Hereditary stomatocytosis (overhydrated)

Overview

Hereditary stomatocytosis (overhydrated) is a rare genetic disorder that affects the body's red blood cells. These cells, which are responsible for carrying oxygen throughout the body, have a unique biconcave disc shape. In people with hereditary stomatocytosis, the red blood cells are abnormally shaped, appearing like a mouth or 'stoma' under a microscope. This specific type is called 'overhydrated' because the red blood cells contain an excess amount of water [PMID:33671239].

These abnormal red blood cells are also more fragile than healthy ones. Their altered shape and increased fragility mean they are often destroyed prematurely in the spleen, leading to a shortage of red blood cells. This shortage is known as haemolytic anaemia. The severity of the anaemia and associated symptoms can differ significantly between individuals.

Symptoms & clinical features

The primary symptom of hereditary stomatocytosis (overhydrated) is haemolytic anaemia, which can range from mild to severe. Common signs of anaemia include fatigue, weakness, paleness of the skin, and shortness of breath, particularly during physical activity. Jaundice, a yellowing of the skin and whites of the eyes, may also occur due to the increased breakdown of red blood cells and the resulting build-up of bilirubin.

Some individuals might experience an enlarged spleen (splenomegaly), as the spleen works harder to remove the abnormal red blood cells from circulation. Gallstones are also a potential complication, forming due to the excess bilirubin from red blood cell breakdown [PMID:17006886]. In some cases, the condition might be relatively mild, and individuals may have few or no symptoms, with the disorder only being discovered during routine blood tests.

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Affected organs

Hereditary stomatocytosis primarily affects the blood and blood-forming organs. The red blood cells themselves are directly impacted, leading to their abnormal shape and function. The spleen is also significantly affected, becoming a site where the fragile red blood cells are prematurely destroyed, often leading to its enlargement (splenomegaly).

Additionally, the liver and gallbladder can be affected due to the increased bilirubin levels resulting from red blood cell destruction. This can predispose individuals to develop gallstones. In severe cases, the constant demand on bone marrow to produce new red blood cells can also have broader effects on the body's energy levels and overall health.

Blood & bone marrow

Haematological involvement

Cellular impact

Mechanism at cellular level

Risks & severity

The severity of hereditary stomatocytosis (overhydrated) is highly variable. Some individuals may experience mild, compensated haemolytic anaemia, meaning their body can largely cope with the red blood cell loss, and they might have minimal symptoms. Others can have more severe anaemia requiring medical intervention, such as regular blood transfusions in extreme cases. The condition is present from birth, although symptoms may not become apparent until childhood or even adulthood.

Lifetime risks associated with the condition include the development of gallstones, which can sometimes require surgical removal. There is also an increased risk of iron overload, particularly for individuals who receive frequent blood transfusions, which can damage organs such as the heart and liver. Individuals who undergo splenectomy (surgical removal of the spleen) to manage severe anaemia face an increased risk of blood clots and certain infections [PMID:17006886].

Genetic causes

Hereditary stomatocytosis (overhydrated) is caused by genetic changes (pathogenic variants) in the RHAG gene. The RHAG gene provides instructions for making a protein called Rh-associated glycoprotein. This protein is located on the surface of red blood cells and plays a crucial role in maintaining their shape and regulating the movement of ions, particularly ammonium, across the cell membrane. It is also thought to be involved in transporting carbon dioxide.

Pathogenic variants in RHAG lead to a disruption in the function of the Rh-associated glycoprotein. This disruption causes the red blood cells to lose their ability to properly regulate water and ion balance, leading to an excessive intake of water, making them 'overhydrated'. This increase in intracellular water contributes to the characteristic abnormal shape and fragility of the red blood cells, leading to their premature destruction and the development of haemolytic anaemia [PMID:24759685].

• RHAG
  Rh associated glycoprotein

Inheritance pattern

Hereditary stomatocytosis (overhydrated) is inherited in an autosomal dominant pattern. This means that only one copy of the altered RHAG gene in each cell is sufficient to cause the condition. An affected individual has a 50% chance of passing the genetic change to each of their children, regardless of the child's sex.

In many cases, an affected person inherits the altered gene from an affected parent. However, the condition can also result from a new genetic change (a de novo variant) in the RHAG gene that occurs for the first time in an individual, with no family history of the disorder. In such instances, the affected individual can then pass the condition on to their children.

Diagnosis & testing

Diagnosis of hereditary stomatocytosis (overhydrated) typically begins with a full blood count, which may show anaemia and abnormalities in red blood cell size and shape. A blood film examination by a haematologist can identify the characteristic 'stomatocytes'. Further specialised tests, such as osmotic fragility tests or cryohaemolysis tests, can help confirm the overhydrated nature of the red blood cells.

Genetic testing is the most definitive way to confirm a diagnosis, identifying pathogenic variants in the RHAG gene. Referrals for genetic testing are typically made by a haematologist or a clinical geneticist. In the UK, genetic testing for hereditary stomatocytosis, including specific gene analysis for RHAG, would fall under the NHS Genomic Medicine Service (GMS) pathways, often initiated via an R-code, after clinical assessment. Genetic counsellors can provide support and information regarding testing options and results.

Management & lifestyle

Management of hereditary stomatocytosis (overhydrated) focuses on managing the symptoms, particularly the haemolytic anaemia, and preventing complications. For individuals with mild anaemia, regular monitoring through blood tests may be sufficient. More severe anaemia might require treatment, such as folic acid supplementation to support red blood cell production.

In some cases of severe anaemia, particularly when associated with significant splenomegaly or gallstones, surgical removal of the spleen (splenectomy) may be considered. However, this decision is carefully weighed against potential risks, such as increased susceptibility to infection and a heightened risk of blood clots. Individuals undergoing splenectomy typically require lifelong vaccinations and may need antibiotics. Regular monitoring for iron overload and gallstone formation is also important. All management decisions are made in consultation with a haematologist, following NHS clinical guidelines.

UK care pathway

In the UK, individuals suspected of having hereditary stomatocytosis would typically be referred by their GP to a haematologist for initial assessment and blood tests. If a hereditary blood disorder is suspected, further referral to a clinical genetics service is common. Genetic testing, often guided by NHS R-codes, is then arranged through the NHS Genomic Medicine Service. Genetic counsellors within these services provide vital support, offering information on inheritance, testing options, and implications for families.

Related conditions

Other rare inherited red blood cell disorders, collectively known as hereditary stomatocytoses, can have similar presentations. These include hereditary stomatocytosis (dehydrated), which also affects red blood cell water content but results in dehydrated cells, and hereditary cryohydrocytosis. These conditions can be challenging to differentiate based on symptoms alone, making specialised laboratory tests and genetic analysis crucial for accurate diagnosis.

Frequently asked questions