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Hereditary spherocytosis
This condition makes red blood cells fragile and prone to premature breakdown, leading to anaemia, jaundice, and an enlarged spleen. It is one of the most common inherited anaemias affecting people of Northern European descent.
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Overview
Hereditary spherocytosis (HS) is a lifelong genetic disorder that primarily affects red blood cells. In individuals with HS, the red blood cells are abnormally shaped, appearing as spheres (spherocytes) instead of their typical biconcave disc shape. This altered shape makes them less flexible and more fragile [PMID:33678564]. These fragile spherocytes are more easily damaged and destroyed, particularly as they pass through the spleen, leading to a condition called haemolytic anaemia.
Haemolytic anaemia occurs when red blood cells are destroyed faster than the body can produce them. Red blood cells are vital for carrying oxygen from the lungs to the rest of the body, so their reduced number can cause fatigue and other symptoms. HS is a relatively common inherited anaemia, particularly in populations of Northern European ancestry, where it affects approximately 1 in 2,000 individuals.
Symptoms & clinical features
The symptoms of hereditary spherocytosis can vary significantly between individuals, ranging from very mild to severe. Many people with mild HS may experience few or no symptoms and only be diagnosed incidentally or later in life. Common symptoms are often related to the ongoing destruction of red blood cells.
Key symptoms include anaemia, which can cause tiredness, weakness, and shortness of breath. Jaundice, a yellowing of the skin and whites of the eyes, can occur due to the build-up of bilirubin, a breakdown product of red blood cells. An enlarged spleen (splenomegaly) is also common, as the spleen works harder to filter out and destroy the abnormal spherocytes. Some individuals may develop gallstones, typically in adolescence or adulthood, formed from excess bilirubin [PMID:24673847]. More severe cases can present in infancy with significant jaundice requiring treatment.
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Affected organs
Hereditary spherocytosis primarily affects the red blood cells, which are produced in the bone marrow and circulate throughout the bloodstream. The main organs impacted by the condition are the spleen and the liver.
The spleen plays a crucial role in filtering abnormal red blood cells from circulation. In HS, the spleen becomes overworked and often enlarged (splenomegaly) due to the increased destruction of spherocytes. The liver can also be affected, as it processes the bilirubin released from the broken-down red blood cells, which can contribute to jaundice and, in some cases, lead to gallstone formation in the gallbladder.
Risks & severity
The severity of hereditary spherocytosis is highly variable. Some individuals may have no noticeable symptoms (asymptomatic), while others experience severe anaemia requiring regular medical intervention. Around 20-30% of people with HS have a mild form, 60-70% have moderate disease, and 10% have severe symptoms [PMID:33678564].
Potential complications include aplastic crises, which are severe, temporary drops in red blood cell production, often triggered by viral infections like parvovirus B19. These crises can lead to very low red blood cell counts and severe anaemia. Gallstones are a common long-term risk, occurring in approximately 40-55% of individuals with HS by adulthood [PMID:24673847]. Without proper management, severe forms of HS can lead to significant health challenges, particularly in childhood.
Genetic causes
Hereditary spherocytosis is caused by genetic changes (variants) in genes that are important for the structure and function of the red blood cell membrane. These genes provide instructions for making proteins that form the 'skeleton' of the red blood cell, helping it maintain its disc shape and flexibility. When these proteins are faulty, the red blood cell membrane becomes unstable and fragments, causing the cell to take on a spherical shape.
Typically, variants in five main genes are associated with HS. These include ANK1, SLC4A1, and SPTB. Variants in ANK1 (ankyrin 1) are responsible for approximately 50-65% of HS cases. SLC4A1 (solute carrier family 4 member 1) and SPTB (spectrin beta, erythrocytic) variants account for about 15-25% and 5-10% of cases, respectively. Each of these genes codes for a protein essential for the red blood cell's structural integrity, and a defect in any of them can lead to the characteristic spherocyte formation.
- ANK1 ankyrin 1
- SLC4A1 solute carrier family 4 member 1 (Diego blood group)
- SPTB spectrin beta, erythrocytic
Inheritance pattern
Hereditary spherocytosis is most commonly inherited in an autosomal dominant pattern. This means that an individual only needs to inherit one copy of an altered gene from one parent to develop the condition. If a parent has autosomal dominant HS, there is a 50% chance that each child they have will also inherit the condition.
In some cases, HS can be inherited in an autosomal recessive manner, or it can arise from a new (de novo) genetic change in an individual with no family history. When the inheritance is autosomal recessive, an individual must inherit two copies of an altered gene (one from each parent) to be affected. Parents who each carry one copy of the altered gene are typically unaffected but have a 25% chance with each pregnancy of having a child with the condition.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
Diagnosis & testing
The diagnosis of hereditary spherocytosis typically involves a combination of clinical assessment, blood tests, and genetic testing. Initial suspicion often arises from symptoms such as anaemia, jaundice, or an enlarged spleen. Standard blood tests, including a full blood count, can show characteristics of haemolytic anaemia, such as decreased red blood cell count and increased reticulocytes (immature red blood cells).
Specific tests to confirm HS include osmotic fragility testing, which assesses how easily red blood cells rupture when exposed to solutions of varying salt concentrations, and flow cytometry-based eosin-5-maleimide (EMA) binding tests. Genetic testing, using techniques like gene panels, can identify specific variants in genes like ANK1, SLC4A1, or SPTB. Referral to a clinical haematologist or a clinical genetics service via your GP or other specialist is the usual pathway within the NHS. Genetic testing for hereditary spherocytosis is available on the NHS Genomic Medicine Service (NHS GMS) testing directory, often under relevant R-codes for inherited anaemias.
Management & lifestyle
Management of hereditary spherocytosis aims to alleviate symptoms and prevent complications. Treatment approaches vary depending on the severity of the condition. For individuals with mild HS, regular monitoring may be sufficient. This typically involves periodic blood tests and clinical assessments to track anaemia and spleen size.
For more severe cases, treatments may include folic acid supplementation to support red blood cell production. In some situations, a splenectomy (surgical removal of the spleen) may be considered, particularly for individuals with severe anaemia, growth problems, or recurrent aplastic crises, typically not before 5-6 years of age [PMID:24673847]. This procedure can significantly reduce red blood cell destruction but also carries risks, including increased susceptibility to certain infections, making vaccinations important. Gallstones, if present and symptomatic, may also require surgical removal. Management is typically guided by a haematologist, often in conjunction with a paediatrician for children, within the NHS framework.
UK care pathway
Within the UK, individuals suspected of having hereditary spherocytosis would typically be referred by their GP to a haematologist or a clinical genetics service. The NHS Genomic Medicine Service (NHS GMS) provides a comprehensive testing pathway. Genetic testing for hereditary spherocytosis is available through the NHS GMS, often specified by particular R-codes depending on the clinical presentation and suspected genes. A clinical geneticist or genetic counsellor can help families understand the genetic basis of the condition, its inheritance pattern, and discuss implications for other family members.
Frequently asked questions
What is a spherocyte?
A spherocyte is an abnormal red blood cell that is sphere-shaped instead of the usual biconcave disc shape. This altered shape makes the cell less flexible and more fragile, leading to its premature destruction in the spleen.
Can hereditary spherocytosis be cured?
Hereditary spherocytosis is a genetic condition, meaning it is present from birth and cannot be cured. However, its symptoms can be effectively managed through various treatments, allowing most individuals to lead full lives. In some cases, removing the spleen can significantly reduce the severity of symptoms.
Will my children inherit hereditary spherocytosis?
If you have autosomal dominant hereditary spherocytosis, each of your children has a 50% chance of inheriting the condition. Genetic counselling can provide a more precise risk assessment based on your specific genetic variant and family history.
What is an aplastic crisis?
An aplastic crisis is a severe, sudden drop in red blood cell production, often triggered by a viral infection like parvovirus B19. It can lead to very low red blood cell counts and severe anaemia, potentially requiring blood transfusions and urgent medical attention.
How often do people with hereditary spherocytosis need blood transfusions?
The need for blood transfusions varies widely. Individuals with mild hereditary spherocytosis may never require a transfusion. Those with more severe forms, especially during aplastic crises or significant illness, may need transfusions to manage severe anaemia. Regular monitoring helps determine the need for such interventions.
References
- Zamora EA, Schaefer CA. Hereditary Spherocytosis. 2023. PMID: 30969619
- Shah S, Vega R. Hereditary spherocytosis. Pediatrics in review. 2004. PMID: 15121908
- Agarwal AM. Ankyrin Mutations in Hereditary Spherocytosis. Acta haematologica. 2019. PMID: 30602149
- Huq S, Pietroni MA, Rahman H. Hereditary spherocytosis. Journal of health, population, and nutrition. 2010. PMID: 20214092
- Russo R, Andolfo I. Hereditary spherocytosis and allied disorders. HemaSphere. 2019. PMID: 35309772
- Cong S, Wang YN, Wang JR. Association between hereditary spherocytosis and gallstone disease: Pathophysiology, diagnosis, and management. World journal of gastrointestinal surgery. 2025. PMID: 40740904
- Ciepiela O. Old and new insights into the diagnosis of hereditary spherocytosis. Annals of translational medicine. 2018. PMID: 30306078
- Matsuura H, Shiraishi Y. Haemolytic crisis of hereditary spherocytosis. Postgraduate medical journal. 2022. PMID: 33184136