Our blood is a dynamic river of life, with red blood cells acting as the tireless couriers that deliver oxygen to every corner of our body. These cells are normally shaped like flexible, biconcave discs, allowing them to bend and squeeze through the narrowest of blood vessels. But what happens when these cells are born with a structural flaw that makes them abnormally round and fragile? This is the case in Hereditary Spherocytosis (HS), the most common inherited disorder of the red blood cell membrane. This genetic condition causes red blood cells to be small, spherical, and delicate, leading to their premature destruction and a type of anemia known as hemolytic anemia. While it is a lifelong condition, its severity varies greatly, and with a proper understanding of its nature and management, most individuals with Hereditary Spherocytosis can live full and healthy lives.

Hereditary spherocytosis (HS) is a genetic blood disorder where red blood cells (RBCs) become abnormally round (spherical) instead of their typical disc shape. This abnormal shape is the direct result of a defect in the proteins that make up the red blood cell’s internal membrane skeleton.

To understand the problem, it is helpful to use an analogy. Think of a normal red blood cell as a soft, partially filled water balloon. Its disc shape gives it extra surface area and allows it to be incredibly flexible, capable of deforming to squeeze through the body’s tiniest capillaries. In Hereditary Spherocytosis, the “skin” of this balloon, the cell membrane is structurally weak due to faulty internal scaffolding. This weakness causes the cell to lose small pieces of its surface over time, forcing it to pull itself into the smallest possible shape for its volume: a tight, rigid sphere.

This spherical shape has two major negative consequences:

1. It is Inflexible: The rigid spherocyte cannot bend and deform like a normal disc-shaped cell.
2. It is Fragile: The membrane is inherently unstable and prone to breaking.

These fragile, inflexible spherocytes circulate through the bloodstream until they reach the spleen. The spleen acts as the body’s primary blood filter, containing a labyrinth of narrow passages designed to remove old and damaged red blood cells. The healthy, flexible disc-shaped cells can easily navigate this filter, but the rigid spherocytes get trapped and are rapidly destroyed by immune cells in the spleen. This premature destruction of red blood cells is called hemolysis, and it leads to hemolytic anemia.

The severity of HS exists on a clinical spectrum, generally divided into mild, moderate, and severe forms, depending on the degree of red blood cell fragility and the rate of hemolysis.

In my experience, parents often bring in children who seem unusually tired or yellow-toned. Once we dig into the blood tests, HS becomes a likely culprit, especially with a family history.

Hereditary spherocytosis is caused by genetic mutations in the proteins that form the cytoskeleton of red blood cells. This cytoskeleton is an intricate, scaffold-like network of proteins on the inner surface of the red blood cell membrane. It is this internal framework that gives the cell its shape, its strength, and its crucial flexibility.

The most common mutations in HS affect the genes that provide the instructions for making key cytoskeletal proteins, including:

• Ankyrin
• Spectrin (both alpha- and beta-spectrin)
• Band 3
• Protein 4.2

A defect in any of these critical structural proteins weakens the connection between the cytoskeleton and the outer lipid layer of the cell membrane. This weakness allows small portions of the membrane to be lost as the cell circulates, leading to the progressive loss of surface area and the eventual formation of the characteristic, fragile spherocyte.

Clinically, I explain to families that the red cells lose their durability, like a balloon that’s been stretched too much and can no longer hold its shape.

You “get” hereditary spherocytosis by inheriting the faulty gene(s) from one or both parents. It is passed down through families, and the specific pattern of inheritance can vary.

• Autosomal Dominant Inheritance: This is the most common pattern, accounting for approximately 75% of all cases. In this form, a person only needs to inherit one copy of the mutated gene from one affected parent to have the disorder. An affected parent has a 50% chance of passing the condition on to each of their children.
• Autosomal Recessive Inheritance: In about 20-25% of cases, the condition is inherited in a recessive pattern. This means an individual must inherit a mutated gene from both of their parents to have the disease. The parents are typically unaffected carriers, each holding one normal gene and one mutated gene.
• De Novo (New) Mutations: In some instances, a child may be born with HS despite having no family history of the disorder. This occurs due to a new, spontaneous mutation in one of the relevant genes that happened by chance during the formation of the egg or sperm cell.

Genetic counseling can be a valuable resource for families affected by HS to help them understand their specific inheritance pattern and the risks for future pregnancies.

Patients often tell me they had no idea they had HS until their child was diagnosed, mild forms can easily go unnoticed for years.

Symptoms of hereditary spherocytosis vary depending on how quickly red blood cells are being destroyed. The severity of the symptoms directly correlates with the severity of the disease.
The classic triad of clinical features seen in moderate to severe HS includes:

1. Anemia: A chronic shortage of red blood cells. Symptoms of anemia can include:
   • Fatigue and lack of energy.
   • Weakness.
   • Pale skin (pallor).
   • Shortness of breath, especially with exertion.
   • A rapid heartbeat.
2. Jaundice: A yellowing of the skin and the whites of the eyes (the sclera). This is caused by a buildup of a yellow pigment called bilirubin. Bilirubin is a byproduct of the breakdown of hemoglobin from the destroyed red blood cells.
3. Splenomegaly: An enlarged spleen. The spleen works overtime to filter out and destroy the billions of abnormal spherocytes, causing it to become enlarged and sometimes palpable during a physical exam.

Other common signs and complications include:

• Gallstones: The high level of bilirubin in the blood can lead to the formation of pigment gallstones in the gallbladder, even in childhood or early adulthood. This is a very common complication.
• Dark Urine: Excess bilirubin can make the urine appear dark.

Crises in Hereditary Spherocytosis: Individuals with HS can also experience acute episodes, or “crises,” where their symptoms suddenly worsen, often triggered by an infection.

• Aplastic Crisis: This is the most serious type of crisis. It is a temporary shutdown of red blood cell production in the bone marrow, most commonly triggered by an infection with Parvovirus B19 (the virus that causes “fifth disease” in children). Because the existing red blood cells are already so short-lived, a sudden halt in production can lead to a rapid and life-threatening drop in hemoglobin levels, requiring an emergency blood transfusion.
• Hemolytic Crisis: This is a sudden acceleration of red blood cell destruction, often triggered by a common viral or bacterial infection, leading to worsening anemia and jaundice.

I’ve often seen kids diagnosed after multiple gallstone episodes in their teens, it’s a big clue when you see stones at a young age without obvious risk factors.

A diagnosis of HS is suspected in a patient with a family history of the condition who presents with the classic signs of anemia, jaundice, and an enlarged spleen. A series of blood tests is used to confirm the diagnosis.

• Complete Blood Count (CBC): This test will show anemia and, characteristically, a high Mean Corpuscular Hemoglobin Concentration (MCHC). The MCHC is a measure of the concentration of hemoglobin in each red blood cell, and it is elevated.
• Peripheral Blood Smear: This is a crucial test where a drop of blood is smeared on a slide and examined under a microscope.
• Tests for Hemolysis: Blood tests will show a high reticulocyte count (indicating the bone marrow is working hard to produce new red blood cells), high levels of indirect bilirubin, and high levels of lactate dehydrogenase (LDH).
• Confirmatory Tests for Cell Fragility: Specialized tests are used to confirm that the red blood cells are abnormally fragile.
  • The osmotic fragility test is the classic method. Red blood cells are placed in solutions with decreasing salt concentrations. Spherocytes, which cannot swell as much as normal discs, will burst (lyse) in less salty solutions than normal red blood cells.
  • Newer, more specific tests like flow cytometry (often an EMA binding test) are now commonly used in many centers to confirm the diagnosis.

The management of Hereditary Spherocytosis depends entirely on the severity of the disease.

Mild HS

Individuals with mild HS who have minimal or no anemia may not require any specific treatment other than folic acid supplementation.

Supportive Care

• Folic Acid Supplementation: This is essential for all individuals with moderate to severe HS. Folic acid (a B vitamin) is a critical nutrient for producing new red blood cells.
• Blood Transfusions: These are used to treat severe anemia, particularly during an aplastic crisis.

Splenectomy: The Main Treatment for Severe HS

For individuals with moderate to severe HS who have significant anemia, require frequent transfusions, or have poor growth, the primary and most effective treatment is a splenectomy.

• Rationale: Removing the spleen allows fragile spherocytes to survive much longer in circulation. This dramatically reduces the rate of hemolysis, cures the anemia, resolves the jaundice, and reduces the risk of gallstones.
• Timing: The spleen plays an important role in the immune system, especially in young children. For this reason, a splenectomy is usually delayed until a child is at least 5 or 6 years old.
• Risks and Precautions: The most significant long-term risk of a splenectomy is a lifelong increased susceptibility to severe infections. This risk is known as Overwhelming Post-Splenectomy Infection (OPSI), which can be life-threatening. To manage this risk, the following precautions are essential:
  • Vaccinations: Patients must receive a series of crucial vaccines before the surgery, including those for Pneumococcus, Meningococcus, and Haemophilus influenzae type b (Hib).
  • Prophylactic Antibiotics: After surgery, patients, especially children, will often be prescribed a daily low dose of an antibiotic (like penicillin) for several years, or sometimes for life.
  • Vigilance: Patients must seek immediate medical attention for any fever, as it could signal the start of a serious infection.

Gallbladder Removal (Cholecystectomy)

Because gallstones are such a common complication, a surgeon will often perform an ultrasound of the gallbladder before a planned splenectomy. If gallstones are present, the gallbladder is typically removed during the same operation.

Clinically, I’ve seen the decision to remove the spleen improve quality of life drastically in severe cases, but it comes with lifelong considerations for infection risk.

Hereditary Spherocytosis is a common inherited blood disorder that results from a structural defect in red blood cells, rendering them fragile and short-lived. While the condition is lifelong, its impact varies greatly, from a mild, asymptomatic trait to a severe hemolytic anemia requiring significant medical intervention. For those with more severe disease, the removal of the spleen offers a highly effective, near-curative treatment for the anemia, but it comes with the lifelong responsibility of taking precautions against infection. Patients and families often feel overwhelmed at first, but with education and good follow-up, the condition becomes manageable and life goes on with confidence.

1. American Society of Hematology (ASH). (n.d.). Hereditary spherocytosis. Retrieved from https://www.hematology.org/education/patients/anemia/hereditary-spherocytosis
2. National Institutes of Health, Genetic and Rare Diseases Information Center (GARD). (2023). Hereditary spherocytosis. Retrieved from https://rarediseases.info.nih.gov/diseases/6612/hereditary-spherocytosis
3. National Organization for Rare Disorders (NORD). (2022). Hereditary spherocytosis. Retrieved from https://rarediseases.org/rare-diseases/hereditary-spherocytosis/