Hereditary spherocytosis

Other Names: Congenital spherocytic hemolytic anemia; Congenital spherocytosis; Spherocytic anemia

Hereditary spherocytosis is a condition characterized by hemolytic anemia (when red blood cells are destroyed earlier than normal). People with this condition typically experience a shortage of red blood cells (anemia), yellowing of the eyes and skin (jaundice), and an enlarged spleen (splenomegaly). Most newborns with hereditary spherocytosis have severe anemia, although it improves after the first year of life. Splenomegaly can occur anytime from early childhood to adulthood. About half of affected individuals develop hard deposits in the gallbladder called gallstones, which typically occur from late childhood to mid-adulthood.

Types

There are four forms of hereditary spherocytosis, which are distinguished by the severity of signs and symptoms. They are known as the mild form, the moderate form, the moderate/severe form, and the severe form. It is estimated that 20 to 30 percent of people with hereditary spherocytosis have the mild form, 60 to 70 percent have the moderate form, 10 percent have the moderate/severe form, and 3 to 5 percent have the severe form.

Epidemiology

Hereditary spherocytosis occurs in 1 in 2,000 individuals of Northern European ancestry. This condition is the most common cause of inherited anemia in that population. The prevalence of hereditary spherocytosis in people of other ethnic backgrounds is unknown, but it is much less common.

Cause

Mutations in at least five genes cause hereditary spherocytosis. These genes provide instructions for producing proteins that are found on the membranes of red blood cells. These proteins transport molecules into and out of cells, attach to other proteins, and maintain cell structure. Some of these proteins allow for cell flexibility; red blood cells have to be flexible to travel from the large blood vessels (arteries) to the smaller blood vessels (capillaries). The proteins allow the cell to change shape without breaking when passing through narrow capillaries.

Mutations in red blood cell membrane proteins result in an overly rigid, misshapen cell. Instead of a flattened disc shape, these cells are spherical. Dysfunctional membrane proteins interfere with the cell's ability to change shape when traveling through the blood vessels. The misshapen red blood cells, called spherocytes, are removed from circulation and taken to the spleen for destruction. Within the spleen, the red blood cells break down (undergo hemolysis). The shortage of red blood cells in circulation and the abundance of cells in the spleen are responsible for the signs and symptoms of hereditary spherocytosis.

Mutations in the ANK1 gene are responsible for approximately half of all cases of hereditary spherocytosis. The other genes associated with hereditary spherocytosis each account for a smaller percentage of cases of this condition.

Inheritance

In about 75 percent of cases, hereditary spherocytosis is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In some cases, an affected person inherits the mutation from one affected parent. Other cases result from new mutations in the gene and occur in people with no history of the disorder in their family.

This condition can also be inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Symptoms

People with the mild form may have very mild anemia or sometimes have no symptoms. People with the moderate form typically have anemia, jaundice, and splenomegaly. Many also develop gallstones. The signs and symptoms of moderate hereditary spherocytosis usually appear in childhood. Individuals with the moderate/severe form have all the features of the moderate form but also have severe anemia. Those with the severe form have life-threatening anemia that requires frequent blood transfusions to replenish their red blood cell supply. They also have severe splenomegaly, jaundice, and a high risk for developing gallstones. Some individuals with the severe form have short stature, delayed sexual development, and skeletal abnormalities. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed.

80%-99% of people have these symptoms

• Increased red cell osmotic fragility

30%-79% of people have these symptoms

• Cholelithiasis(Gallstones)
• Hepatomegaly(Enlarged liver)
• Hyperbilirubinemia(High blood bilirubin levels)
• Hypercoagulability
• Hypofibrinogenemia
• Increased mean corpuscular hemoglobin concentration
• Jaundice(Yellow skin)
• Muscular weakness
• Pallor
• Reticulocytosis(Increased immature red blood cells)
• Spherocytosis
• Splenomegaly(Increased spleen size)
• Spontaneous hemolytic crises

5%-29% of people have these symptoms

• Abdominal pain(Pain in stomach)
• Ataxia
• Chills
• Extramedullary hematopoiesis
• Fever
• Maculopapular exanthema
• Myalgia(Muscle ache)
• Restrictive cardiomyopathy

1%-4% of people have these symptoms

• Abdominal distention(Abdominal bloating)
• Gout
• Growth delay(Delayed growth)
• Skin ulcer(Open skin sore)

Diagnosis

In most cases, the spleen is enlarged. Laboratory tests can help diagnose this condition. Tests may include:

• Blood smear to show abnormally shaped cells
• Bilirubin level
• Complete blood count to check for anemia
• Coombs test
• LDH level
• Osmotic fragility or specialized testing to evaluate for the red blood cell defect
• Reticulocyte count

Treatment

The treatment of hereditary spherosytosis (HS) is dependent on the severity of the condition and recommendations vary a bit in the medical literature. In general, folate therapy (a type of vitamin B to support red blood cell production) is recommended for those with moderate to severe anemia, although some doctors may also recommend it for those with mild anemia. Red blood cell transfusions may be required in severe cases of anemia, particularly in the first years of life or during infections and pregnancy. If red blood cell transfusions are needed repeatedly, iron chelating therapy may be required to reduce iron overload. Regular monitoring for anemia and gallstones is advised. Removal of the spleen (splenectomy) is usually only performed in severe HS or in moderate to severe cases with significant anemia and gallstone complications. Splenectomy is not recommended in cases of mild HS except in specific cases. The majority of medical researchers no longer recommend that the spleen be removed during gallbladder removal (cholecystectomy), unless there are other reasons to do so. In some cases only removing of part of the spleen is advised. Expert evaluation is recommended in order to avoid unnecessary spleen removal.

Prognosis

Overall, the long-term outlook (prognosis) for people with hereditary spherocytosis (HS) is usually good with treatment.However, it may depend on the severity of the condition in each person. HS is often classified as being mild, moderate or severe. People with very mild HS may not have any signs or symptoms unless an environmental "trigger" causes symptom onset. In many cases, no specific therapy is needed other than monitoring for anemia and watching for signs and symptoms. Moderately and severely affected people are likely to benefit from splenectomy. Most people who undergo splenectomy are able to maintain a normal hemoglobin level. However, people with severe HS may remain anemic post-splenectomy, and may need blood transfusions during an infection.

NIH genetic and rare disease info

• NIH info on Hereditary spherocytosis

Hereditary spherocytosis is a rare disease.

Hereditary spherocytosis Resources
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