Hereditary Spherocytosis

Hereditary spherocytosis (HS) is the most common type of hereditary hemolytic anemia Hemolytic Anemia Hemolytic anemia (HA) is the term given to a large group of anemias that are caused by the premature destruction/hemolysis of circulating red blood cells (RBCs). Hemolysis can occur within (intravascular hemolysis) or outside the blood vessels (extravascular hemolysis). Hemolytic Anemia. The condition is caused by a cytoskeletal protein deficiency in the RBC membrane. This results in loss of membrane stability and deformability of the RBC, giving the cell its spherical shape (spherocyte). These cells are predisposed to splenic degradation, leading to hemolysis. Examination may show jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Jaundice and splenomegaly Splenomegaly Splenomegaly is pathologic enlargement of the spleen that is attributable to numerous causes, including infections, hemoglobinopathies, infiltrative processes, and outflow obstruction of the portal vein. Splenomegaly, while laboratory tests are consistent with hemolytic anemia Hemolytic Anemia Hemolytic anemia (HA) is the term given to a large group of anemias that are caused by the premature destruction/hemolysis of circulating red blood cells (RBCs). Hemolysis can occur within (intravascular hemolysis) or outside the blood vessels (extravascular hemolysis). Hemolytic Anemia and increased hemoglobin concentration. Among multiple confirmatory tests for HS, the eosin-5’-maleimide (EMA) binding test is preferred. The only definitive treatment for HS is splenectomy.

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Epidemiology and Etiology

Epidemiology

  • The most common type of hereditary hemolytic anemia Hemolytic Anemia Hemolytic anemia (HA) is the term given to a large group of anemias that are caused by the premature destruction/hemolysis of circulating red blood cells (RBCs). Hemolysis can occur within (intravascular hemolysis) or outside the blood vessels (extravascular hemolysis). Hemolytic Anemia due to red cell membrane Cell Membrane A cell membrane (also known as the plasma membrane or plasmalemma) is a biological membrane that separates the cell contents from the outside environment. A cell membrane is composed of a phospholipid bilayer and proteins that function to protect cellular DNA and mediate the exchange of ions and molecules. The Cell: Cell Membrane defect
  • Common in those of northern European descent, affecting 1 in 3,000 individuals
  • United States: 1.4% of the population may be silent carriers of hereditary spherocytosis (HS)

Etiology

  • Majority of cases are autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance with variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables penetrance
  • Involves the RBC cell membrane Cell Membrane A cell membrane (also known as the plasma membrane or plasmalemma) is a biological membrane that separates the cell contents from the outside environment. A cell membrane is composed of a phospholipid bilayer and proteins that function to protect cellular DNA and mediate the exchange of ions and molecules. The Cell: Cell Membrane, which has 3 main components:
    • Lipid bilayer
    • Membrane proteins (band 3 is one of them)
    • Cytoskeletal network, of which spectrin is the most abundant protein

In HS, gene mutations lead to cytoskeletal protein deficiency:

  • Spectrin deficiency
    • Spectrin, a protein comprising α and β heterodimers, keeps the cell shape and elasticity.
    • Genes: 
    • Deficiency can be from:
      • Other defective membrane proteins that bind spectrin (even in ANK1 mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations causing ankyrin defect, there is spectrin deficiency due to loss of ankyrin attachment sites)
      • Impaired spectrin synthesis from SPTA1/SPTB1 mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations
    • Degree of spectrin deficiency correlates with the severity of spherocytosis.
  • Ankyrin deficiency
    • Anchors transmembrane proteins to the skeleton through spectrin, band 3, and protein 4.2
    • Encoded by ANK1 gene ( autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations)
    • Mutation of ANK1 causes combined ankyrin and spectrin deficiency (see above), which is found in 75% of  autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance HS patients.
  • Band 3 
    • Encoded by SLC4A1 gene ( autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations)
    • Mutations can present with distal renal tubule acidosis.
  • Protein 4.2 
    • Regulates binding of band 3 to ankyrin
    • Encoded by EPB42 gene (mutations mostly autosomal recessive)
    • Mutations commonly found in Japan
Hereditary spherocytosis

Major proteins of the RBC membrane

Image by Lecturio.

Pathophysiology

  • Normal biconcave RBCs circulate repeatedly through narrow channels → requires extensive reversible deformation
  • Defective cytoskeletal proteins → interrupt the vertical structure (spectrin-actin interaction) → disrupted cohesion of the inner membrane skeleton and the outer lipid bilayer → loss of surface area and stability of the RBC → spherocytes
  • Spherocytes are prone to hemolysis:
    • Abnormal RBCs without cellular deformability → trapped by the spleen Spleen The spleen is the largest lymphoid organ in the body, located in the LUQ of the abdomen, superior to the left kidney and posterior to the stomach at the level of the 9th-11th ribs just below the diaphragm. The spleen is highly vascular and acts as an important blood filter, cleansing the blood of pathogens and damaged erythrocytes. Spleen → successively destroyed by macrophages
    • Low pH, low glucose, and high free radicals in the splenic environment lead to more membrane damage.

Clinical Presentation

General features

  • Anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview: pallor, tachycardia, fatigue, shortness of breath, transfusion dependency
  • Extravascular hemolysis causing bilirubin 
    • Recurrent jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Jaundice 
    • Hemoglobinuria
    • Gallstones (+/- pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain in right upper quadrant) 
    • Splenomegaly

Categories

Four clinical categories have been established based on hemoglobin (Hb), reticulocyte (retic) count, and bilirubin (bili) level.

  1. HS trait: 
    • No anemia, normal reticulocyte count, asymptomatic
  2. Mild HS: 
    • Hb 11–15 g/dL, retic 3-6%, bili 1–2 mg/dL
    • 20%–30% of cases
  3. Moderate HS: 
    • Hb 8–12 g/dL, retic > 6%, bili > 2 mg/dL
    • 60%–75% of cases
  4. Severe HS
    • Hb 6–8 g/dL, retic > 10%, bili > 3%
    • 5% of cases
Jaundice eye

Scleral icterus: The 1st clinical sign of bilirubin deposition in the body

Image: “Jaundice eye new” by CDC/Dr. Thomas F. Sellers/Emory University. License: Public Domain

Diagnosis

History and physical exam

  • Check for family history of HS, gallstones
  • Jaundice or splenomegaly Splenomegaly Splenomegaly is pathologic enlargement of the spleen that is attributable to numerous causes, including infections, hemoglobinopathies, infiltrative processes, and outflow obstruction of the portal vein. Splenomegaly (currently present or in history)

Initial tests

  • CBC
    • Anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview (↓ hemoglobin)
    • Normal to mildly MCV (mean corpuscular volume)
    • MCHC (mean corpuscular hemoglobin concentration) 
      • ≥ 36 g/dL
      • Most common finding in neonates 
      • Often the most useful parameter for spherocytosis
  • Peripheral blood smear
    • Spherocytes: lack of central pallor, increased density (not specific to HS)
    • Abnormal RBC shapes
    • Polychromatophilia (affinity for multiple stains)
  • Hemolysis work-up:
    • lactate dehydrogenase (LDH)
    • reticulocytes 
    • indirect/unconjugated bilirubin
    • ↓ haptoglobin

Confirmatory tests

  • Eosin-5’-maleimide (EMA) binding test
    • Most reliable test
    • Eosin-based fluorescent dye binds to cell membrane Cell Membrane A cell membrane (also known as the plasma membrane or plasmalemma) is a biological membrane that separates the cell contents from the outside environment. A cell membrane is composed of a phospholipid bilayer and proteins that function to protect cellular DNA and mediate the exchange of ions and molecules. The Cell: Cell Membrane protein (band 3) in RBC 
    • ↓ fluorescence intensity in HS
    • Advantages: high specificity and sensitivity, short turnaround time, minimal amount of blood used (5 µL)
    • Mild HS may come out false negative.
  • Osmotic fragility test 
    • Positive in hereditary spherocytosis 
    • RBCs placed in serial solutions of saline; Spherocytes, with low surface-to-volume area, hemolyze in hypoosmotic solutions.
    • Labor Labor Labor is the normal physiologic process defined as uterine contractions resulting in dilatation and effacement of the cervix, which culminates in expulsion of the fetus and the products of conception. Normal and Abnormal Labor-intensive, takes 18–24 hours
    • Low sensitivity in detecting mild HS and newborn Newborn A neonate, or newborn, is defined as a child less than 28 days old. A thorough physical examination should be performed within the first 24 hours of life to identify abnormalities and improve outcomes by offering timely treatment. Physical Examination of the Newborn HS 
  • Acidified glycerol lysis test (AGLT): 
    • Modified osmotic fragility test using glycerol solution
    • “Pink test”: a modified AGLT
    • Comparable sensitivity with EMA test
    • Combination of EMA test with AGLT identifies all patients with HS.
  • Molecular analysis for gene mutations 
    • Further characterization of mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations for family members
    • Done if test(s) us equivocal and/or management will be altered (e.g., splenectomy)
Hereditary spherocytosis

Hereditary spherocytosis (HS): peripheral blood smear

The black arrow shows a spherocyte. The white arrow shows a normal RBC (the lack of central pallor is an artifact). Hereditary spherocytosis forms having different membrane defects can show different red cell morphologies.

Image: “Previously undiagnosed HS” by US National Library of Medicine. License: CC BY 4.0

Management and Complications

Management

  • Education about the risks of aplastic crisis and splenic rupture Splenic rupture Splenic rupture is a medical emergency that carries a significant risk of hypovolemic shock and death. Injury to the spleen accounts for nearly half of all injuries to intra-abdominal organs. The most common reason for a rupture of the spleen is blunt abdominal trauma, specifically, motor vehicle accidents. Rupture of the Spleen (in those with splenomegaly Splenomegaly Splenomegaly is pathologic enlargement of the spleen that is attributable to numerous causes, including infections, hemoglobinopathies, infiltrative processes, and outflow obstruction of the portal vein. Splenomegaly)
  • Folate Folate Folate and vitamin B12 are 2 of the most clinically important water-soluble vitamins. Deficiencies can present with megaloblastic anemia, GI symptoms, neuropsychiatric symptoms, and adverse pregnancy complications, including neural tube defects. Folate and Vitamin B12 supplementation
    • For pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care (4–5 mg/day)
    • In moderate to severe HS (1–2 mg/day)
  • Transfusion in aplastic crisis
  • Cholecystectomy Cholecystectomy Cholecystectomy is a surgical procedure performed with the goal of resecting and extracting the gallbladder. It is one of the most common abdominal surgeries performed in the Western world. Cholecystectomy is performed for symptomatic cholelithiasis, cholecystitis, gallbladder polyps > 0.5 cm, porcelain gallbladder, choledocholithiasis and gallstone pancreatitis, and rarely, for gallbladder cancer. Cholecystectomy: Approaches and Technique for symptomatic gallstones
  • Splenectomy
    • Definitive management for severe hemolysis (> 6 years old to reduce risk of sepsis Sepsis Organ dysfunction resulting from a dysregulated systemic host response to infection separates sepsis from uncomplicated infection. The etiology is mainly bacterial and pneumonia is the most common known source. Patients commonly present with fever, tachycardia, tachypnea, hypotension, and/or altered mentation. Sepsis and Septic Shock), especially those requiring recurrent transfusion
    • Immunization for encapsulated organisms ( Streptococcus Streptococcus Streptococcus is one of the two medically important genera of gram-positive cocci, the other being Staphylococcus. Streptococci are identified as different species on blood agar on the basis of their hemolytic pattern and sensitivity to optochin and bacitracin. There are many pathogenic species of streptococci, including S. pyogenes, S. agalactiae, S. pneumoniae, and the viridans streptococci. Streptococcus pneumoniae, Haemophilus Haemophilus Haemophilus is a genus of Gram-negative coccobacilli, all of whose strains require at least 1 of 2 factors for growth (factor V [NAD] and factor X [heme]); therefore, it is most often isolated on chocolate agar, which can supply both factors. The pathogenic species are H. influenzae and H. ducreyi. Haemophilus influenzae type B, and Neisseria Neisseria Neisseria is a genus of bacteria commonly present on mucosal surfaces. Several species exist, but only 2 are pathogenic to humans: N. gonorrhoeae and N. meningitidis. Neisseria species are non-motile, gram-negative diplococci most commonly isolated on modified Thayer-Martin (MTM) agar. Neisseria meningitidis) before splenectomy
  • Pediatric cases:
    • Erythropoietin (EPO) can be administered in anemic infants to decrease the need for transfusion.
    • Neonatal jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Jaundice
      • Phototherapy
      • Exchange transfusion

Complications

  • Exacerbations of anemia
    • Transient aplastic crisis can be caused by viral or bacterial infections (commonly parvovirus B19 Parvovirus B19 Primate erythroparvovirus 1 (generally referred to as parvovirus B19, B19 virus, or sometimes erythrovirus B19) ranks among the smallest DNA viruses. Parvovirus B19 is of the family Parvoviridae and genus Erythrovirus. In immunocompetent humans, parvovirus B19 classically results in erythema infectiosum (5th disease) or "slapped cheek syndrome." Parvovirus B19).
      • RBC production in bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow is suppressed so that it cannot compensate for the peripheral loss of RBCs by chronic hemolysis.
    • Splenomegaly:
      • Noted in 75% of affected patients
      • If augmented by a superimposed cause of splenomegaly Splenomegaly Splenomegaly is pathologic enlargement of the spleen that is attributable to numerous causes, including infections, hemoglobinopathies, infiltrative processes, and outflow obstruction of the portal vein. Splenomegaly, (e.g., infectious mononucleosis Mononucleosis Infectious mononucleosis (IM), also known as "the kissing disease," is a highly contagious viral infection caused by the Epstein-Barr virus. Its common name is derived from its main method of transmission: the spread of infected saliva via kissing. Clinical manifestations of IM include fever, tonsillar pharyngitis, and lymphadenopathy. Mononucleosis, cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis, lymphoma), then increased sequestration (pooling) of RBCs and/or hemolysis may occur.
    • Nutrient deficiencies: Deficiencies in folate, iron, or vitamin B12 may interfere with RBC production.
      • Pregnancy: added stress of increasing RBC mass and expanding plasma volume may worsen anemia, and folic acid and iron deficiencies may occur
    • Pigment (bilirubin) gallstones:
      • Rare before the age of 10
      • Due to hyperbilirubinemia
      • May present as cholecystitis Cholecystitis Cholecystitis is the inflammation of the gallbladder (GB) usually caused by the obstruction of the cystic duct (acute cholecystitis). Mechanical irritation by gallstones can also produce chronic GB inflammation. Cholecystitis is one of the most common complications of cholelithiasis but inflammation without gallstones can occur in a minority of patients. Cholecystitis
  • Newborns at risk for kernicterus (neurologic damage from severe hyperbilirubinemia)

Differential Diagnosis

The differential diagnosis includes other causes of hemolysis, most of which will show at least some spherocytes in the peripheral blood.

  • Sickle cell disease Sickle cell disease Sickle cell disease (SCD) is a group of genetic disorders in which an abnormal Hb molecule (HbS) transforms RBCs into sickle-shaped cells, resulting in chronic anemia, vasoocclusive episodes, pain, and organ damage. Sickle Cell Disease: a group of hereditary disorders characterized by abnormal hemoglobin structure leading to polymerization and deformation of RBCs. Patients present in early childhood with chronic hemolytic anemia Hemolytic Anemia Hemolytic anemia (HA) is the term given to a large group of anemias that are caused by the premature destruction/hemolysis of circulating red blood cells (RBCs). Hemolysis can occur within (intravascular hemolysis) or outside the blood vessels (extravascular hemolysis). Hemolytic Anemia, chronic pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain, and infections. Sickle cell crises are episodes of acute increased hemolysis requiring blood transfusions. Bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones marrow transplantation is the only curative treatment.
  • Glucose-6-phosphate dehydrogenase deficiency Glucose-6-phosphate Dehydrogenase Deficiency Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a type of intravascular hemolytic anemia. The condition is inherited in an X-linked recessive manner. Patients have episodic hemolysis due to an oxidative stressor that causes damage to red blood cells, which lack sufficient NADPH to protect them from oxidative injury. Glucose-6-phosphate Dehydrogenase (G6PD) Deficiency (G6PD): an X-linked recessive defect that increases the susceptibility of RBCs to oxidative stress, resulting in episodes of hemolytic anemia Hemolytic Anemia Hemolytic anemia (HA) is the term given to a large group of anemias that are caused by the premature destruction/hemolysis of circulating red blood cells (RBCs). Hemolysis can occur within (intravascular hemolysis) or outside the blood vessels (extravascular hemolysis). Hemolytic Anemia. Patients present with abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain, jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Jaundice, hemoglobinuria, and enlargement of the spleen Spleen The spleen is the largest lymphoid organ in the body, located in the LUQ of the abdomen, superior to the left kidney and posterior to the stomach at the level of the 9th-11th ribs just below the diaphragm. The spleen is highly vascular and acts as an important blood filter, cleansing the blood of pathogens and damaged erythrocytes. Spleen. Triggers include consumption of fava beans, drugs (antimalarials, antibiotics, nonsteroidal anti-inflammatory drugs (NSAIDs)), and infections. Management includes avoidance of triggers. There is no curative treatment.
  • Immune-related hemolysis: caused by cold or warm reactive immunoglobulins Immunoglobulins Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins that attach to RBCs and destroy the membrane. Many cases are idiopathic; secondary causes include malignancy, infections, and other autoimmune diseases such as SLE SLE Systemic lupus erythematosus (SLE) is a chronic autoimmune, inflammatory condition that causes immune-complex deposition in organs, resulting in systemic manifestations. Women, particularly those of African American descent, are more commonly affected. Systemic Lupus Erythematosus. Treatment includes trigger avoidance, immunosuppressants Immunosuppressants Immunosuppressants are a class of drugs widely used in the management of autoimmune conditions and organ transplant rejection. The general effect is dampening of the immune response. Immunosuppressants ( glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids, rituximab), and IV immunoglobulins Immunoglobulins Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins.

References

  1. Bianchi, P. et al. (2012). Diagnostic power of laboratory tests for hereditary spherocytosis: a comparison study in 150 patients grouped according to molecular and clinical characteristics. 97(4): 516–523. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3347664/
  2. Ciepiela,O. (2018). Old and new insights into the diagnosis of hereditary spherocytosis. Ann Transl Med. 6(17): 339. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6174190/
  3. Gonzalez, G.; Talavera, F. & Sacher, R. (Eds.). (2018). Hereditary Spherocytosis. Medscape. Retrieved 24 Aug, 2020, from https://emedicine.medscape.com/article/206107
  4. Mentzer, W.; Leung, L. (Ed.); Tirnauer, J. (Ed.). (2019). Hereditary Spherocytosis. Uptodate. Retrieved 24 Aug, 2020, from https://www.uptodate.com/contents/hereditary-spherocytosis
  5. Saavides, P.; Shalev, O.; John, K.; Lux, S.(1993). Combined Spectrin and Ankyrin deficiency is common in autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance hereditary spherocytosis. Blood.82:2953-2960.
  6. Tole, S., Dhir, P., Pugi, J., et al. (2020). Genotype–phenotype correlation in children with hereditary spherocytosis. Br J Haematol. doi:10.1111/bjh.16750
  7. Perrotta, S., Gallagher, P.G., Mohandas, N. (2008). Hereditary spherocytosis. Lancet 2008; 372: 1411–26
  8. Lynch, E.. (1990). Peripheral Blood Smear. In: Walker, H.K., Hall, W.D., Hurst, J.W. (Eds.). Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd edition. Boston: Butterworths; 1990. Chapter 155. Retrieved 16 Oct, 2020, from https://www.ncbi.nlm.nih.gov/books/NBK263/

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