Hereditary Spherocytosis Differential Diagnoses

Updated: Feb 18, 2021
  • Author: Gus Gonzalez, MD; Chief Editor: Emmanuel C Besa, MD  more...
  • Print
DDx

Diagnostic Considerations

Hereditary spherocytosis (HS) can be caused by any of several genetic anomalies, which have different patterns of inheritance and produce disease with a range of severity. Thus, the clinical and laboratory features of HS can vary widely.

Moderate HS is the most common form, accounting for 60-75% of all HS cases. Patients present with mild-to-moderate anemia, modest splenomegaly, and intermittent jaundice. In most cases, the pattern of transmission is autosomal dominant, although recessive inheritance also is observed.

Mild HS occurs in 20-30% of cases of autosomal dominant HS. Anemia generally is not present because the bone marrow is able to fully compensate for the persistent destruction of red cells. Little or no splenomegaly occurs. These patients usually are asymptomatic. They often are not diagnosed until later in life, when they experience hemolytic or aplastic episodes triggered by infection or other stresses. The condition may be identified only through family surveys.

Severe HS occurs in approximately 5% of all patients with HS. Severe hemolytic anemia that requires red cell transfusions and an incomplete response to splenectomy characterize severe HS. The pattern of inheritance is recessive. The parents of affected patients have no signs of HS or have only a mild increase in the reticulocyte count, a few spherocytes on peripheral blood smear, a minimally abnormal incubated osmotic fragility test result, or an abnormal spectrin content detected when sensitive techniques are used.

Gilbert syndrome

HS may occasionally be mistaken for Gilbert syndrome, a hereditary disorder in which reduced conjugation of bilirubin in the liver results in jaundice. Although patients with Gilbert syndrome may be asymptomatic, most have nonspecific symptoms such as abdominal cramps, fatigue, and malaise. Laboratory studies may reveal unconjugated hyperbilirubinemia. In contrast to HS, patients with Gilbert syndrome have normal results on reticulocyte count and blood smear.

Hereditary xerocytosis (HX)

Hereditary xerocytosis (HX), also known as dehydrated hereditary stomatocytosis (DHS), is a rare autosomal dominant congenital hemolytic anemia characterized by erythrocyte dehydration with presentation of various degrees of hemolytic anemia. Over 80% of cases are caused by missense mutations in the PIEZO1 gene. In a subset of HX patients, mutations in the gene coding for calcium-activated potassium channel (KCNN4) have been identified. [15]

The severity of chronic anemia varies; transient perinatal edema and hydrops fetalis may be present. Laboratory findings include spherocytes on the peripheral blood smear, elevated reticulocyte count, and slightly increased MCHC and red cell mean corpuscular volume (MCV). Genetic testing may be required to confirm the diagnosis. Differentiating HX from HS is important because splenectomy is not beneficial in patients with HX and increases the risk for venous thrombosis. [15]

Hemolytic disease of the fetus and newborn

Patients with this disorder, which is also called neonatal alloimmune hemolytic anemia, may present with jaundice and anemia requiring aggressive support. They may have spherocytosis. This disorder is transient and resolves once maternal antibodies are cleared.

Differential Diagnoses