Introduction and Epidemiology
The typical features of HS include a dominantly inherited hemolytic anemia of mild to moderate severity, spherocytosis on the peripheral blood film, and a favorable response to splenectomy. The clinical spectrum of HS is variable and includes both mild and asymptomatic forms, as well as severe forms that appear in infancy. The previously reported HS prevalence in Western populations of 1 in 4000 persons is an underestimation because milder forms of HS might be asymptomatic, suggesting a prevalence of 1 in 2000 individuals. HS has been reported worldwide, particularly in Northern European and Japanese populations, but its prevalence in other ethnic groups is unknown.
Pathobiology
Two major factors are involved in HS pathophysiology: (1) an intrinsic RBC defect and (2) an intact spleen that selectively retains and damages abnormal HS erythrocytes. An inherited deficiency or dysfunction of proteins of the erythrocyte membrane leads to a multistep process of accelerated HS RBC destruction. Destabilization of the lipid bilayer facilitates a release of lipids from the membrane, leading to surface area deficiency and the formation of poorly deformable spherocytes that are selectively retained and damaged in the spleen.
Molecular Pathology
The molecular basis of HS is heterogeneous. Based on densitometric quantitation of membrane proteins separated by polyacrylamide gel electrophoresis, HS can be divided into the following subsets: (1) isolated deficiency of spectrin, (2) combined deficiencies of spectrin and ankyrin, (3) deficiency of band 3 protein, (4) deficiency of protein 4.2, and (5) no abnormality identified.
Isolated Spectrin Deficiency
The reported mutations of isolated spectrin deficiency include defects of both α- and β-spectrin. Mutations of the β-spectrin gene have been identified in a number of patients with dominantly inherited HS associated with spectrin deficiency. A few cases have been associated with de novo β-spectrin gene mutations. With a few exceptions, these mutations are private and may be associated with decreased β-spectrin messenger ribonucleic acid (mRNA) accumulation. Mutations in the highly conserved region of β-spectrin involved in the interaction with protein 4.1R likely lead to dysfunctional binding to protein 4.1R and thereby the linkage of spectrin to actin.
In nondominantly inherited HS associated with isolated spectrin deficiency, the defect involves α-spectrin. In normal erythroid cells, α-spectrin is synthesized in large excess of β-spectrin. Thus, patients with one normal and one defective α-spectrin allele are asymptomatic because α-spectrin production remains in excess of β-spectrin synthesis, allowing normal amounts of spectrin heterodimers to be assembled on the membrane. Patients who are homozygotes or compound heterozygotes for α-spectrin defects suffer from moderate to severe HS.
Combined Deficiency of Spectrin and Ankyrin
The biochemical phenotype of combined spectrin and ankyrin deficiency is the most common abnormality found in the erythrocytes of HS patients. Ankyrin represents the principal binding site for spectrin on the membrane; thus, it is not surprising that ankyrin deficiency is accompanied by a proportional decrease in spectrin assembly on the membrane despite normal spectrin synthesis. Similar to HS associated with β-spectrin mutations, most ankyrin defects are private point mutations associated with decreased mRNA accumulation. In some cases, mutations of the ankyrin promoter leading to decreased ankyrin expression have been found. Approximately 15% to 20% of ankyrin gene mutations reported are de novo mutations.
A number of patients with atypical HS associated with karyotypic abnormalities involving deletions or translocations of the ankyrin gene locus on chromosome 8p have been described. Ankyrin deletions may be part of a contiguous gene syndrome with manifestations of spherocytosis, mental retardation, typical facies, and hypogonadism.
Deficiency of Band 3 Protein
Deficiency of band 3 protein is found in a subset of HS patients who present with a phenotype of a mild to moderate dominantly inherited HS. Most, if not all, of these patients also have concomitant protein 4.2 deficiency. Numerous band 3 mutations associated with HS have been reported, spread throughout both the cytoplasmic and the membrane-spanning domains.
A number of band 3 mutations clustered in the membrane spanning domain that replace highly conserved arginines have been described. These arginines, which are all located at the cytoplasmic end of a predicted transmembrane helix, exhibit defective cellular trafficking from the endoplasmic reticulum to the plasma membrane.
Alleles have been identified that influence band 3 expression and that, when inherited in trans to a band 3 mutation, aggravate band 3 deficiency and worsen the clinical severity of the disease.
Deficiency of Protein 4.2
Recessively inherited HS caused by mutations in protein 4.2 is relatively common in Japan. In these cases, an almost total absence of protein 4.2 from the erythrocyte membranes of homozygous patients is detected. Protein 4.2–deficient erythrocytes can also have a decreased content of ankyrin and band 3. Protein 4.2 deficiency also occurs in association with band 3 mutations, probably as a result of abnormal binding of protein 4.2 to the cytoplasmic domain of band 3.
A detailed listing of HS mutations is available in mutation data bases maintained by the Human Gene Mutation Database (HGMD, http://www.hgmd.org).
