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EPB42-Related Hereditary Spherocytosis.


GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016.
2014 Mar 13.



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.


The diagnosis of hereditary spherocytosis is based on the findings of anemia (decreased hemoglobin [Hgb] level) and reticulocytosis (increased percent of reticulocytes), along 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) and increased Omin (osmolality at which 50% of red blood cells hemolyze) measured by ektacytometry. The diagnosis of EPB42-HS is established by the presence of biallelic pathogenic variants in EPB42 (encoding protein 4.2)


Treatment of manifestations: Treatment for mild EPB42-HS (Hgb 11-15 g/dL, reticulocytes 3%-8%) includes folic acid supplementation (400 µg once daily up to age 1 year, then 1 mg once 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 and antibiotic prophylaxis after. Patients 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 typically is begun after about ten transfusions (which correlate to a serum ferritin concentration of approximately 1000 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 for significant anemia. Those dependent on frequent transfusions and those receiving iron chelation therapy require monitoring of serum ferritin concentration. 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 Pregnancy management: Folic acid supplementation is necessary; monitoring for exacerbation of anemia with CBC and reticulocyte count is recommended.


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.

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