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EPB42-Related Hereditary Spherocytosis

, MD, PhD, , MS, and , PhD, FACMG.

Author Information

Initial Posting: ; Last Update: November 10, 2016.

Estimated reading time: 23 minutes

Summary

Clinical characteristics.

EPB42-related hereditary spherocytosis (EPB42-HS) is a chronic non-immune hemolytic anemia that is usually of mild to moderate severity. EPB42-HS can present with jaundice as early as the first 24 hours of life or can present later in childhood with anemia resulting from a hemolytic crisis or aplastic crisis (usually associated with a viral infection). In addition to the hematologic manifestations, serious complications include splenomegaly that can become evident in early childhood and cholelithiasis that usually becomes evident in the second or third decade of life.

Typical laboratory findings in EPB42-HS include anemia (decreased hemoglobin [Hgb] level) and reticulocytosis (increased percent of reticulocytes), with high mean corpuscular hemoglobin concentration (MCHC), presence of spherocytes in the peripheral blood smear, significantly decreased or absent haptoglobin, mildly increased osmotic fragility, and decreased maximal deformability index (DImax) with increased Omin (osmolality at which 50% of red blood cells hemolyze) measured by ektacytometry.

Diagnosis/testing.

The diagnosis of EPB42-HS is established by the identification of biallelic pathogenic variants in EPB42.

Management.

Treatment of manifestations: Treatment for mild EPB42-HS (Hgb 11-15 g/dL, reticulocytes 3%-8%) includes folic acid supplementation (400 µg 1x daily until age 1 year; 1 mg 1x daily thereafter) and RBC transfusion as needed for a hemolytic or aplastic crisis. Although splenectomy is rarely indicated in EPB42-HS since disease severity is usually mild or moderate, it may be recommended in those with moderately severe EPB42-HS (Hgb 6-8 g/dL, reticulocytes ≥10%) who are older than age five years when quality of life is compromised. Although curative, splenectomy entails a long-term increased risk for potential life-threatening infection, and thus requires complete immunizations before the procedure and antibiotic prophylaxis after. Affected individuals with a history of cholelithiasis should have cholecystectomy at the time of splenectomy.

Prevention of primary manifestations: See Treatment of manifestations for information on use of splenectomy.

Prevention of secondary complications: Regular immunizations to prevent infections that can trigger a hemolytic or aplastic crisis. Iron overload is a risk especially if frequent transfusions are required; treatment with an iron chelator is typically begun after about ten transfusions (which correlate to a serum ferritin concentration of approximately 1,000 ng/mL).

Surveillance: Neonates require monitoring of serum bilirubin concentration during the first week of life and infants require monitoring of Hgb in the first two to four months of life to screen for significant anemia. Those dependent on frequent transfusions and those receiving iron chelation therapy require monitoring of serum ferritin concentration. Abdominal ultrasound examination to evaluate for cholelithiasis either when symptoms are present or, when hemolysis is significant, by age ten to 12 years, and every five to ten years thereafter.

Agents/circumstances to avoid: Any preparations containing iron; however, if iron studies have documented iron deficiency, treatment with supplemental iron must be closely monitored and then discontinued when iron stores have been repleted. Avoidance of contact sports is recommended in those with splenomegaly; of note, acute or excessive splenomegaly is a greater risk than chronic mild splenomegaly.

Evaluation of relatives at risk: When EPB42-HS has been diagnosed in a family member, the following is recommended for at-risk sibs: (1) Neonates at risk require monitoring of serum bilirubin concentration during the first week of life so that treatment for hyperbilirubinemia can be instituted promptly; and (2) infants at risk require monitoring in the first two to four months of life for significant anemia, which may require RBC transfusion and initiation of folate supplementation. Laboratory evaluation (CBC and reticulocyte count, blood smear, osmotic fragility or ektacytometry) and/or molecular genetic testing for the EPB42 pathogenic variants in the family (if known) is appropriate for at-risk relatives.

Pregnancy management: Folic acid supplementation (800-1,000 µg daily) is necessary; monitoring for exacerbation of anemia with CBC and reticulocyte count is recommended.

Genetic counseling.

EPB42-HS is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the pathogenic variants in the family have been identified.

Diagnosis

Suggestive Findings

EPB42-related hereditary spherocytosis (EPB42-HS) should be suspected in individuals with any of the following clinical and supportive laboratory findings:

Clinical findings

  • Pallor and/or fatigue due to anemia, which is usually of mild to moderate severity
  • Jaundice
    • Usually intermittent and caused by unconjugated hyperbilirubinemia resulting from exacerbated hemolysis
    • In rare cases, caused by conjugated hyperbilirubinemia resulting from biliary obstruction
  • Splenomegaly
  • Cholelithiasis in the second or third decade of life
  • Family history consistent with autosomal recessive inheritance
    Note: Absence of a family history of EPB42-HS does not preclude the diagnosis.

Supportive laboratory findings

  • Complete blood count consistent with:
    • Chronic, non-immune hemolytic anemia (decreased hemoglobin with reticulocytosis), usually of mild to moderate severity
      • Decreased hemoglobin (Hgb) level (See Table 1 for Hgb levels that define the severity of hereditary spherocytosis.)
        Note: Hgb values in EPB42-HS may also vary depending on the clinical status of the affected individual (baseline or during a hemolytic or aplastic crisis).
      • Increased percent of reticulocytes as well as increased absolute reticulocyte count (ARC) (See Table 1 for percent of reticulocytes that define the severity of hereditary spherocytosis.)
        Note: Percent of reticulocytes may vary (depending on baseline or crisis status) from 2.5 to greater than 10% (or even normal or low when in aplastic crisis).
    • High mean corpuscular hemoglobin concentration (MCHC). Normal values are typically 31-37 g/dL. Values in HS are usually 35.5-37.5 g/dL.
  • Negative (i.e., normal) direct anti-globulin test (DAT)
    Note: DAT should always be evaluated in a person with newly diagnosed hemolytic anemia to evaluate for an acute immune-mediated (acquired) hemolytic anemia.
  • Peripheral blood smear demonstrating presence of spherocytes and occasionally a few ovalocytes and elliptocytes
    Note: The term spherocyte refers to the sphere-shaped red blood cells (with a decreased surface/volume ratio) that characterize the RBC cytoskeleton disorders (see Differential Diagnosis).
  • Significantly decreased or absent haptoglobin. After age six months normal haptoglobin values are 16-200 mg/dL. In HS, haptoglobin is typically undetectable; however, haptoglobin can be normal in the presence of concurrent inflammation (as it is an acute phase reactant).
  • Mildly increased osmotic fragility (as in Figure 1B of Hammill et al [2011]; see full text)
  • Decreased maximal deformability index (DImax) and increased Omin (osmolality at which 50% of red blood cells hemolyze) measured by ektacytometry, giving a typical HS curve [Clark et al 1983, Hammill et al 2011]

Table 1.

Severity of Hereditary Spherocytosis

SeverityHgb (g/dL)Reticulocytes (%)Splenectomy
Mild11-153-8Not necessary
Moderate8-11.5>8Consider if activity level & quality of life are decreased
Moderately severe6-8≥10Indicated at age >5 yrs
Severe<6≥10Indicated at age >3 yrs
Normal 111.7-15.7 (adult females) 13.3-17.7 (adult males)0.5-1.5 2

Based on table by Eber & Lux [2004]

1.

Normal values may vary somewhat depending on age and gender.

2.

ARC 45-90 x 103/µL

Establishing the Diagnosis

The diagnosis of EPB42-related hereditary spherocytosis is established in a proband by the identification of biallelic pathogenic variants in EPB42 (see Table 2).

Molecular genetic testing approaches can include single-gene testing or use of a multigene panel:

  • Single-gene testing. Sequence analysis of EPB42 is performed.
  • A multigene panel that includes EPB42 and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Table 2.

Molecular Genetic Testing Used in EPB42-Related Hereditary Spherocytosis

Gene 1Test MethodProportion of Probands with Pathogenic Variants 2 Detectable by This Method
EPB42Sequence analysis 316/16 4
Gene-targeted deletion/duplication analysis 5Unknown 6, 7
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Most are case reports with no information on the number of individuals with hereditary spherocytosis who did not have pathogenic variants identified in EPB42 [Kanzaki et al 1997, Toye et al 2008].

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

6.

No data on detection rate of gene-targeted deletion/duplication analysis are available.

7.

The only gross deletion reported to date is a 32-base pair deletion [Hammill et al 2011] that is expected to be detectable by sequence analysis.

Clinical Characteristics

Clinical Description

Children with EPB42-related hereditary spherocytosis (EPB42-HS) frequently present within the first 24 hours of life with jaundice that requires treatment with phototherapy or, rarely, exchange transfusion to prevent kernicterus. They may also present later in childhood with anemia resulting from a hemolytic crisis or aplastic crisis usually associated with a viral infection.

Toddlers with hereditary spherocytosis are occasionally found to have age-related iron deficiency anemia; however, the anemia fails to completely resolve with iron supplementation and reticulocytosis persists.

As with all forms of mild or moderate hereditary spherocytosis (see Table 1 for definitions), EPB42-HS can be more severe in the first four to six months of life, requiring regular red blood cell transfusions. Thus, frequent transfusions during the first few months of life do not necessarily correlate with disease severity later on.

EPB42-HS, if not recognized during infancy or early childhood, may be diagnosed later in life as a mild (Hgb 11-15 g/dL) to moderate (Hgb 8-11.5 g/dL) chronic hemolytic anemia (see Table 1), with jaundice, splenomegaly, and cholelithiasis at a relatively young age [Eber & Lux 2004].

Genotype-Phenotype Correlations

Homozygosity for p.Ala142Thr has been found most commonly in Japan and was reported to lead to moderately severe HS, with Hgb as low as 6.1 g/dL [Bouhassira et al 1992]. A non-Japanese affected individual with the same genotype was reported in Italy; her phenotype included moderate hemolytic anemia from birth and splenomegaly [Perrotta et al 1999].

Homozygosity for p.Ala142Thr or homozygosity for p.Asp175Tyr results in atypical HS with the presence of ovalostomatocytes in addition to few spherocytes in the blood smear. Hemolysis may be mild to moderately severe and improves after splenectomy [Bouhassira et al 1992, Kanzaki et al 1995].

Compound heterozygosity for p.Ala142Thr with another EPB42 pathogenic variant causes typical HS with microspherocytes in the blood smear and increased osmotic fragility [Takaoka et al 1994, Kanzaki et al 1995]. Case reports of individuals with other EPB42 pathogenic variants also indicate mild to moderate HS with only occasional need for blood transfusion [Hayette et al 1995, van den Akker et al 2010, Hammill et al 2011].

One individual homozygous for the null c.950delG variant (resulting in premature termination of the transcript and lack of production of any viable erythrocyte membrane protein band 4.2 – known in recent literature as protein 4.2) developed a strong antibody response against protein 4.2 after multiple red blood cell transfusions for gastrointestinal bleeding, causing alloimmune hemolytic anemia [Beauchamp-Nicoud et al 2000]. Antibody development has not been described yet following red blood cell transfusion in persons with other EPB42 pathogenic variants, although in most of the cases of EPB42-associated HS no protein 4.2 is detectable in the RBC membrane [Satchwell et al 2009].

Prevalence

Hereditary spherocytosis is the most common inherited anemia in individuals of northern European ancestry, with a prevalence of 1:2000 or higher when the very mild forms (which are frequently underdiagnosed) are included. The worldwide prevalence is lower.

EPB42-associated hereditary spherocytosis is responsible for 40%-50% of hereditary spherocytosis in Japan, where the carrier frequency of p.Ala142Thr among healthy persons is as high as 3% [Yawata 1994, Yawata et al 2000].

In other populations, EPB42-HS accounts for 5% or less of HS [Eber & Lux 2004, Perrotta et al 2008].

Differential Diagnosis

The initial evaluation of a person with hemolytic anemia typically includes: complete blood count (CBC) and reticulocyte count; blood smear review; direct anti-globulin test (DAT) and indirect Coombs to evaluate for auto-immune (or, in an infant, allo-immune) hemolytic anemia; hemoglobin electrophoresis; and G6PD enzyme activity (especially in males). Osmotic fragility testing and/or ektacytometry can focus the diagnosis within an erythrocyte membrane disorder. Figure 1 demonstrates ektacytometry results typical of hereditary spherocytosis. Classification of hereditary spherocytosis based on genetic etiology is shown in Table 3.

Figure 1. . Ektacytometry indicating a typical curve for HS (red), characterized by increased Omin and decreased EImax and Ohyp in comparison to normal control (blue).

Figure 1.

Ektacytometry indicating a typical curve for HS (red), characterized by increased Omin and decreased EImax and Ohyp in comparison to normal control (blue). Omin corresponds to the osmolality where 50% of the cells hemolyze in the osmotic fragility test (more...)

For the individual with non-immune hemolytic anemia, the differential diagnosis includes the other causes of hereditary hemolytic anemia, including the other forms of hereditary spherocytosis:

  • Other RBC membrane disorders
  • Hereditary spherocytosis (see Table 3)
  • Hereditary elliptocytosis, stomatocytosis, or Southeast Asian ovalocytosis, since individuals homozygous for either p.Ala142Thr or p.Asp175Tyr in EPB42 are reported to also have ovalocytes and stomatocytes in the blood smear. Note: Splenectomy has been associated with significant and life-threatening thrombotic events in persons with hereditary stomatocytosis (overhydrated or dehydrated/xerocytosis); therefore, differentiation between hereditary stomatocytosis and EPB42-associated HS (EPB42-HS) is necessary if splenectomy is contemplated.
  • Hemoglobin disorders. EPB42-HS is usually easily distinguished from β-thalassemia or HbH disease, both of which are characterized by microcytosis and hypochromia. Chronic mild hemolytic anemias due to unstable hemoglobin chains may require further evaluation, including hemoglobin analysis by electrophoresis or HPLC and/or globin gene sequencing.
  • Erythrocyte enzymopathies, such as glucose-6-phospate dehydrogenase (G6PD) deficiency (OMIM 300908) or pyruvate kinase (PK) deficiency (OMIM 266200); typically distinguished from EPB42-HS by absence of spherocytic RBC morphology and by normal ektacytometry or osmotic fragility. Some erythrocyte enzyme disorders (e.g., triose phosphate isomerase [TPI] deficiency [OMIM 615512] or phosphoglycerate kinase 1 [PGK1] deficiency [OMIM 300653]) also have neurologic and musculoskeletal manifestations. Enzymatic activity assays and/or gene sequencing establishes the diagnosis.
  • Congenital dyserythropoietic anemia, especially type II when it presents with a mild phenotype (i.e., mild anemia, reticulocytosis [although suboptimal], jaundice, and splenomegaly) (See Congenital Dyserythropoietic Anemia Type I.)

Table 3.

Classification of Hereditary Spherocytosis

LocusGeneProteinMOISeverity 1CommentOMIM
SPH1ANK1Ankyrin-1ADMild -moderate182900
ARModerately severe -severeOften transfusion dependent
SPH2SPTBSpectrin beta chain, erythrocyticADMild -moderate616649
ARSevere1 fatal infantile case described
SPH3SPTA1Spectrin alpha chain, erythrocytic 1ARSevereTransfusion dependent270970
SPH4SLC4A1Band 3 (anion transport protein)ADMild -moderateCertain SLC4A1 pathogenic variants cause disease only when biallelic.612653
SPH5EPB42Protein 4.2 2ARMild -moderate 31 moderately severe case described612690
1.

Defined in Table 1

2.

Significant decrease or absence of erythrocyte membrane protein band 4.2 (known in recent literature simply as protein 4.2) in erythrocytes of persons with HS may also be secondary to biallelic SLC4A1 pathogenic variants (SPH4) by either decreasing band 3 in the red blood cell membrane [Toye et al 2008] or affecting the band 3 binding site for protein 4.2 [Kanzaki et al 1997].

3.

SPH5 is typically milder than the other forms of hereditary spherocytosis inherited in an AR manner (i.e., SPH1 [AR] and SPH3).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with EPB42-related hereditary spherocytosis (EPB42-HS), the following evaluations are recommended:

  • Hemoglobin concentration and reticulocyte count to evaluate severity of disease
  • Serum bilirubin concentration
  • Transfusion history
  • Serum ferritin concentration to evaluate iron load status
  • Abdominal ultrasound examination to evaluate:
    • Spleen size if physical examination is not conclusive due to body habitus or if contact sports are contemplated
    • For evidence of cholelithiasis when symptoms are present. If hemolysis is significant a screening ultrasound may be considered after age 10-12 years, even without symptoms.
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Detailed management guidelines for hereditary spherocytosis (HS) have been published [Eber & Lux 2004, Bolton-Maggs et al 2012].

Conservative management recommendations for mild EPB42-HS (Hgb 11-15 g/dL, reticulocytes 3-8%) (Table 1) include the following:

  • Folic acid supplementation (400 µg 1x daily until age 1 year; then 1 mg 1x daily thereafter)
  • Avoidance of iron supplementation unless concurrent iron deficiency is confirmed with iron studies, in which case treatment with supplemental iron should be carefully monitored and discontinued after iron stores are repleted to avoid iron overload
    Note: Hereditary spherocytosis (as all chronic hemolytic anemias) involves an increased risk for iron overload even with oral iron supplementation (see Prevention of Secondary Complications).
  • Red blood cell (RBC) transfusion, if needed, for hemolytic or aplastic crisis

Splenectomy is rarely indicated in EPB42-HS, as disease severity is usually mild or moderate. However, when disease is moderate (see Table 1) and normal activity or quality of life is compromised, splenectomy can be performed after age five years provided that hereditary stomatocytosis has been ruled out (see Differential Diagnosis). Note: Total splenectomy is not recommended for children younger than age five years even if the child requires frequent transfusions for moderately severe HS (which is rare in EPB42-HS).

Although splenectomy is curative, it entails potential long-term increased risk for life-threatening infection and, thus, should not be undertaken before the risks and benefits have been fully weighed [Casale & Perrotta 2011].

Ideally, the following immunizations should be completed before splenectomy:

  • Immunizations for Streptococcus pneumoniae with the 23-valent pneumococcal polysaccharide vaccine (PPSV23) and for N meningitidis with a meningococcal conjugate vaccine against the serogroups A, C, W, and Y (MenACWY) at least two weeks before splenectomy. A two-dose primary series of MenACWY is recommended 8-12 weeks apart [Committee on Infectious Diseases 2011].
  • Prevnar-13® and H influenzae type b vaccines during infancy per general pediatric immunization guidelines

The incidence of post-splenectomy sepsis varies among studies. Although low overall, the risk for sepsis, a life-threatening complication, is higher than in the general population [Iolascon et al 1998]. To reduce the risk of infection post splenectomy, the following are recommended:

  • Give booster vaccination for PPSV23 five years after the first dose. No more than two PPSV23 doses are recommended [Nuorti et al 2010].
  • Give booster dose for meningococcal vaccine three years after the primary series if the primary two-dose series was given between ages two and six years and every five years for persons whose two-dose primary series or booster dose was given at age seven years or older [Cohn et al 2013].
  • Serogroup B meningococcal vaccines are recommended for people age ten years and older with history of splenectomy.

Controversy exists regarding the duration of use of antibiotics for prophylaxis post-splenectomy: some hematologists recommend prophylactic antibiotics for the first three years post splenectomy and others for life [Eber & Lux 2004]. The antibiotics recommended are penicillin V-K 250 mg twice daily or erythromycin for those allergic to penicillin.

In any case, an individual who has undergone splenectomy needs immediate medical attention for fever and prompt use of IV antibiotics with good coverage for encapsulated organisms (typically ceftriaxone in doses adequate to treat meningitis: 100 mg/kg/day up to 2 g/day in single daily dose).

Partial splenectomy appears to be associated with a lesser risk for post-splenectomy sepsis and a sustained decrease (although not elimination) of hemolysis and may be preferable for young children if the surgeon is experienced in the procedure [Bader-Meunier et al 2001]. An ongoing prospective observation of more than 100 children in a congenital hemolytic anemia multi-institutional registry, who have undergone total or partial splenectomy, may elucidate better the risks and benefits of each procedure [Rice et al 2012, Rice et al 2015].

Antibiotic prophylaxis may be discontinued one year after partial splenectomy if immune splenic function is adequate as assessed by pit count (percentage of pitted or pocked red cells) or the uptake of radioactive colloid by the spleen [Eber & Lux 2004].

Cholecystectomy

  • The gallbladder should be removed in affected individuals undergoing splenectomy who have a history of cholelithiasis.
  • In children who require cholecystectomy, concurrent splenectomy is not recommended automatically any more. The need for splenectomy should be assessed on a case-by-case basis and the indication of splenectomy justified independently [Bolton-Maggs et al 2012, Ruparel et al 2014].

Prevention of Primary Manifestations

Splenectomy is rarely indicated in EPB42-HS, as disease severity is usually mild or moderate. Note: When indicated, splenectomy is curative; however, it can have potential life-threatening complications (see Treatment of Manifestations). Note: Total splenectomy is not recommended for children younger than age five years even if the child requires frequent transfusions for moderately severe HS (which is rare in EPB42-HS).

Prevention of Secondary Complications

Regular immunizations are recommended as well as influenza vaccine annually to prevent infections that can precipitate hemolytic or aplastic crisis.

Iron overload and its associated chronic organ failure are risks with any chronic hemolytic anemia especially if frequent transfusions are required.

  • Treatment with an iron chelator should be implemented, typically after about ten transfusions (which correlate to a serum ferritin concentration of approximately 1000 ng/mL).
  • The effectiveness of chelation should be monitored by evaluation of liver iron by T2*-weighted MRI or FerriScan® so that the dose of iron chelator can be adjusted appropriately.

Surveillance

Neonates with HS require monitoring of serum bilirubin concentration during the first week of life so that treatment for hyperbilirubinemia can be instituted promptly to avoid complications such as kernicterus.

Infants with HS require monitoring in the first two to four months of life for significant anemia, which may require RBC transfusion

Those dependent on frequent transfusions require at least annual measurement of serum ferritin concentration.

If iron chelation is required secondary to frequent transfusions in children too young to undergo splenectomy, appropriate monitoring for toxicity and effectiveness of chelation treatment is necessary [Musallam et al 2013].

When hemolysis is significant, ultrasound examination to evaluate for cholelithiasis is indicated by age ten to twelve years, and every five to ten years thereafter.

Agents/Circumstances to Avoid

Any preparations containing iron should be avoided (see Treatment of Manifestations).

Contact sports are not advisable in those with splenomegaly; of note, acute or excessive splenomegaly is a greater risk than chronic mild splenomegaly.

Evaluation of Relatives at Risk

It is appropriate to perform laboratory evaluation of the phenotype (CBC and reticulocyte count, blood smear, osmotic fragility or ektacytometry) and clarify the genetic status of apparently asymptomatic older and younger sibs of an affected individual by molecular genetic testing of the EPB42 pathogenic variants in the family in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures.

  • Neonates require monitoring of serum bilirubin concentration during the first week of life so that treatment for hyperbilirubinemia can be instituted promptly to avoid complications such as kernicterus.
  • Infants require monitoring in the first two to four months of life for significant anemia, which may require RBC transfusion and initiation of folate supplementation

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Folic acid supplementation (800-1000 µg daily) is necessary in pregnant women with chronic hemolytic anemias such as EPB42-HS.

Monitoring for exacerbation of anemia with CBC and reticulocyte count is recommended in pregnant women with HS, as hemolytic crisis and persistent anemia have been reported during pregnancy, especially in women who have not undergone splenectomy [Pajor et al 1993].

Therapies Under Investigation

Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

EPB42-related hereditary spherocytosis (EPB42-HS) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes (i.e., carriers of one EPB42 pathogenic variant).
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. The offspring of an individual with EPB42-HS are obligate heterozygotes (carriers) for an EPB42 pathogenic variant.

Other family members. Each sib of the proband’s parents is at a 50% risk of being a carrier of an EPB42 pathogenic variant.

Carrier (Heterozygote) Detection

Carrier testing for at-risk relatives requires prior identification of the EPB42 pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the EPB42 pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for EPB42-HS are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

EPB42-Related Hereditary Spherocytosis: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
EPB4215q15​.2Erythrocyte membrane protein band 4.2EPB42 databaseEPB42EPB42

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for EPB42-Related Hereditary Spherocytosis (View All in OMIM)

177070PROTEIN 4.2, ERYTHROCYTIC; EPB42
612690SPHEROCYTOSIS, TYPE 5; SPH5

Molecular Genetic Pathogenesis

Erythrocyte membrane protein band 4.2 (also known as protein 4.2), encoded by EPB42, is a major component of the red blood cell cytoskeleton and maintains the stability and flexibility of red cells through interactions with other key RBC proteins, many of which (in their pathogenic forms) also cause hereditary spherocytosis.

Protein 4.2 is a part of the ankyrin-band 3 complex, connecting band 3 protein (encoded by SLC4A1; see Table 3, SPH4) with the CD47 and Rhesus protein complex antigens. Protein 4.2 supports physical associations between the cytoskeleton and the membrane lipid bilayer [Bruce et al 2003].

Protein 4.2 interacts with spectrin, a tetramer comprising an alpha-subunit (see Table 3, SPH3) and beta-subunit (see Table 3, SPH2), which is the largest protein in the RBC cytoskeleton [Mandal et al 2002, Korsgren et al 2010].

Gene structure. EPB42 (previously known as ELB42) spans approximately 23 kb of genomic DNA. The longer transcript isoform (NM_000119.2) has 2554 bp and 13 exons. Alternative splicing produces a shorter transcript variant (NM_001114134.1) excluding the last 90 nucleotides of exon 1. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. To date, at least 13 distinct EPB42 pathogenic variants have been described, including missense, nonsense, frameshift, and splicing variants and small deletions. More than 50% of the identified pathogenic variants have been in the Japanese population [Bouhassira et al 1992, Yawata et al 2000]. Affected individuals from Europe [Perrotta et al 1999, van den Akker et al 2010] and North America [Hammill et al 2011] have also been identified.

The p.Ala142Thr variant has been observed in a homozygous state in affected individuals. While this variant has a carrier frequency of approximately 3% in persons of Japanese ancestry, it was also found in an affected individual from central Italy who had no Japanese ancestry [Perrotta et al 1999]. Although the frequency in the Japanese population is likely explained by a founder effect, the apparent random occurrence of this variant in another population may be explained by the fact that the G>A transition occurs within a CpG site on the antisense DNA strand [Elango et al 2008].

Table 4.

EPB42 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein Change
(Alias 1)
Reference Sequences
c.424G>Ap.Ala142Thr
(4.2 Nippon)
NM_000119​.2
NP_000110​.2
c.523G>Tp.Asp175Tyr
(4.2 Komatsu)
c.920C>Tp.Thr307Ile
(4.2 Cincinnati)
c.929G>Ap.Arg310Gln
(4.2 Tozeur)
c.949C>Tp.Arg317Cys
(4.2 Shiga)
c.950delGFrameshift
(4.2 Nancy)

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Variant designation that does not conform to current naming conventions

Normal gene product. The long and short EPB42 transcript variants encode the two protein 4.2 isoforms: the 74-kd minor isoform of 721 amino acids (NP_000110.2) and the 72-kd major isoform of 691 amino acids (NP_001107606.1). Although homologous to transglutaminases, protein 4.2 lacks two of the catalytic triad residues required for transglutaminase activity, and thus is an enzymatically inactive protein [Toye et al 2005].

Protein 4.2 is a major component of the red blood cell cytoskeleton and maintains the stability and flexibility of red cells through interactions with other key RBC proteins, many of which (in their pathogenic forms) also cause hereditary spherocytosis (see Molecular Genetic Pathogenesis and Table 3).

Aggravation of hemolysis during the neonatal period has been attributed to the presence of fetal hemoglobin, which has poor affinity for 2,3-diphosphoglycerate (2,3-DPG), resulting in increased free intracellular 2,3-DPG that destabilizes the spectrin-protein 4.1 interactions and intensifies hemolysis [Mentzer et al 1987].

Protein 4.2 interacts with its binding partners in the RBC cytoskeleton via specific domains. Protein 4.2 amino acid residues 187-211 of the long isoform NP_000110.2 have been shown to mediate binding to ankyrin (see Table 3, SPH1) and band 3, bridging these two proteins [Su et al 2006] and linking band 3 and the lipid bilayer with the cytoskeletal scaffold.

Abnormal gene product. More than half of the identified EPB42 pathogenic variants are predicted to result in complete loss of protein, which is presumed to be the mechanism of pathogenesis.

At least six distinct pathogenic missense variants have been observed. Functional analyses include the following:

Of note, although band 3 levels in protein 4.2-deficient RBCs are not altered, the extractability and lateral diffusion of band 3 are significantly increased [Rybicki et al 1996].

References

Published Guidelines / Consensus Statements

  • Bolton-Maggs PH, Langer JC, Iolascon A, Tittensor P, King MJ. Guidelines for the diagnosis and management of hereditary spherocytosis--2011 update. Available online. 2012. Accessed 4-17-18.
  • Bolton-Maggs PH, Stevens RF, Dodd NJ, Lamont G, Tittensor P, King MJ. Guidelines for the diagnosis and management of hereditary spherocytosis. Available online. 2004. Accessed 4-17-18.
  • Eber S, Lux SE. Hereditary spherocytosis--defects in proteins that connect the membrane skeleton to the lipid bilayer. 2004. [PubMed: 15071790]

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Suggested Reading

  • Cohen CM, Dotimas E, Korsgren C. Human erythrocyte membrane protein band 4.2 (pallidin). Semin Hematol. 1993;30:119–37. [PubMed: 8480187]
  • Dotimas E, Speicher DW. GuptaRoy B, Cohen CM. Structural domain mapping and phosphorylation of human erythrocyte pallidin (band 4.2). Biochim Biophys Acta. 1993;1148:19–29. [PubMed: 8499466]
  • Korsgren C, Cohen CM. Associations of human erythrocyte band 4.2. Binding to ankyrin and to the cytoplasmic domain of band 3. J Biol Chem. 1988;263:10212–8. [PubMed: 2968981]

Revision History

  • 10 November 2016 (ma) Comprehensive update posted live
  • 13 March 2014 (me) Review posted live
  • 20 October 2013 (tk) Original submission
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