EPB42-Related Hereditary Spherocytosis

Clinical characteristics: EPB42-related hereditary spherocytosis (EPB42-HS) is a chronic nonimmune 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, which can become evident in early childhood, and cholelithiasis, which 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 percentage of reticulocytes), with high mean corpuscular Hgb concentration, presence of spherocytes in the peripheral blood smear, significantly decreased or absent haptoglobin, mildly increased osmotic fragility in osmotic fragility assay, increased O_min (osmolality at which 50% of red blood cells hemolyze), and decreased maximal elongation index (EI_max) in osmotic gradient ektacytometry.

Diagnosis/testing: The diagnosis of EPB42-HS is established by identification of biallelic pathogenic variants in EPB42.

Management: Treatment of manifestations: Treatment of hyperbilirubinemia as needed; folic acid supplementation; red blood cell transfusion as needed for a hemolytic or aplastic crisis; routine immunizations; iron chelation therapy as needed. Prior to splenectomy, immunizations for S pneumoniae, N meningitidis, and H influenzae. Although splenectomy is rarely indicated in EPB42-HS because disease severity is usually mild or moderate, partial or total splenectomy may be recommended in those with moderately severe EPB42-HS who are older than age five years when quality of life is compromised. Following splenectomy, booster immunizations for S pneumoniae and N meningitidis, prophylactic antibiotics, and prompt antibiotics for fever are recommended. Cholecystectomy in those with signs and/or symptoms of cholelithiasis; affected individuals with a history of cholelithiasis should have cholecystectomy at the time of splenectomy.

Surveillance: Monitor serum bilirubin concentration in neonates during the first week of life and Hgb in infants during the first two to four months of life. Those dependent on frequent transfusions and those receiving iron chelation therapy require monitoring of serum ferritin concentration. Monitor efficacy of chelation via T₂*-weighted liver MRI and adjust appropriately. Abdominal ultrasound examination to evaluate for cholelithiasis either when symptoms are present or, when hemolysis is significant, every five to ten years beginning at age ten to 12 years.

Agents/circumstances to avoid: Avoid supplements containing iron unless iron studies have documented iron deficiency. If so, 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; (2) Infants at risk require monitoring in the first two to four months of life for significant anemia, which may require red blood cell transfusion and initiation of folic acid 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); monitor for exacerbation of anemia with CBC and reticulocyte count.

Genetic counseling: EPB42-HS is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an EPB42 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial EPB42 pathogenic variants. Once the EPB42 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.