We mainly searched our personal database of references, which was prospectively built by monthly search of PubMed in the past 15–20 years, with the following key words and their combinations in all fields: “hereditary spherocytosis”, “red cell membrane”, “spectrin”, “ankyrin”, “band 3”, “spherocytes”, “splenectomy”, “gallstones”, or “cholecystectomy”. We mainly selected studies from the past 10 years, but did not exclude commonly cited older publications. We only read the abstracts of
SeminarHereditary spherocytosis
Introduction
Hereditary spherocytosis refers to a group of heterogeneous inherited anaemias that are characterised by the presence of spherical-shaped erythrocytes (spherocytes) on the peripheral blood smear.1, 2, 3 This disorder, including the very mild or subclinical forms, is the most common cause of inherited chronic haemolysis in northern Europe and North America where it affects about one person in 2000.4, 5, 6, 7, 8, 9, 10, 11 It has also been frequently described in other populations, notably in Japan.12 Although the disease arises in all racial and ethnic groups, on the basis of clinical reports, it seems to be less common in African-American and southeast Asian people; however, comprehensive population survey data are unavailable for these populations.
Section snippets
Pathophysiological effects
The red blood cell or erythrocyte membrane is a dynamic and fluid structure with the strength and flexibility needed to survive 120 days in the circulation. Its lipid bilayer is composed mainly of phospholipids and cholesterol, with integral proteins embedded in the lipid bilayer that span the membrane and a membrane skeleton on the cytoplasmic side (figure 1).1, 13, 14, 15, 16 The polar heads of the lipid bilayer are turned outward and their apolar fatty-acid chains face one another and form
Causes
Membrane loss in hereditary spherocytosis is associated with defects in several membrane proteins. On the basis of densitometric quantification of membrane proteins separated by sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) and western blot analysis, this disease can be divided into subsets: (1) isolated deficiency of spectrin; (2) combined deficiency of spectrin and ankyrin; (3) deficiency of band-3 protein; (4) deficiency of protein 4.2; (5) deficiency of Rh complex;
Clinical features
The clinical manifestations of hereditary spherocytosis vary widely (panel 1). Manifestations of typical disease are haemolysis with anaemia, jaundice, reticulocytosis, gallstones, and splenomegaly, and spherocytes on peripheral blood smear (figure 3), increased erythrocyte osmotic fragility, and a positive family history of disease.1, 2, 3, 74 It is most commonly associated with dominant inheritance, although non-dominant and recessive inheritance has been described.75 Initial assessment of a
Gallbladder disease
Chronic haemolysis leads to the formation of bilirubinate gallstones, which are the most common complication of hereditary spherocytosis. Gallstones are noted in at least 5% of children less than 10 years of age;7 the proportion increases to 40–50% in the second to fifth decades, with most stones arising between 10 and 30 years of age.88 The co-inheritance of Gilbert's syndrome increases the risk of cholelithiasis by four-fold to five-fold.89 Timely diagnosis and treatment will help prevent
Diagnosis and laboratory features
Hereditary spherocytosis is usually diagnosed based on a combination of clinical and family histories, physical examination (for splenomegaly or jaundice), and laboratory data (full blood count, especially red blood cell indices and morphology, and reticulocyte count; figure 4).1, 3 Other causes of anaemia should be excluded, particularly autoimmune haemolytic anaemia, congenital dyserythropoietic anaemia type II, and hereditary stomatocytosis.
Interpretation of the direct antiglobulin
Splenectomy
Splenic sequestration is the main determinant of erythrocyte survival in patients with hereditary spherocytosis. Thus, splenectomy cures almost all patients with this disorder, eliminating the anaemia and hyperbilirubinaemia and reducing the reticulocyte count to nearly normal.3, 23, 75 After splenectomy, spherocytosis and altered osmotic fragility persist, but the tail of the osmotic fragility curve disappears. Although patients with very severe disease are not completely cured by splenectomy,
Conclusion and future directions
Challenges for the future are: (1) development of accurate, sensitive, and specific diagnostic laboratory tests for hereditary spherocytosis; (2) identification of the molecular basis of disease, especially for the 10–15% of patients for whom the genetic defects have yet to be defined; and (3) establishment of criteria to assess appropriate indications for splenectomy, timing of splenectomy in children with severe disease, and the long-term outcome of near-total splenectomy.147
Search strategy and selection criteria
References (147)
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Hereditary spherocytosis-defects in proteins that connect the membrane skeleton to the lipid bilayer
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Red cell membrane protein deficiencies in Mexican patients with hereditary spherocytosis
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Characterization of red cell membrane proteins as a function of red cell density: annexin VII in different forms of hereditary spherocytosis
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Tropomyosin modulates erythrocyte membrane stability
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Deformation-enhanced fluctuations in the red cell skeleton with theoretical relations to elasticity, connectivity, and spectrin unfolding
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Analysis of integral membrane protein contributions to the deformability and stability of the human erythrocyte membrane
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Splenectomy prolongs in vivo survival of erythrocytes differently in spectrin/ankyrin- and band 3-deficient hereditary spherocytosis
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(2002) Hematologically important mutations: ankyrin variants in hereditary spherocytosis
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(2005)- et al.
Sequences downstream of the erythroid promoter are required for high level expression of the human alpha-spectrin gene
J Biol Chem
(2004)
Characterization of the underlying molecular defect in hereditary spherocytosis associated with spectrin deficiency
Blood
Combined spectrin and ankyrin deficiency is common in autosomal dominant hereditary spherocytosis
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Comparison of the ankyrin (AC)n microsatellites in genomic DNA and mRNA reveals absence of one ankyrin mRNA allele in 20% of patients with hereditary spherocytosis
Blood
A complex splicing defect associated with homozygous ankyrin-deficient hereditary spherocytosis
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Erythrocyte ankyrin promoter mutations associated with recessive hereditary spherocytosis cause significant abnormalities in ankyrin expression
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Molecular basis of spectrin and ankyrin deficiencies in severe hereditary spherocytosis: evidence implicating a primary defect of ankyrin
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Characterization of 13 novel band 3 gene defects in hereditary spherocytosis with band 3 deficiency
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Hereditary spherocytosis due to a novel frameshift mutation in AE1 cytoplasmic COOH terminal tail: band 3 Vesuvio
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Hereditary spherocytosis with band 3 deficiency. Association with a nonsense mutation of the band 3 gene (allele Lyon), and aggravation by a low-expression allele occurring in trans (allele Genas)
Blood
Modulation of clinical expression and band 3 deficiency in hereditary spherocytosis
Blood
Identification of quantitative trait loci that modify the severity of hereditary spherocytosis in wan, a new mouse model of band-3 deficiency
Blood
Severe hereditary spherocytosis and distal renal tubular acidosis associated with the total absence of band 3
Blood
A band 3-based macrocomplex of integral and peripheral proteins in the RBC membrane
Blood
The N-terminal 11 amino acids of human erythrocyte band 3 are critical for aldolase binding and protein phosphorylation: implications for band 3 function
Blood
An alanine-to-threonine substitution in protein 4.2 cDNA is associated with a Japanese form of hereditary hemolytic anemia (protein 4.2 NIPPON)
Blood
Protein-4.2 association with band 3 (AE1, SLCA4) in Xenopus oocytes: effects of three natural protein-4.2 mutations associated with hemolytic anemia
Blood
Evidence that the red cell skeleton protein 4.2 interacts with the Rh membrane complex member CD47
Blood
RH blood group system and molecular basis of Rh-deficiency
Baillieres Best Pract Res Clin Haematol
Rh-deficiency syndrome
Lancet
Mouro-Chanteloup I. Rh-RhAG/ankyrin-R, a new interaction site between the membrane bilayer and the red cell skeleton, is impaired by Rh(null)-associated mutation
J Biol Chem
Molecular biology and genetics of the Rh blood group system
Semin Hematol
Rh-deficiency of the regulator type caused by splicing mutations in the human RH50 gene
Blood
Hereditary spherocytosis in association with severe G6PD deficiency: report of an unusual case
Clin Chim Acta
Diagnosis of hereditary spherocytosis in newborn infants
J Pediatr
UGT1 promoter polymorphism accounts for increased neonatal appearance of hereditary spherocytosis
Blood
Deficiency of alpha-spectrin synthesis in burst-forming units-erythroid in lethal hereditary spherocytosis
Blood
Natural history of hereditary spherocytosis during the first year of life
Blood
Coinheritance of Gilbert syndrome increases the risk for developing gallstones in patients with hereditary spherocytosis
Blood
The role of prophylactic cholecystectomy during splenectomy in children with hereditary spherocytosis
J Pediatr Surg
Haematological consequences of parvovirus B19 infection
Baillieres Best Pract Res Clin Haematol
Human parvovirus infection revealing hereditary spherocytosis
Lancet
Angioid streaks associated with hereditary spherocytosis
Am J Ophthalmol
Temporal differences in membrane loss lead to distinct reticulocyte features in hereditary spherocytosis and in immune hemolytic anemia
Blood
Disorders of the erythrocyte membrane
Red cell membrane disorders
Studies on hereditary spherocytosis in Iceland
Acta Med Scand
High prevalence of increased osmotic fragility of red blood cells among Norwegian blood donors
Scand J Haematol
Prevalence of increased osmotic fragility of erythrocytes in German blood donors: screening using a modified glycerol lysis test
Ann Hematol
The Italian survey on hereditary spherocytosis
Int J Pediatr Hematol Oncol
Erythropoiesis: Hereditary Spherocytosis in Greece: Collective data on a large number of patients
Hematology
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