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Key words:. Dorantes-Mesa S. Hereditary spherocytosis. An Esp Pediatr.

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NCBI Bookshelf. EPB42 -related hereditary spherocytosis EPBHS is a chronic non-immune hemolytic anemia that is usually of mild to moderate severity. EPBHS 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.

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. 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.

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 EPBHS 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.

EPBHS is inherited in an autosomal recessive manner. 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. EPB42 -related hereditary spherocytosis EPBHS should be suspected in individuals with any of the following clinical and supportive laboratory findings:.

View in own window. 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 :.

See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants detected in this gene. Sequence analysis detects variants that are benign, likely benign, of uncertain significance , likely pathogenic, or pathogenic.

For issues to consider in interpretation of sequence analysis results, click here. 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 , Toye et al ]. 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.

The only gross deletion reported to date is a base pair deletion [ Hammill et al ] that is expected to be detectable by sequence analysis. Children with EPB42 -related hereditary spherocytosis EPBHS 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 , EPBHS 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. Homozygosity for p. AlaThr has been found most commonly in Japan and was reported to lead to moderately severe HS, with Hgb as low as 6.

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 ].

AlaThr or homozygosity for p. AspTyr 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 , Kanzaki et al ]. Compound heterozygosity for p. AlaThr with another EPB42 pathogenic variant causes typical HS with microspherocytes in the blood smear and increased osmotic fragility [ Takaoka et al , Kanzaki et al ].

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 , van den Akker et al , Hammill et al ]. One individual homozygous for the null c. 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. Hereditary spherocytosis is the most common inherited anemia in individuals of northern European ancestry, with a prevalence of or higher when the very mild forms which are frequently underdiagnosed are included.

The worldwide prevalence is lower. No phenotypes other than those discussed in this GeneReview are known to be associated with pathogenic variants in EPB 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.

Figure 1 demonstrates ektacytometry results typical of hereditary spherocytosis. Classification of hereditary spherocytosis based on genetic etiology is shown in Table 3. Ektacytometry indicating a typical curve for HS red , characterized by increased O min and decreased EI max and O hyp in comparison to normal control blue.

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:. Defined in Table 1. Significant decrease or absence of erythrocyte membrane protein band 4. SPH5 is typically milder than the other forms of hereditary spherocytosis inherited in an AR manner i. To establish the extent of disease and needs in an individual diagnosed with EPB42 -related hereditary spherocytosis EPBHS , the following evaluations are recommended:.

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 EPBHS.

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 ].

To reduce the risk of infection post splenectomy, the following are recommended:. The antibiotics recommended are penicillin V-K mg twice daily or erythromycin for those allergic to penicillin. 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 ].

An ongoing prospective observation of more than 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 , Rice et al ]. Note: When indicated, splenectomy is curative; however, it can have potential life-threatening complications see Treatment of Manifestations.

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. 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 ].

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. 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. 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.

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

Note: There may not be clinical trials for this disorder. 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. Offspring of a proband. Other family members. Carrier testing for at-risk relatives requires prior identification of the EPB42 pathogenic variants in the family. See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

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. 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 EPBHS 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. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here. Erythrocyte membrane protein band 4. Protein 4. Gene structure. 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.

Affected individuals from Europe [ Perrotta et al , van den Akker et al ] and North America [ Hammill et al ] have also been identified.

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Hereditary spherocytosis

NCBI Bookshelf. EPB42 -related hereditary spherocytosis EPBHS is a chronic non-immune hemolytic anemia that is usually of mild to moderate severity. EPBHS 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. 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.

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Skip to search form Skip to main content You are currently offline. Some features of the site may not work correctly. DOI: Christensen and Hassan Yaish and Richard S. Christensen , Hassan Yaish , Richard S. Lemons Published Medicine Neonatology. Background: Many cases of severe neonatal hyperbilirubinemia never have the underlying cause of the jaundice clearly identified.

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Hereditary spherocytosis is an abnormality of red blood cells, or erythrocytes. The disorder is caused by mutations in genes relating to membrane proteins that allow for the erythrocytes to change shape. The abnormal erythrocytes are sphere-shaped spherocytosis rather than the normal biconcave disk shaped. Dysfunctional membrane proteins interfere with the cell's ability to be flexible to travel from the arteries to the smaller capillaries.

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