dyserythropoietic anemia type II, thermal injury and hemoglobinopathies. Hereditary spherocytosis can present at any age, having a positive family history is an important risk factor for the disease. Mean corpuscular hemoglobin concentration (MCHC) and erythrocyte distribution width (RDW) tests can be used for the screening of hereditary spherocytosis. Complications of the disease include; jaundice, kernicterus, pigment gallstones, splenomegaly, hemolytic, aplastic and megaloblastic crises. It can present with yellowing of skin, fatigue, irritability, shortness of breath or it can be asymptomatic altogether. Physical examination findings include scleral icterus, jaundice and splenomegaly. Laboratory testing includes CBC, MCHC, blood smear, hemolysis testing and coombs test. There is no specific medical therapy for the hereditary spherocytosis, however surveillance is needed to help detect and manage the complications. Folic acid supplementation, blood transfusions and erythropoietin may also be tried. Splenectomy is very effective in reducing the hemolysis. Partial splenectomies are tried in children to control hemolysis and preserve splenic function as well. Administration of vaccines (pneumococcal, hemophilus influenzae, meningococcal and influenza), antibiotics (penicillin) and folic acid should be prescribed for postsplenectomy patients.

The hereditary spherocytosis was first described in 1871 by Vanlair and Masius, where they described chronically icteric patients who had no bile in the urine, no evidence of liver disease and often splenomegaly and family history of jaundice. It is the commonest cause of inherited chronic hemolysis in the northern europe and north america.

The hereditary spherocytosis classified into 05 subtypes on the basis of underlying protein defect including; ankyrin 1, spectrin beta chain (erythrocytic), spectrin alpha chain (erythrocytic 1), band 3 and protein 4.2. It is also classified on the basis of clinical severity into mild, moderate and severe subtypes.

The defects in hereditary spherocytosis lie in the cell membrane. The proteins essential for integrity of cell membrane structure lie immediately under the lipid bilayer, horizental alpha & beta spectrin molecules form heterodimers with linkage to vertical elements including ankyrin, proteins 4.1 & 4.2 and band 3 (transmembrane protein). The shorter the lifespan of red blood cells, the worse the clinical effects. Spectrin protein is a tetramer composed of alpha & beta dimers, its deficiency is most frequently seen in hereditary spherocytosis. Spectrin deficiency can result from impaired synthesis of spectrin or from qualitative or quantitative defects in other proteins that integrate proteins into red blood cells. Ankyrin is the principal binding site for spectrin on red blood cell membrane, its deficiency leading to decreased incorporation of spectrin, leading to proportional decrease in spectrin content as well despite normal synthesis of spectrin. Band 3 deficiency is seen in 10-20% of patients with mild to moderate autosomal dominant hereditary spherocytosis and is considerably greater in older red blood cells. Protein 4.2 (Pallidin) deficiency leads to abnormal red blood cell morphology including spherocytes, elliptocytes or sphero-ovalocytes, it is relatively common in japan. Red blood cell antibodies may also have a pathogenic role in red blood cell opsonization and removal by spleen.

Hereditary spherocytosis is caused by a variety of genetic mutations. The 05 genes associated with hereditary spherocytosis include; alpha spectrin (SPTA1), beta spectrin (SPTB), ankyrin (ANK1), band 3 (SLC4A1) and protein 4.2 (EPB42). Mutations in one or more of these genes can cause membrane protein deficiency leading to hereditary spherocytosis.

Hereditary spherocytosis usually presents with hemolysis, therefore should be differentiated from other diseases including; autoimmune hemolysis, thermal injury, clostridial septicemia, wilson disease, hemoglobinopathies, hereditary stomatocytosis, congenital dyserythropoietic anemia type II, infantile pyknocytosis and hemolytic disease of fetus and newborn (HDFN).

Hereditary spherocytosis can present at any age with any presentation from hydrops fetalis inutero through diagnosis in the ninth decade of life, and is reported worldwide in all racial and ethnic groups. It is most common inherited anemia in northern european ancestry and north america. The reported incidence is 1 in 2000 births. Approximately 25% of all hereditary spherocytosis is autosomal recessive. It is most often diagnosed in childhood or early adulthood.

There are no clearly identified risk factors for the hereditary spherocytosis, but having a positive family history is an important risk factor for the disease.

The combination of two tests; mean corpuscular hemoglobin concentration (MCHC) and erythrocyte distribution width are an excellent screening tests for hereditary spherocytosis. For young patients with the disease, a full family history, complete blood count (CBC), reticulocyte count and examination of peripheral blood smear on each parent and sibling is required to determine whether the spherocytic mutation is dominant or recessive. For individuals of childbearing age with hereditary spherocytosis, review of familial mutation and its mode of transmission is useful for discussions of likelihood of disease in children.

Hereditary spherocytosis can present at any age with any severity, ranging from hydrops fetalis in utero through diagnosis in the ninth decade of life, with variable clinical course depending upon the severity of disease. Majority of affected individuals have mild or moderate hemolysis and known family history, making the diagnosis and treatment relatively easy. Complications include; jaundice, kernicterus, pigment gallstones, hemolytic, aplastic and megaloblastic crises, splenomegaly and leukemia. The prognosis is usually good with early diagnosis, regular followup and management. Patients with mild disease may develop symptoms only with environmental triggers. Many patients who undergo splenectomy are able to maintain normal hemoglobin levels, however patients with severe hereditary spherocytosis may remain anemic postsplenectomy and require regular blood transfusions. Postsplenectomy patients are at increased risk of life threatening infections (sepsis), therefore require vaccinations and antibiotics.

The diagnosis of hereditary spherocytosis can be based on physical examination, complete blood count (CBC), reticulocyte count, medical history and specific tests including eosin-5-maleimide binding (EMA) test and acidified glycerol lysis time (AGLT) test. The diagnosis can be made at any age. EMA binding test has high sensitivity and specificity for the hereditary spherocytosis. Other tests include; osmotic fragility (OF) test, pink test and ektacytometry. Gel electrophoresis analysis of erythrocyte membranes is the method of choice for diagnosis of atypical cases.

The hereditary spherocytosis is a familial hemolytic disorder with increased heterogeneity. Clinical features range from asymptomatic to fulminant hemolytic anemia. History and symptoms of hereditary spherocytosis include; yellowing of skin, fatigue, irritability, weakness, shortness of breath, anemia, hemolysis, thrombocytopenia and hyperbilirubinemia. Pigment gallstones may be found in young children, but incidence of gallstones increases markedly with age, however jaundice is more prominent in newborns.

The physical examination findings in hereditary spherocytosis include; scleral icterus, jaundice, splenomegaly. Right upper quadrant abdominal pain may be elicited if gallbladder disease is present.

The initial laboratory testing for hereditary spherocytosis include; complete blood count (CBC), mean corpuscular hemoglobin concentration (MCHC), blood smear review, hemolysis testing and coombs testing. All individuals suspected of having hereditary spherocytosis based on family history, neonatal jaundice or other findings should have a complete blood count (CBC), reticulocyte count and RBC indices done. Confirmatory tests for hereditary spherocytosis includes EMA binding test, osmotic fragility test, glycerol lysis test, cryohemolysis and plasma membrane electrophoresis.

There are chest X-ray, CT scan or MRI findings associated with hereditary spherocytosis.

There are no other diagnostic studies associated with hereditary spherocytosis.

There is no specific medical therapy for the hereditary spherocytosis, as the diagnosis is made, surveillance is needed to help detect and manage any complications. A routine annual review is usually sufficient to detect any complications. Folic acid supplementation is not always required, but is used as a routine for children with severe hemolysis and in pregnancy regardless of severity of disease. Blood transfusion may also be required in severely affected infants and may be needed during aplastic crisis or pregnancy. However, erythropoietin (EPO) may be helpful in reducing the need for transfusion in some infants.

Generally, the treatment of hereditary spherocytosis involves presplenectomy care, splenectomy and management of postsplenectomy complications. Splenectomy is very effective in reducing hemolysis, leading to significant prolongation of red blood cell lifespan. Partial splenectomies can be used in pediatric patients as it controls hemolysis and preserves splenic function. Patients having concomitant gallstones are likely to benefit from combined splenectomy and cholecystectomy in terms of life expectancy. Post splenectomy complications may include; infections & sepsis caused by encapsulated organisms (streptococcus pneumoniae, neisseria meningitidis, haemophilus influenza), deep venous thrombosis (DVT), pulmonary emboli and portal vein thrombosis.

There is no primary prevention available for the hereditary spherocytosis, however administration of vaccines including pneumococcal, hemophilus influenzae, meningococcal and influenza should be given two to three weeks before splenectomy. Folic acid supplementation as well as oral penicillin is also suggested for postsplenectomy patients untill reaching adulthood.

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The hereditary spherocytosis was first described in 1871 by Vanlair and Masius, where they described chronically icteric patients who had no bile in the urine, no evidence of liver disease and often splenomegaly and family history of jaundice. It is the commonest cause of inherited chronic hemolysis in the northern europe and north america.

• Hereditary spherocytosis was first described in 1871 by Vanlair and Masius, where they described chronically icteric patients who had no bile in the urine, no evidence of liver disease and often splenomegaly and family history of jaundice.^[1]
• It is the commonest cause of inherited chronic hemolysis in the northern europe and north america.^[2]
• With remarkable discernment, Vanlair and Masius stated, ‘The jaundice of our patient appears to be a peculiar type of icterus. The fact that the patient’s mother and sister had a slight jaundice and that the sister had an enlarged spleen may indicate that this condition is one disease entity.’.^[3]

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The hereditary spherocytosis classified into 05 subtypes on the basis of underlying protein defect including; ankyrin 1, spectrin beta chain (erythrocytic), spectrin alpha chain (erythrocytic 1), band 3 and protein 4.2. It is also classified on the basis of clinical severity into mild, moderate and severe subtypes.

• Hereditary spherocytosis is classified on basis of underlying defect in protein and also on the basis of severity of hemolysis.

• Classification of hereditary spherocytosis on the basis of underlying protein defect

• Classification of hereditary spherocytosis on the basis of clinical severity.^[1]“GeneReviews® – NCBI Bookshelf”.^[2][3]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

The defects in hereditary spherocytosis lie in the cell membrane. The proteins essential for integrity of cell membrane structure lie immediately under the lipid bilayer, horizental alpha & beta spectrin molecules form heterodimers with linkage to vertical elements including ankyrin, proteins 4.1 & 4.2 and band 3 (transmembrane protein). The shorter the lifespan of red blood cells, the worse the clinical effects. Spectrin protein is a tetramer composed of alpha & beta dimers, its deficiency is most frequently seen in hereditary spherocytosis. Spectrin deficiency can result from impaired synthesis of spectrin or from qualitative or quantitative defects in other proteins that integrate proteins into red blood cells. Ankyrin is the principal binding site for spectrin on red blood cell membrane, its deficiency leading to decreased incorporation of spectrin, leading to proportional decrease in spectrin content as well despite normal synthesis of spectrin. Band 3 deficiency is seen in 10-20% of patients with mild to moderate autosomal dominant hereditary spherocytosis and is considerably greater in older red blood cells. Protein 4.2 (Pallidin) deficiency leads to abnormal red blood cell morphology including spherocytes, elliptocytes or sphero-ovalocytes, it is relatively common in japan. Red blood cell antibodies may also have a pathogenic role in red blood cell opsonization and removal by spleen.

• The defects in hereditary spherocytosis lie in the cell membrane.^[1]
• The proteins essential for integrity of cell membrane structure lie immediately under the lipid bilayer, horizontal alpha and beta spectrin molecules form heterodimers with linkage to vertical elements- ankyrin, proteins 4.1 and 4.2 and band 3 (a transmembrane protein).
• Different genes code for each of these proteins, therefore hereditary spherocytosis is a heterogenous disorder that can result from a defect in any one of these proteins.
• The destabilization of membrane leads to both abnormal morphology and reduced red cell life span.
• The shorter the lifespan of red blood cells, the worse the clinical effects.
• The genetic defect and clinical severity tend to be fairly constant within a given family, but between families varies from mild asymptomatic hemolysis to severe continuous anemia with jaundice.
• The four RBC membrane protein abnormalities recognized in hereditary spherocytosis include; spectrin deficiency alone, combined spectrin & ankyrin deficiency, band 3 deficiency and protein 4.2 deficiency.
• Spectrin deficiency
  • Spectrin protein is a tetramer composed of alpha and beta dimers.^[2][3]
  • The most frequent defect in hereditary spherocytosis is spectrin deficiency.
  • Mutations of alpha spectrin are associated with recessive forms of hereditary spherocytosis and beta spectrin mutations occur in autosomal dominant forms of hereditary spherocytosis.
  • Spectrin deficiency can result from impaired synthesis of spectrin or from quantitative or qualitative defects in other proteins that integrate spectrin into the red cell membrane.
  • Approximately 50% of patients with severe recessive hereditary spherocytosis have a point mutation at the codon (969) resulting in amino acid substitution (alanine/aspartic acid) at the corresponding site in apha spectrin protein leading to defective binding of spectrin to protein 4.1.
• Akyrin deficiency
  • Ankyrin is the principal binding site for spectrin on the red blood cell membrane.
  • Ankyrin gene is located on chromosome 8, therefore translocation of chromosome 8 or deletion of short arm of chromosome 8 can lead to hereditary spherocytosis.
  • Ankyrin deficiency leads to decreased incorporation of spectrin, leading to a proportional decrease in spectrin content as well despite the normal synthesis of spectrin.
• Band 3 deficiency
  • Band 3 deficiency is seen in 10-20% of patients with mild to moderate autosomal dominant hereditary spherocytosis.
  • Band 3 deficiency is considerably greater in older RBCs due to unstable nature of band 3 protein.
• Protein 4.2 (Pallidin) Deficiency
  • Protein 4.2 deficiency leads to abnormal RBC morphology including spherocytes, elliptocytes or sphero-ovalocytes.
  • Its deficiency is relatively common in japan.
  • A point mutation causing complete absence of protein 4.2 is associated with typical hereditary spherocytosis phenotype.
• Red Blood Cell Antibodies
  • Zaninoni et all found RBC antibodies in 61% of patients with hereditary spherocytosis using a mitogen stimulated direct antiglobulin test.^[4]
  • They concluded that the more evident hemolytic pattern in patients with RBC autoantibodies suggests that these antibodies have a pathogenic role in RBC opsonization and removal by spleen.

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Hereditary spherocytosis is caused by a variety of genetic mutations. The 05 genes associated with hereditary spherocytosis include; alpha spectrin (SPTA1), beta spectrin (SPTB), ankyrin (ANK1), band 3 (SLC4A1) and protein 4.2 (EPB42). Mutations in one or more of these genes can cause membrane protein deficiency leading to hereditary spherocytosis.

• Hereditary spherocytosis is caused by a variety of genetic mutations.^[1][2]
• There are 05 genes associated with hereditary spherocytosis including, alpha spectrin (SPTA1), beta spectrin (SPTB), ankyrin (ANK1), band3 (SLC4A1) and protein 4.2 (EPB42).
• Mutations in one or more of hereditary spherocytosis related genes can cause membrane protein deficiency leading to hereditary spherocytosis.

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Hereditary spherocytosis usually presents with hemolysis, therefore should be differentiated from other diseases including; autoimmune hemolysis, thermal injury, clostridial septicemia, wilson disease, hemoglobinopathies, hereditary stomatocytosis, congenital dyserythropoietic anemia type II, infantile pyknocytosis and hemolytic disease of fetus and newborn (HDFN).

• Hereditary spherocytosis presents with hemolysis, therefore should be differentiated from following diseases.^[1][2]
  • Autoimmune hemolysis
    • Autoimmune hemolytic anemia (AIHA), in which autoantibodies directed against self-RBC antigens lead to hemolysis, is a common cause of hemolysis and/or anemia, especially in adults.
    • Warm AIHA associated with an underlying disorder such as systemic lupus erythematosus (SLE) or without an underlying disorder is more common than cold AIHA, which is typically triggered by an infection such as infectious mononucleosis.
    • Like hereditary spherocytosis, patients can have anemia and/or hemolysis of variable severity and abundant spherocytes on the peripheral blood smear.
    • Unlike hereditary spherocytosis, in AIHA, the coombs test is typically positive, there is not family history of hemolytic anemia, and prior complete blood counts (CBCs) will show a normal hemoglobin level and reticulocyte count.
  • Thermal injury
  • Clostridial septicemia
  • Wilson disease
  • Hemoglobinopathies
  • Hereditary stomatocytosis
  • Congenital dyserythropoietic anemia type II
    • CDA type II is a group of inherited anemias caused by one of several gene variants that results in abnormal RBC production in the bone marrow.
    • Like hereditary spherocytosis, some individuals may have significant hemolysis and/or splenomegaly, and some specialized tests such as EMA binding may be positive.
    • Unlike hereditary spherocytosis, individuals with one of the CDAs are likely to have characteristic morphology of RBC precursors in the bone marrow, and the reticulocyte count is usually lower in the CDAs.^[3]
  • Infantile pyknocytosis
    • It is a disorder of unknown etiology in which RBCs become hyperdense and dehydrated.^[4]
    • Like hereditary spherocytosis, this condition presents in neonates with anemia and an increased mean corpuscular hemoglobin concentration (MCHC), but unlike hereditary spherocytosis, the RBCs have irregular borders and varying numbers of projections, and the condition resolves spontaneously during the first year of life without intervention.
  • Other inherited hemolytic anemias
    • Other inherited RBC membrane disorders include hereditary elliptocytosis (HE) and elliptocytosis variants (eg, Southeast Asian ovalocytosis (SAO), hereditary pyropoikilocytosis (HPP), hereditary stomatocytosis (HSt), and hereditary xerocytosis (HX).
    • RBC enzyme disorders include glucose-6-phosphate dehydrogenase (G6PD) deficiency, pyruvate kinase (PK) deficiency, and other rare metabolic disorders.
    • Like hereditary spherocytosis, these present with variable degrees of anemia and hemolysis and can be diagnosed at any age.
    • Unlike the other disorders, G6PD deficiency typically presents with more discreet episodes of hemolysis after exposure to oxidant drugs.
    • Unlike the other membrane disorders, which each have distinctive morphologies on the blood smear, and the enzyme disorders, which typically have nonspecific findings (eg, mild reticulocytosis), hereditary spherocytosis is characterized by spherocytosis as the predominant morphology.
  • Hemolytic disease of the fetus and newborn (HDFN)
    • Neonates may present with severe HDFN (also called neonatal alloimmune hemolytic anemia), which is caused by maternal antibodies crossing the placenta and recognize foreign fetal RBC antigens, leading to alloimmune hemolysis.
    • Like hereditary spherocytosis, neonates can present with severe jaundice and anemia requiring aggressive treatment, and HDFN can be associated with abundant spherocytes on the blood smear.
    • Unlike hereditary spherocytosis, HDFN is a transient condition that resolves after the maternal antibodies are cleared, and HDFN is characterized by positive coombs testing, which typically reveals the alloantibodies on fetal RBCs, as well as evidence of an immunologically significant discordance between maternal and neonatal blood type.

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Hereditary spherocytosis can present at any age with any presentation from hydrops fetalis inutero through diagnosis in the ninth decade of life, and is reported worldwide in all racial and ethnic groups. It is most common inherited anemia in northern european ancestry and north america. The reported incidence is 1 in 2000 births. Approximately 25% of all hereditary spherocytosis is autosomal recessive. It is most often diagnosed in childhood or early adulthood.

• Hereditary spherocytosis is reported worldwide in all racial and ethnic groups.^[1]
• It is the most common inherited anemia in the northern European ancestry and north america.^[2]
• The reported incidence of hereditary spherocytosis is 1 in 2000 births.^[3]
• It is less commonly seen in african american and southeast asian people.^[4]

• In the United States, the incidence of the disorder is approximately one case in 5000 people.
• Given that approximately 25% of all hereditary spherocytosis is autosomal recessive, calculations indicate that 1.4% of the US population might be silent carriers of hereditary spherocytosis.

• In northern European, hereditary spherocytosis affects as many as 1 in 2000 to 1 in 5000 (prevalence, approximately 0.02 to 0.05 percent) [6,7,62,75].
• The frequency is thought to be lower in individuals from other parts of the world such as Africa and Southeast Asia, although comprehensive population survey data are unavailable.

• Hereditary spherocytosis can present at any age and with any severity, with case reports describing a range of presentations, from hydrops fetalis in utero through diagnosis in the ninth decade of life.^[5][6]
• Hereditary spherocytosis is most often diagnosed in childhood or early adulthood.
• Children diagnosed early in life usually have a severe form of hereditary spherocytosis that results in their early presentation. Jaundice is likely to be most prominent in newborns. The magnitude of hyperbilirubinemia may be such that exchange transfusion is required. Approximately 30-50% of adults with hereditary spherocytosis had a history of jaundice during the first week of life. Recognition of hereditary spherocytosis as a potential cause of neonatal anemia and hyperbilirubinemia and institution of prompt treatment may reduce the risk of bilirubin-induced neurologic dysfunction in these patients.^[7]

• Hereditary spherocytosis occurs in all racial and ethnic groups but is more common in northern Europeans,

• There is no significant data from US related to gender difference. In 2011, the number of cases was 114 reported from CBM(China Biology Medicine) database, the male: female ratio was 1.04:1.^[8]
• In 2011, overall literature reported prevalence of hereditary spherocytosis in China was estimated to be: 1.27 cases per 100,000 people in males and 1.49 cases per 100,000 people in females

• Hereditary spherocytosis occurs in 1 in 5,000 individuals of Northern European ancestry. This condition is the most common cause of inherited anemia in that population. The prevalence of hereditary spherocytosis in people of other ethnic backgrounds is unknown, but it is much less common.

There is no particular relation of FA with developed countries.

There is no particular relation of FA with developing countries.

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There are no clearly identified risk factors for the hereditary spherocytosis, but having a positive family history is an important risk factor for the disease.

• A positive family history is an important risk factor for hereditary spherocytosis, as it is an inherited condition.^[1]
• There are no other risk factors have been clearly identified for this condition.^[2]

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The combination of two tests; mean corpuscular hemoglobin concentration (MCHC) and erythrocyte distribution width are an excellent screening tests for hereditary spherocytosis. For young patients with the disease, a full family history, complete blood count (CBC), reticulocyte count and examination of peripheral blood smear on each parent and sibling is required to determine whether the spherocytic mutation is dominant or recessive. For individuals of childbearing age with hereditary spherocytosis, review of familial mutation and its mode of transmission is useful for discussions of likelihood of disease in children.

• The screening test used for hereditary spherocytosis is automated mean cell hemoglobin concentration (MCHC).^[1]
• Erythrocyte distribution width when raised is also useful as a powerful screening test.^[2]
• The combination of these two tests (MCHC & erythrocyte distribution width) is an excellent predictor for the diagnosis of hereditary spherocytosis.^[3]
• For young patients with hereditary spherocytosis, a full family history and CBC, reticulocyte count, and examination of the peripheral blood smear on each parent and sibling is required to determine whether the spherocytic mutation is dominant or recessive.
• Appropriate counseling is also required once this information has been obtained and it is especially important to test a newborn sibling for hereditary spherocytosis, as this may be associated with severe degrees of hyperbilirubinemia and anemia during this period.

• For individuals of childbearing age with hereditary spherocytosis, review of the familial mutation and its mode of transmission (autosomal dominant or recessive) may be useful for informing discussions of the likelihood of hereditary spherocytosis in children. If the familial mutation is known to act in an autosomal dominant fashion, it is important to make this information clear in the prenatal record and to make the information available to the pediatrician before delivery.^[4]
• It is also important to test newborns of affected parents for hereditary spherocytosis, as affected newborns may have severe hyperbilirubinemia and anemia.

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Hereditary spherocytosis can present at any age with any severity, ranging from hydrops fetalis in utero through diagnosis in the ninth decade of life, with variable clinical course depending upon the severity of disease. Majority of affected individuals have mild or moderate hemolysis and known family history, making the diagnosis and treatment relatively easy. Complications include; jaundice, kernicterus, pigment gallstones, hemolytic, aplastic and megaloblastic crises, splenomegaly and leukemia. The prognosis is usually good with early diagnosis, regular followup and management. Patients with mild disease may develop symptoms only with environmental triggers. Many patients who undergo splenectomy are able to maintain normal hemoglobin levels, however patients with severe hereditary spherocytosis may remain anemic postsplenectomy and require regular blood transfusions. Postsplenectomy patients are at increased risk of life threatening infections (sepsis), therefore require vaccinations and antibiotics.

• The clinical course of hereditary spherocytosis is variable depending upon the severity of disease.^[1]
• During infancy, hemoglobin level falls rapidly after 20 days of birth leading to transient & severe anemia, causing inappropriate erythrocyte response and splenic filtering function.^[2]
• About 20-30% of patients have mild disease with compensated hemolysis.
• About 60-70% of patients have moderate disease, presenting in childhood but can present at any age.
• About 3-5% of patients have severe hereditary disease with life threatening anemia, requiring regular transfusions to maintain a hemoglobin concentration of greater than 60g/L.
• Without regular transfusions or splenectomy or both, patients may develop kernicterus, severe hemolytic anemia, gallstones, growth retardation, delayed sexual maturation, extramedullary hematopoiesis with hepatosplenomegaly and bony changes (thalassemic facies).^[3]

• Hereditary spherocytosis can present at any age and with any severity, with case reports describing a range of presentations, from hydrops fetalis in utero through diagnosis in the ninth decade of life. ^[4][5][6]

• The majority of affected individuals have mild or moderate hemolysis or hemolytic anemia and a known family history, making diagnosis and treatment relatively straightforward. Individuals with significant severe hemolysis may develop additional complications such as jaundice/hyperbilirubinemia, folate deficiency, or splenomegaly.

Hemolytic anemia — A classification for hereditary spherocytosis has been developed based on the severity of anemia and markers of hemolysis (reticulocyte count and bilirubin) ^[7][8]; it characterizes patients as having one of the following:

●Hereditary spherocytosis trait – Normal hemoglobin and reticulocyte count

●Mild hereditary spherocytosis (20 to 30 percent of cases) – Hemoglobin 11 to 15 g/dL; reticulocytes 3 to 6 percent; bilirubin 17 to 34 micromol/L

●Moderate hereditary spherocytosis (60 to 75 percent of cases) – Hemoglobin 8 to 12 g/dL; reticulocytes >6 percent; bilirubin >34 micromol/L

●Severe hereditary spherocytosis (5 percent of cases) – Hemoglobin 6 to 8 g/dL; reticulocytes >10 percent; bilirubin >51 micromol/L

• Neonates may have a relatively normal hemoglobin level at birth that is followed by development of severe anemia, especially during the first three weeks and, in some cases, the first year of life, when the erythropoietic response may not be adequate.
• According to one review, more than half of neonates with hereditary spherocytosis are not anemic during the first week of life ^[9].
• However, anemia can develop after several days, and is most likely to be severe during the second or third week of life. Some infants require chronic transfusions during the first year; however, transfusion dependence beyond the first year of life is unusual.

• In older children and adults, the presentation may be that of an incidental finding of hemolysis, hemolytic anemia, or spherocytes on the blood smear or the individual may be symptomatic from anemia, splenomegaly, pigment gallstones, or jaundice. Jaundice due to severe hemolysis is less common after the newborn period.

• In some cases, co-inheritance of another disorder affecting RBC survival such as sickle cell disease or thalassemia can influence the severity of anemia and make diagnosis more challenging. ^[10]

• The complications of hereditary spherocytosis include:^[11][12][13]
  • hemolytic anemia
  • jaundice
  • kernicterus
  • cholelithiasis
  • hemolytic, aplastic and megaloblastic crises
  • growth failure
  • leg ulcers
  • skeletal abnormalities resulting from bone marrow expansion
  • multiple myeloma
  • leukemia
• Infections that impair RBC production in the bone marrow and thus diminish the capacity to compensate for chronic hemolysis may lead to a period of aplasia. A commonly cited cause of transient aplastic crisis is parvovirus B19 infection; other viral or bacterial infections may also cause transient aplasia. This is because individuals with chronic hemolysis are highly dependent on the accelerated production of new RBCs by the bone marrow, and they can experience a rapid drop in hemoglobin level when the bone marrow is unable to compensate for hemolysis. If a patient with hereditary spherocytosis develops a precipitous decline in hemoglobin level or reticulocyte count, testing for parvovirus infection is appropriate.
• Conditions that increase the size of the spleen, such as infectious mononucleosis, may cause increased splenic pooling of RBCs and/or increased hemolysis.
• Individuals who develop folate, vitamin B12, or iron deficiency may be unable to produce sufficient RBCs to compensate for those lost by hemolysis.
• Anemia may worsen during pregnancy, as the RBC mass and plasma volume expand to meet the physiologic needs of the pregnancy. Attention to folic acid supplementation and iron stores are also important so as not to impair RBC production.

Complications of hemolysis — Common complications of hemolysis include neonatal jaundice, splenomegaly, and pigment gallstones.

• Rarely, hemolysis may be severe enough to cause extramedullary hematopoiesis and/or growth delay.^[14][15]
• A small subset of these children may be at risk for iron overload due to increased iron absorption and/or transfusions, although the majority of patients with hereditary spherocytosis do not develop iron overload.
• Other rare complications that have been reported include leg ulcers, priapism, neuromuscular disorders, cardiac disease, and gout; in some cases, these may represent coincidental rather than causal associations.^[16]

Neonatal jaundice — hereditary spherocytosis may present in the neonatal period with jaundice and hyperbilirubinemia, and the serum bilirubin level may not peak until several days after birth. Some experts have proposed that hereditary spherocytosis is underdiagnosed as a cause of neonatal jaundice. A requirement for phototherapy and/or exchange transfusion during this period is common.^[17]

Splenomegaly — Splenomegaly is rare in neonates, but can often be seen in older children and adults with hereditary spherocytosis. Early reports of family studies found palpable spleen in over three-fourths of affected members, but this may reflect a skewed population with the most severe disease. In these studies, the relationship between disease severity and splenic size was not linear.^[18]

Pigment gallstones — Pigment (bilirubin) gallstones are common in individuals with hereditary spherocytosis and may be the presenting finding in adults. Gallstones are unlikely before the age of 10 years but are seen in as many as half of adults, especially those with more severe hemolysis. Gallstones appear to be more common in individuals with Gilbert syndrome.^[19]

• Obstructive jaundice or cholecystitis is treated similarly to that in individuals without hereditary spherocytosis. If cholecystectomy is performed, it may be worthwhile to discuss whether splenectomy was also planned, as the procedures could be combined; however, splenectomy should not be routinely performed during cholecystectomy.^[20]

• The prognosis of patients with hereditary spherocytosis is usually good with early diagnosis, regular followup and management.^[21]
• Patients with hereditary spherocytosis may remain undiagnosed for years if their hemolysis is mild.
• Overall, the long-term outlook for people with hereditary spherocytosis is usually good with treatment. However, it may depend on the severity of the condition in each person.
• People with very mild hereditary spherocytosis may not have any signs or symptoms unless an environmental “trigger” causes symptom onset. In many cases, no specific therapy is needed other than monitoring for  and watching for signs and symptoms. Moderately and severely affected people are likely to benefit from splenectomy.^[22]
• Most people who undergo splenectomy are able to maintain a normal hemoglobin level. However, people with severe hereditary spherocytosis may remain anemic post-splenectomy, and may need blood transfusions during an infection.
• In all people who undergo splenectomy, there is a lifelong, increased risk of developing a life-threatening infection (sepsis). Although most septic episodes have been observed in children whose spleens were removed in the first years of life, older children and adults also are susceptible. Fortunately, taking certain precautions can reduce this risk and can prevent minor infections from becoming life threatening.

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The diagnosis of hereditary spherocytosis can be based on physical examination, complete blood count (CBC), reticulocyte count, medical history and specific tests including eosin-5-maleimide binding (EMA) test and acidified glycerol lysis time (AGLT) test. The diagnosis can be made at any age. EMA binding test has high sensitivity and specificity for the hereditary spherocytosis. Other tests include; osmotic fragility (OF) test, pink test and ektacytometry. Gel electrophoresis analysis of erythrocyte membranes is the method of choice for diagnosis of atypical cases.

• The diagnosis of hereditary spherocytosis can be based on the physical examination, complete red cell count, reticulocyte count, medical history and specific tests, preferentially, the EMA (eosin-5-maleimide binding) test and AGLT (acidified glycerol lysis time).
• The diagnosis can be made at any age, including the neonatal period from day of birth.
• The diagnostic guidelines of hereditary spherocytosis from the British Committee for Standards in hematology do not recommend any additional tests for patients with classical clinical features and laboratory data.
• The eosin-5-maleimide (EMA) binding test has high sensitivity (92–93%) and specificity (99%) for hereditary spherocytosis, although a positive test can also be obtained in patients affected by related conditions, such as congenital dyserythropoietic anemia type II (CDA II)
• Other tests, such as the osmotic fragility (OF) test, acidified glycerol lysis test (AGLT) and the pink test, exhibit lower sensitivity compared to the EMA test (68%, 61% and 91%, respectively).
• Ektacytometry is a highly sensitive test of membrane deformability.

• Newly diagnosed patients with a family history of hereditary spherocytosis, typical clinical features and laboratory investigations (spherocytes, raised mean corpuscular hemoglobin concentration (MCHC), increase in reticulocytes) do not require any additional tests.
•  If the diagnosis is equivocal, a screening test with high predictive value for hereditary spherocytosis is helpful. The recommended screening tests are the cryohaemolysis test and EMA binding.
•  Gel electrophoresis analysis of erythrocyte membranes is the method of choice for diagnosis of atypical cases.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

The hereditary spherocytosis is a familial hemolytic disorder with high heterogeneity. Clinical features range from asymptomatic to fulminant hemolytic anemia. History and symptoms of hereditary spherocytosis include: yellowing of skin, fatigue, irritability, weakness, shortness of breath, anemia, hemolysis, thrombocytopenia and hyperbilirubinemia. Pigment gallstones may be found in young children, but incidence of gallstones increases markedly with age, however jaundice is more prominent in newborns.

• Hereditary spherocytosis is a familial hemolytic disorder with marked heterogeneity.^[1][2][3]
• Clinical features range from asymptomatic to fulminant hemolytic anemia.^[4]
• Children diagnosed early in life usually have a severe form of hereditary spherocytosis that results in their early presentation. Jaundice is likely to be most prominent in newborns. The magnitude of hyperbilirubinemia may be such that exchange transfusion is required. Approximately 30-50% of adults with hereditary spherocytosis had a history of jaundice during the first week of life. Recognition of hereditary spherocytosis as a potential cause of neonatal anemia and hyperbilirubinemia and institution of prompt treatment may reduce the risk of bilirubin-induced neurologic dysfunction in these patients.^[5]
• Beyond the neonatal period, jaundice rarely is intense. Icterus is intermittent and may be triggered by fatigue, cold exposure, emotional distress, or pregnancy. An increase in scleral icterus and a darker urine color commonly are observed in children with nonspecific viral infections. Adults who remain undiagnosed usually have a very mild form, and their hereditary spherocytosis remains undetected until challenged by an environmental stressor.
• Gallstones of the pigment type, resulting from excess unconjugated bilirubin in bile, may be found in very young children, but the incidence of gallstones increases markedly with age. In patients with mild hereditary spherocytosis, cholelithiasis may be the first sign of an underlying red cell disorder.

• Symptoms and history of hereditary spherocytosis include:
  • hemolysis
  • anemia
  • jaundice
  • weakness
  • irritability
  • shortness of breath
  • pallor
  • thrombocytopenia
  • pyelonephritis
  • hyperbilirubinemia

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Shyam Patel [2] Associate Editor(s)-in-Chief:

The physical examination findings in hereditary spherocytosis include; scleral icterus, jaundice, splenomegaly. Right upper quadrant abdominal pain may be elicited if gallbladder disease is present.

• The physical examination findings in hereditary spherocytosis include:^[1]
  • scleral icterus
  • jaundice
  • splenomegaly
• Palpable spleens have been detected in more than 75% of affected subjects. The liver is normal in size and function.
• Another important clue is right upper quadrant abdominal pain indicative of gallbladder disease. This is especially important if the patient has a family history of gallbladder disease.
• Any patient who presents with profound and sudden anemia and reticulocytopenia with the aforementioned physical findings also should have hereditary spherocytosis in the differential diagnosis.^[2]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

The initial laboratory testing for hereditary spherocytosis include; complete blood count (CBC), mean corpuscular hemoglobin concentration (MCHC), blood smear review, hemolysis testing and coombs testing. All individuals suspected of having hereditary spherocytosis based on family history, neonatal jaundice or other findings should have a complete blood count (CBC), reticulocyte count and RBC indices done. Confirmatory tests for hereditary spherocytosis includes EMA binding test, osmotic fragility test, glycerol lysis test, cryohemolysis and plasma membrane electrophoresis.

Initial testing

CBC and RBC indices

• All individuals with suspected hereditary spherocytosis based on family history, neonatal jaundice, or other findings should have a complete blood count (CBC) with reticulocyte count and red blood cell (RBC) indices.
• The mean corpuscular hemoglobin concentration (MCHC) is often the most useful parameter for assessing spherocytosis; a MCHC ≥36 g/dL is consistent with spherocytes.
• A low mean corpuscular volume (MCV) is also helpful in some cases, especially in neonates, but variable degrees of reticulocytosis make the MCV less useful in older children and adults.^[1]

Red cell indices

• Reticulocytosis
• Decreased mean corpuscular volume
• Increased mean corpuscular hemoglobin concentration
• Increased red cell distribution width

Blood smear review

• All individuals with suspected hereditary spherocytosis should have a blood smear reviewed by an experienced individual. In a peripheral blood smear, the abnormally small red blood cells lacking the central pallor i.e. spherocytes are seen. Other abnormal RBC shapes, and the degree of polychromatophilia, which reflects reticulocytosis.

Hemolysis testing

• Testing for hemolysis is also appropriate in all patients. This includes lactate dehydrogenase (LDH), indirect bilirubin, haptoglobin, and reticulocyte count. Findings consistent with hemolysis include increased LDH and indirect bilirubin, decreased or absent haptoglobin, and an elevated reticulocyte count.

Coombs testing

• If hemolysis is present, Coombs testing (also called direct antiglobulin testing [DAT]) is usually done to eliminate the possibility of immune-mediated hemolysis, which may be due to hemolytic disease of the fetus and newborn (HDFN) in neonates or autoimmune hemolytic anemia (AIHA) in older children and adults. The results of testing may also be useful to the transfusion service if transfusion is indicated.
• Coombs testing in hereditary spherocytosis is negative.

Neonates

• The evaluation of a neonate with suspected hereditary spherocytosis depends on whether a parent (or both parents) are known to have hereditary spherocytosis.
• If an infant with hyperbilirubinemia has a known family history of hereditary spherocytosis, then the likelihood of hereditary spherocytosis is high, and we rely heavily on the RBC indices. As noted above, an MCHC ≥36 g/dL is highly suggestive of hereditary spherocytosis.
• If an infant with hyperbilirubinemia or hemolytic anemia does not have a known family history of hereditary spherocytosis, then a number of other possible diagnoses must be considered.
• Appropriate therapy should not be delayed while determining the underlying cause; likewise, the importance of making the diagnosis of hereditary spherocytosis should be emphasized regardless of the management interventions needed.
• Hemolytic anemia with a negative Coombs test and a high MCHC (eg, >36 g/dL) is consistent with hereditary spherocytosis but must be considered in the context of the entire clinical picture.

• Neonates with hereditary spherocytosis tend to have an elevated MCHC (typical range in hereditary spherocytosis, 35 to 38 g/dL).
• This is a useful discriminator between hereditary spherocytosis and hemolytic disease of the fetus and newborn (HDFN) because HDFN RBCs tend to have MCHC in the range of 33 to 36 g/dL.
• Spherocytes on the blood smear are helpful if present, but up to one-third of neonates with hereditary spherocytosis do not have prominent spherocytes, and some neonates without hereditary spherocytosis have spherocytes. ^[2]
• It may be difficult to assess spherocytes on the peripheral blood smear in a neonate, either because neonates with hereditary spherocytosis may have fewer spherocytes or because spherocytic cells are often present after birth in neonates without hereditary spherocytosis.^[3] If the infant is well, it is reasonable to postpone testing until approximately six months of age or older, at which time the RBC morphology will be easier to assess.^[4]

Older children and adults

• Hereditary spherocytosis may be suspected in a patient of any age who has evidence of hemolysis (eg, elevated serum LDH, elevated indirect bilirubin, reduced haptoglobin, increased reticulocyte count) or hemolytic anemia that is Coombs-negative and not explained by another condition.

• Hereditary spherocytosis may also be suspected in an individual who presents with a complication of hemolysis, such as splenomegaly, pigmented gallstones, or an abrupt drop in hemoglobin level when the bone marrow cannot compensate for hemolysis (eg, during a viral illness, pregnancy, or other condition). In such cases, a CBC will be obtained and RBC indices will be available; the reticulocyte count should also be measured if not done already.

• Evidence consistent with hereditary spherocytosis as the likely diagnosis in an older child or adult include the following:
  • Positive family history of hereditary spherocytosis, although this is not always present as some cases arise as new mutations and not all individuals will have a complete family history available.
  • Chronic hemolytic anemia, although in mild cases, there may be chronic compensated hemolysis without anemia.
  • Jaundice and/or splenomegaly, although these may be absent if the hemolysis is mild.
  • Spherocytes on the peripheral blood smear. The percentage of spherocytes is variable. The typical reticulocyte count in older children and adults with hereditary spherocytosis is approximately 5 to 20 percent, but it may be as high as 20 to 30 percent in severe cases. Certain genetic defects have been associated with specific spherocyte morphologies, although the diagnostic value of these findings has not been rigorously tested.^[5][6][7][8]
  • Pincered or notched spherocytes – Band 3 deficiency
  • Acanthocytic spherocytes – Spectrin deficiency
  • Dense and irregularly shaped cells – Spectrin/ankyrin deficiency
  • Elliptocytic spherocytes – Spherocytic elliptocytosis
  • RBC indices consistent with spherocytosis (eg, MCHC >36 g/dL; normal to slightly low MCV). The MCV and red cell distribution width (RDW) may be increased by greater degrees of reticulocytosis in older children and adults; thus, the MCHC is the most useful of the RBC indices. The combination of increased MCHC and increased RDW further improves diagnostic performance.^[9] If reticulocyte indices are available, a higher-than-average reticulocyte MCHC and a low reticulocyte MCV are also consistent with hereditary spherocytosis.^[10]
• In cases that are unclear or if additional diagnostic confirmation is needed, specialized testing can be pursued.

Confirmatory tests

• A number of tests are available for confirming the diagnosis of hereditary spherocytosis. We perform confirmatory testing in all cases, although some experts may omit this testing, especially in resource-limited settings and/or if there are classic clinical findings in an individual with a known family history of hereditary spherocytosis.
• Available tests include the following:

EMA (eosin-5-maleimide) binding

• If specialized testing is indicated, EMA (eosin-5-maleimide) binding is our preferred test. EMA is an eosin-based fluorescent dye that binds to RBC membrane proteins, especially band 3 and Rh-related proteins.^[11]
• The mean fluorescence of EMA-labeled RBCs from individuals with hereditary spherocytosis is lower than controls, and this reduction in fluorescence can be detected in a flow cytometry-based assay. Two case series of individuals with hereditary spherocytosis have found the EMA fluorescence in individuals with hereditary spherocytosis to be approximately two-thirds that of controls. Samples can be stored and tested; one of the studies also analyzed the effect of delayed testing and found that samples stored for 24 hours in the darkness gave similar results to those tested immediately.^[12]
• Advantages of EMA binding include its high sensitivity and specificity; rapid turnaround time (approximately two hours); and need for only a minimal amount of blood (a few microliters), which is especially advantageous for testing neonates [99-101].
• In addition, EMA testing can be used to identify hereditary spherocytosis in a patient who has recently received a transfusion. In various studies, the sensitivity and specificity of the test appear to be in the ranges of 93 to 96 and 93 to 99 percent, respectively.^[13][14]
• EMA binding may also be positive in some forms of hereditary elliptocytosis (HE; eg, hereditary pyropoikilocytosis [HPP] and Southeast Asian ovalocytosis [SAO]), in individuals with congenital dyserythropoietic anemia (CDA) type II, and/or in autoimmune hemolytic anemia. False negative results may be seen in mild cases of hereditary spherocytosis.

Osmotic fragility

• If EMA binding is not available, osmotic fragility testing (OFT) is another useful specialized test for hereditary spherocytosis. In this test, RBCs are incubated in hypotonic buffered salt solutions of various osmolarities, and the fraction of hemoglobin released (due to hemolysis) is measured.
• The test takes advantage of the increased sensitivity of spherocytes to hemolysis, which is due to their reduced surface area to volume (SA/V) ratio. Incubation of patient samples for 24 hours prior to testing may accentuate osmotic fragility and improve diagnostic yield.
• The OFT has relatively low sensitivity and specificity. It fails to identify a significant number of individuals with hereditary spherocytosis and, particularly in the newborn, it may be positive in other conditions including immune hemolytic anemia, hemolytic transfusion reactions, RBC enzyme defects such as glucose-6-phosphate dehydrogenase (G6PD) deficiency, and unstable hemoglobin variants.^[15] In one series of 86 individuals with hereditary spherocytosis, only 57 (66 percent) had positive osmotic fragility testing.^[16]

Glycerol lysis

• The glycerol lysis test (GLT) and the acidified GLT (AGLT) are modifications of the OFT that add glycerol (in the GLT) or glycerol plus a sodium phosphate (to lower the pH to 6.85, in the AGLT) to the hypotonic buffered salt solutions in which the patient’s RBCs are incubated.^[17][18]
• Like the OFT, these tests may also be positive in acquired spherocytosis conditions such as AIHA.
• The “pink test” is a modification of the GLT in which the final extent of hemolysis is measured in a blood sample incubated in the glycerol solution at pH 6.66. A further modification has been proposed (the direct pink test) in which the test sample is obtained from fingerprick (or heel puncture in newborns), rather than venipuncture, and incubated directly in the glycerol solution; this requires only a few microliters of blood.^[19]

Cryohemolysis

• In the cryohemolysis test, RBCs are suspended in a hypertonic solution, briefly heated to 37°C, then cooled to 4°C for 10 minutes.^[20]
• The ease of performance and the wide separation in degree of hemolysis between spherocytes and normal cells are two attractive features of this test.^[21]
• This test has limited availability in the United States.
• Plasma membrane electrophoresis^[22][23]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief:

There are no particular Chest Xray findings associated with hereditary spherocytosis.

There are no particular Chest Xray findings associated with hereditary spherocytosis.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Shyam Patel [2] Associate Editor(s)-in-Chief:

There are no particular CT scan findings associated with hereditary spherocytosis.

• There are no particular CT scan findings associated with hereditary spherocytosis.

• In abdominal CT scan the preferred sites of extramedullary hematopoietic involvement are the spleen, liver and lymph nodes, but in hereditary spherocytosis the posterior paravertebral mediastinum is also commonly involved.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief:

There are no particular MRI findings associated with hereditary spherocytosis.

There are no particular MRI findings associated with hereditary spherocytosis.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief:

An ultrasound of abdomen can be performed to help detect the cholecystitis or cholelithiasis, which may develop in hereditary spherocytosis cases.

• Cholecystitis and cholelithiasis are common complications of hereditary spherocytosis. If the patient presents with signs and symptoms of hemolysis in addition to right upper abdominal quadrant pain, fever, and leukocytosis, an ultrasound of the biliary tree should be performed.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief:

There are no particular other imaging findings associated with hereditary spherocytosis.

• There are no other imaging findings associated with hereditary spherocytosis.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief:

There are no other specilaized testing available for the hereditary spherocytosis.

• There are no other specilaized tests available for the hereditary spherocytosis.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

There is no specific medical therapy for the hereditary spherocytosis, as the diagnosis is made, surveillance is needed to help detect and manage any complications. A routine annual review is usually sufficient to detect any complications. Folic acid supplementation is not always required, but is used as a routine for children with severe hemolysis and in pregnancy regardless of severity of disease. Blood transfusion may also be required in severely affected infants and may be needed during aplastic crisis or pregnancy. However, erythropoietin (EPO) may be helpful in reducing the need for transfusion in some infants.

• There is no specific medical therapy for hereditary spherocytosis. As the diagnosis of hereditary spherocytosis is made, surveillance is needed to help detect and manage any complications.^[1]
• A routine annual review is usually sufficient to detect any complications such as parvovirus infection or abdominal pain which may necessitate the investigation for gallstones.
• Folic acid
  • Folate supplementation is not always required, but is used as a routine for children with severe hemolysis and in pregnancy, regardless of severity of hereditary spherocytosis.^[2]
  • Folic acid supplementation is appropriate for those with moderate to severe hemolysis and/or during pregnancy.
  • This is based on an increased requirement for folate in RBC production; there are no clinical trials investigating the role of folic acid treatment, and observational studies that documented megaloblastic anemia in a small number of patients with hereditary spherocytosis were performed before the institution of routine folic acid supplementation of grains and cereals.^[3]
  • The typical dose for those with moderate to severe hemolysis is 1 to 2 mg/day, while those who have hereditary spherocytosis of any severity and are pregnant should receive doses as high as 4 to 5 mg/day, as discussed separately.
  • For individuals with mild hemolysis who have normal intake of fresh fruits and vegetables (or folic-acid-supplemented grains), daily folic acid is not required, but for those who place a high value on avoiding folate deficiency, which could cause worsening anemia, taking daily folic acid (typical dose, 1 to 2 mg daily) is safe and inexpensive, and there are essentially no side effects or contraindications.

• Transfusions
  • Blood transfusion is often required in severely affected infants and may be needed during certain times in other settings (eg, aplastic crisis, pregnancy).However, transfusions usually are not required on a chronic basis or for a long enough time to cause iron overload.
  • Typical hemoglobin thresholds for transfusion depend on the age of the patient, symptoms, and comorbidities.
  • Some infants may require transfusions for anemia and/or hyperbilirubinemia. Older children may be able to tolerate a hemoglobin level of 5 to 6 g/dL without transfusions.
  • Adults may require transfusions for anemia, with thresholds determined by their clinical status,
  • Individuals with an aplastic crisis due to parvovirus infection or other bone marrow insult may require transfusions if they have a decreasing hemoglobin level without a robust reticulocytosis.
  • The usual course of parvovirus associated anemia is spontaneous resolution within a few days or weeks. Infected individuals are monitored with twice-weekly complete blood counts (CBCs) and reticulocyte counts to determine the expected hemoglobin nadir and the need for transfusion.
  • Consideration of transfusional iron overload typically occurs after transfusion of more than 15 to 20 units of RBCs (more than 10 units in smaller children).
  • Adults with mild hemolysis may have a slight increase in iron absorption, and if this occurs in the setting of hereditary hemochromatosis, which is common, iron overload may occur.

• Erythropoietin
  • Erythropoietin (EPO) may be helpful in reducing the need for transfusion in some infants.^[4]
  • Typically, this can be discontinued around the age of nine months. In one study, the use of recombinant human erythropoietin (1000 international units/kg per week) with iron supplementation obviated the need for transfusion in 13 of 16 infants with severe hereditary spherocytosis.^[5]
  • As the infants grew and began to mount an adequate erythropoietic response, the erythropoietin dose could be tapered and discontinued before the age of nine months.

• Other therapies
  • Allogeneic hematopoietic cell transplantation (HCT) is not used in hereditary spherocytosis due to an unfavorable risk-benefit ratio, but a case was reported in which an individual with both hereditary spherocytosis and chronic myelogenous leukemia (CML) underwent allogeneic hematopoietic stem cell transplantation, which cured both disorders.^[6]

• There are no special restrictions (eg, no activity limitations) on children with splenomegaly due to hereditary spherocytosis.^[7]

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

There is no specific medical therapy for the hereditary spherocytosis, as the diagnosis is made, surveillance is needed to help detect and manage any complications. A routine annual review is usually sufficient to detect any complications. Folic acid supplementation is not always required, but is used as a routine for children with severe hemolysis and in pregnancy regardless of severity of disease. Blood transfusion may also be required in severely affected infants and may be needed during aplastic crisis or pregnancy. However, erythropoietin (EPO) may be helpful in reducing the need for transfusion in some infants.

• There is no specific medical therapy for hereditary spherocytosis. As the diagnosis of hereditary spherocytosis is made, surveillance is needed to help detect and manage any complications.^[1]
• A routine annual review is usually sufficient to detect any complications such as parvovirus infection or abdominal pain which may necessitate the investigation for gallstones.
• Folic acid
  • Folate supplementation is not always required, but is used as a routine for children with severe hemolysis and in pregnancy, regardless of severity of hereditary spherocytosis.^[2]
  • Folic acid supplementation is appropriate for those with moderate to severe hemolysis and/or during pregnancy.
  • This is based on an increased requirement for folate in RBC production; there are no clinical trials investigating the role of folic acid treatment, and observational studies that documented megaloblastic anemia in a small number of patients with hereditary spherocytosis were performed before the institution of routine folic acid supplementation of grains and cereals.^[3]
  • The typical dose for those with moderate to severe hemolysis is 1 to 2 mg/day, while those who have hereditary spherocytosis of any severity and are pregnant should receive doses as high as 4 to 5 mg/day, as discussed separately.
  • For individuals with mild hemolysis who have normal intake of fresh fruits and vegetables (or folic-acid-supplemented grains), daily folic acid is not required, but for those who place a high value on avoiding folate deficiency, which could cause worsening anemia, taking daily folic acid (typical dose, 1 to 2 mg daily) is safe and inexpensive, and there are essentially no side effects or contraindications.

• Transfusions
  • Blood transfusion is often required in severely affected infants and may be needed during certain times in other settings (eg, aplastic crisis, pregnancy).However, transfusions usually are not required on a chronic basis or for a long enough time to cause iron overload.
  • Typical hemoglobin thresholds for transfusion depend on the age of the patient, symptoms, and comorbidities.
  • Some infants may require transfusions for anemia and/or hyperbilirubinemia. Older children may be able to tolerate a hemoglobin level of 5 to 6 g/dL without transfusions.
  • Adults may require transfusions for anemia, with thresholds determined by their clinical status,
  • Individuals with an aplastic crisis due to parvovirus infection or other bone marrow insult may require transfusions if they have a decreasing hemoglobin level without a robust reticulocytosis.
  • The usual course of parvovirus associated anemia is spontaneous resolution within a few days or weeks. Infected individuals are monitored with twice-weekly complete blood counts (CBCs) and reticulocyte counts to determine the expected hemoglobin nadir and the need for transfusion.
  • Consideration of transfusional iron overload typically occurs after transfusion of more than 15 to 20 units of RBCs (more than 10 units in smaller children).
  • Adults with mild hemolysis may have a slight increase in iron absorption, and if this occurs in the setting of hereditary hemochromatosis, which is common, iron overload may occur.

• Erythropoietin
  • Erythropoietin (EPO) may be helpful in reducing the need for transfusion in some infants.^[4]
  • Typically, this can be discontinued around the age of nine months. In one study, the use of recombinant human erythropoietin (1000 international units/kg per week) with iron supplementation obviated the need for transfusion in 13 of 16 infants with severe hereditary spherocytosis.^[5]
  • As the infants grew and began to mount an adequate erythropoietic response, the erythropoietin dose could be tapered and discontinued before the age of nine months.

• Other therapies
  • Allogeneic hematopoietic cell transplantation (HCT) is not used in hereditary spherocytosis due to an unfavorable risk-benefit ratio, but a case was reported in which an individual with both hereditary spherocytosis and chronic myelogenous leukemia (CML) underwent allogeneic hematopoietic stem cell transplantation, which cured both disorders.^[6]

• There are no special restrictions (eg, no activity limitations) on children with splenomegaly due to hereditary spherocytosis.^[7]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief:

Generally, the treatment of hereditary spherocytosis involves presplenectomy care, splenectomy and management of postsplenectomy complications. Splenectomy is very effective in reducing hemolysis, leading to significant prolongation of red blood cell lifespan. Partial splenectomies can be used in pediatric patients as it controls hemolysis and preserves splenic function. Patients having concomitant gallstones are likely to benefit from combined splenectomy and cholecystectomy in terms of life expectancy. Post splenectomy complications may include; infections & sepsis caused by encapsulated organisms (streptococcus pneumoniae, neisseria meningitidis, haemophilus influenza), deep venous thrombosis (DVT), pulmonary emboli and portal vein thrombosis.

• Splenectomy
  • Splenectomy is very effective in reducing hemolysis, leading to significant prolongation of the red blood cell lifespan.^[1][2]
  • Patients should be selected for splenectomy on the basis of their clinical symptoms and presence of complications such as gallstones, not simply on the basis of diagnosis alone.
  • Generally, the treatment of hereditary spherocytosis involves presplenectomy care, splenectomy, and management of postsplenectomy complications.
  • In pediatric cases, splenectomy ideally should not be performed until a child is older than 6 years because of the increased incidence of postsplenectomy infections with encapsulated organisms such as streptococcus pneumoniae and haemophilus influenzae in young children.
  • Partial splenectomies are increasingly used in pediatric patients, as this approach appears to both control hemolysis and preserve splenic function.
  • European guidelines on splenectomy for hereditary spherocytosis note that a laparoscopic approach is currently considered the gold standard for removal of a normal-sized or slightly enlarged spleen and is preferred to open splenectomy, but it should be performed only by experienced surgeons.
  • Children or young adults with mild hereditary spherocytosis who also has gallstones are likely to benefit from combined splenectomy and cholecystectomy in terms of life expectancy.^[3]
  • Following splenectomy, the clinical manifestations and complications (anemia & gallstones) are much reduced in severe hereditary spherocytosis and abolished in milder cases, but at the risk of increased life threatening sepsis from encapsulated organisms, particularly streptococcus pneumoniae.^[3][4]

• Complications of splenectomy
  • Splenectomy has a number of known risks of which patients (or parents) should be aware^[5]
  • Operative risks (eg, infection, bleeding, or injury to adjacent organs such as the stomach or tail of the pancreas); these are relatively infrequent.
  • Infections, including overwhelming sepsis, from encapsulated organisms (streptococcus pneumoniae, neisseria meningitidis, hemophilus influenzae) that can no longer be removed by normal splenic clearance mechanisms, as well as certain other microorganisms including plasmodia, Babesia, Bordetella and Capnocytophaga species (from animal bites).^[6]
  • These risks are thought to be highest in the first year following splenectomy and in individuals undergoing splenectomy before five to six years of age.
  • However, risks of sepsis are likely to have declined with improved options for preoperative vaccinations and postoperative prophylactic penicillin. This was illustrated in a 1991 study from the Danish National Patient Registry that demonstrated a dramatic reduction in serious streptococcus pneumoniae infections following pneumococcal vaccination.^[7]
  • Individuals who did not receive appropriate pre-splenectomy vaccinations should have a thorough review of their immunization history and should receive vaccinations.
  • Venous thromboembolic (VTE) complications including thromboses of the deep veins, pulmonary emboli, splenic or portal vein thrombosis, as well as thrombosis in other unusual sites.^[8][9]
  • Venous thromboembolism events appear to be more common in individuals with hereditary spherocytosis who undergo splenectomy than in those who do not, but the individuals who undergo splenectomy may have had more severe underlying disease, making direct comparisons difficult.
  • Thromboprophylaxis at the time of surgery should be used based on standard practices; there is no indication for extended thromboprophylaxis beyond the usual duration.
  • Arterial thrombotic events may also be increased relative to individuals with hereditary spherocytosis who do not undergo splenectomy, with the same caveat that applies to venous thromboembolism (patients who undergo splenectomy may have more severe underlying disease).^[10][11]
  • It is not clear whether pulmonary artery hypertension (PAH) is a complication of splenectomy in hereditary spherocytosis.^[12]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief:

There is no primary prevention available for the hereditary spherocytosis.

• There is no primary prevention available for the hereditary spherocytosis.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Shyam Patel [2] Associate Editor(s)-in-Chief:

The administration of vaccines including pneumococcal, hemophilus influenzae, meningococcal and influenza should be given two to three weeks before splenectomy. Folic acid supplementation as well as oral penicillin is also suggested for postsplenectomy patients untill reaching adulthood.

• The administration of vaccines (pneumococcal, haemophilus influenzae type b, meningococcal group C and influenza) is indicated 2 to 3 weeks before splenectomy.^[1]
• Postsplenectomy patients should also be given 1mg of folic acid daily for preventing secondary folic acid deficiency and oral penicillin (penicillin V) for preventing secondary infection until reaching adulthood.
• In general, once the diagnosis and baseline severity of hereditary spherocytosis in a child are established, it is not necessary to perform repeated blood tests unless there is an additional clinical indication (such as intercurrent infection and pallor, or an increase in jaundice).^[2]
• Avoidance of precipitants of hemolysis (such as sulfa drugs or quinines) and certain foods (such as fava beans) may help prevent hemolysis.

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