Rare Anaemias

Rare Anaemias are a group of rare diseases, in which anaemia is the key clinical manifestation. They are a large group of disorders, mostly hereditary (congenital) and chronic although some acquired forms that develop later in life also exist (acquired). Each disorder has its own distinct pathophysiology although there are common, similar and shared needs across diseases. Some are enzyme deficiencies, dyserythropoietic anaemias (disorders of red cell formation) leading to red cell destruction (haemolysis), and bone marrow aplasias or hypoplasias.

A classification system of 10 categories based on mechanism of disease, prevalence and/or relevant clinical and/or social impact in the European population subdivides rare anaemias as follows:

1. Haemoglobin defects


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Haemoglobinopathies (i.e. Sickle Cell Anaemia)

Sickle cell Anaemia is an inherited structural red blood cell disorder where the hemoglobin structure is abnormal, causing the red blood cells to become hard and sticky and to eventually look like a C-shaped farm tool called a “sickle.” This prevents the red blood cells to freely move through blood vessels around the body carrying oxygen. When they travel through small blood vessels, they get stuck and clog the blood flow. This can cause pain and other serious complications (health problems) such as infection, acute chest syndrome and stroke (see below). Moreover, the sickle cells die early, thus causing a constant shortage of red blood cells.

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2. Hereditary Haemolytic Anaemias (HHA)

Red blood cell enzymopathies

A group of hereditary anaemias in which enzymes, active in red cell metabolism, are deficient; this disturbs the function and so reduces the life span of the cells, hence causes haemolysis (destruction of red blood cells). Diagnosis is mainly by enzyme assay. There are many enzymes which are affected, and most are extremely rare. The most common types of red blood cell enzymopathies are:

Glucose-6-phosphate dehydrogenase deficiency (G6PD deficiency) is by far the most common enzyme deficiency, caused by various mutations. In some populations the prevalence is very high (e.g. in Cyprus 10% of the male population is deficient). The inheritance is in most cases x-linked and so males are affected, with only rare female homozygotes having symptoms. In the majority of patients, haemolysis occurs under conditions of oxidative stress; this means that an individual is well unless he is in contact with a substance that causes oxidation, in which case an acute haemolytic episode is triggered. The best known substance is found in the fava bean (favism) but there also various medications which have such an effect. In populations where other mutations cause the deficiency, a chronic haemolytic anaemia is the most usual manifestation. Most patients with chronic anaemia do not require treatment but in an acute haemolytic crisis blood transfusion is usually necessary.

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Pyruvate kinase deficiency (PK Deficiency or PKD) is another rare genetic disorder (exact prevalence is unknown) involving the premature destruction of red blood cells. It is caused by mutations to the pklr gene, which leads to a reduction in the amount of the enzyme pyruvate kinase. This enzyme is involved in converting sugar molecules into energy for the body. Insufficient energy provided to red blood cells leads to their premature death and destruction (haemolysis). The severity of the disease is highly variable between patients, with some patients experiencing little to no symptoms, while others experience quite severe illness. Due to very mild cases that may be undiagnosed, the true prevalence may be higher than the known cases. Diagnosis is made by determining the red cell enzyme activity and molecular characterisation of the defect. Treatment: Possible splenectomy, folic acid, transfusion. Mitapivat (currently approved in the USA and UK, and pending approval in the EU is a substance which activates the enzyme and is given orally twice daily). Other new enzyme activators under investigation.

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Red blood cell membranopathies

This is a group of hereditary haemolytic anaemias, which are caused by an inherited defect defect in the structure of the membrane covering the red cell (erythrocyte). The main conditions in this group are:

  • Hereditary Spherocytosis – this is the commonest, encountered in 1:2000 individuals, present in all racial groups
  • Hereditary Elliptocytosis – more common in patients of African and Mediterranean descent in whom 1:1000-4000 may be affected. A rare form is pyropoikilocytosis (1-2 families in Cyprus for our information)
  • Hereditary Stomatocytosis – very rare. Has two forms, the dehydrated type (xerocytosis) found in 1:50000 people, and the overhydrated type found in less than 1:million.
  • Southeast Asian Ovalocytosis, very common only in SE Asian populations, where it may reach 5-25% of the population

Most cases have an autosomal dominant mode of inheritance (a carrier may have symptoms).

In Spherocytosis, a protein that is part of the cell membrane is mutated (deficient or dysfunctional), resulting in a dysfunctional red cell membrane, which progressively loses its surface area, making the red cell more spherical, and with reduced deformability, making it difficult to pass through the capillary circulation and shortening the life span of each cell (haemolysis). Moreover, the spleen traps these abnormal cells contributing in this way to the degree of anaemia. The resulting anaemia varies in severity, so that in some patients the anaemia along with jaundice becomes obvious in infancy, while in others there is compensation and the condition becomes manifest in later life. The diagnosis can be made by red cell morphology (appearance of red cells under the microscope), and confirmed by osmotic fragility and osmotic gradient ektacytometry. A special electrophoresis allows the identification of the defective protein. Treatment is by splenectomy. For more information click here.

In Elliptocytosis, defects in the cell membrane proteins result in a decreased membrane stability, with an increased red cell destruction, and loss of cell surface area. The result may be mild asymptomatic or moderately severe haemolytic anaemia. Splenectomy is again the only treatment option according to the severity of the anaemia. Diagnosis includes red cell morphology and osmotic gradient ektacytometry. For more information click here.

Stomatocytosis, is due to abnormal red cell permeability, meaning that there is abnormal concentration of salts (sodium and potassium) in the cell. In one form this increases the water content of the cell and in another form the cell is dehydrated (xerocytosis). Both forms cause a mild to moderate haemolytic anaemia which rarely leads to splenectomy.  Osmotic gradient ektacytometry is again diagnostic.

More information: Dehydrated hereditary stomatocytosis, Overhydrated hereditary stomatocytosis

In Southeast Asian Ovalocytosis, the altered membrane proteins cause a marked membrane rigidity, which does not allow deformability of the red cells as they pass from small blood vessels. Diagnosis and Treatment are similar to the other membranopathies.

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3. Erythropoietic failure or aplasia

Diamond-Blackfan anaemia (DBA)

Diamond-Blackfan anaemia (DBA) is characterised by a deficiency of red cell progenitor cells in the bone marrow. The cause are mutations in the gene coding for a ribosomal protein, the absence of which leads to early cell death of the red cell progenitors. It is inherited as an autosomal dominant and most cases are sporadic. The clinical effects are variable, even among family members. Presentation is usually before the age of one year, with a macrocytic anaemia (increased MCV) and reduced reticulocytes. Diagnosis is by these findings in peripheral blood, bone marrow examination (with reduced erythroblasts), and by molecular identification of the mutations. HbF is usually elevated and an enzyme (erythrocyte deaminase) is elevated in 80-85% of cases. A positive family history will support the diagnosis. Treatment is initially with the use of steroids to which most (50%) will respond but many will develop resistance and will need regular and lifelong blood transfusions and iron chelation. The an increase risk of malignancies has been noted. Haematopoietic Stem Cell Transplantation (HSCT) offers a curative option for eligible patients.

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Fanconi Anaemia

Fanconi Anaemia is characterised by bone marrow failure, severe anaemia and accompanied by congenital abnormalities (including skeletal abnormalities in upper limbs, short stature, microcephaly), in addition to a predisposition for the development of malignancies, especially leukaemia, myelodysplasia and skin cancer.  Fanconi Anaemia genes are recessively inherited (both parents must be carriers). There is instability of the chromosomes that result in congenital malformations and anaemia. This combination will raise the suspicion by doctors for pursuing diagnosis. Tests which confirm the diagnosis include: chromosomal fragility detected by special cytogentic tests, along with molecular detection of the mutations. The bone marrow failure responds in many cases to androgen (male hormone) treatment, including danazol. Blood transfusion may be required. Final cure can be achieved by Haematopoietic Stem Cell Transplantation (HSCT).

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Aplastic anaemia

Aplastic anaemia is an acquired disorder characterized by an inability of the body to produce blood cells in sufficient numbers in the bone marrow. It affects all blood cell types, including red blood cells, neutrophils (<1000/cmm) and low platelets (< 20,000). It can be caused by autoimmunity (inhibiting the growth of progenitor cells in the bone marrow) or exposure to certain environmental chemicals, many drugs, radiation or even infection (especially parvovirus B19). Definitive diagnosis is obtained via bone marrow biopsy, although differentiation from inherited bone marrow failure syndromes may be difficult. It is rare, immune-mediated and a potentially fatal disorder with an estimated incidence of 0.7 – 4.1 per million people per year. Bone marrow transplantation from a human leukocyte antigen-identical sibling donor is the only potentially curative therapy for marrow failure. Where transplant is not possible, other available treatment is immunosuppressive therapy (IST) with antithymocyte/antilymphocyte globulin and cyclosporine, which produces a hematologic response rate of approximately 60% to 70%.

More information: Autosomal dominant aplastic anemia and myelodysplasia, Hereditary isolated aplastic anemia

4. Dyserythropoietic Anaemias

This is a group of hereditary and acquired anaemias characterised by ineffective erythropoiesis.

Congenital dyserythropoietic anaemias (CDA)

Different mutations result in subtypes of Congenital dyserythropoietic anaemias (CDA) which share some common features but also differ in clinical manifestations, and require different treatment approaches. The subtypes are classified as I-III plus variant types. With the exception of type II the rest are very rare. The pattern of inheritance is autosomal recessive (both parents must be carriers). CDA Type I is a rare anaemia with increased size of red cells (macrocytosis), and usually not transfusion dependent. CDA Type II (HEMPAS) is an anaemia with a distinct pattern of red cells under the microscope; the cell are of mostly normal size but varying shapes and contain characteristic spots (basophilic stpling). In the bone marrow the developing red cells (erythroblasts) are increased in number,but may have two or more nuclei. Apart from morphological changes in peripheral blood and bone marrow, there are changes in the cell membrane and mutations which confirm the diagnosis. Prevalence varies in various populations and may be as high as 3 per million in some regions. Splenomegaly and gallstones are common and iron overload increases over time. In CDA Type II patients may benefit from splenectomy. Haematopoietic Stem Cell Transplantation (HSCT) has also been curative to severe cases.

Click on the links for more information about Congenital dyserythropoietic anemia type I, type II, type III, and type IV.


Myelodysplastic syndromes

Myelodysplastic syndromes (MDS) are a varied (heterogeneous) group of malignant hematopoietic (blood forming) stem cell (HSC) disorders in the bone marrow. They are characterized by ineffective maturation and production of blood cells, resulting in low counts of all or some blood cells (red cells, white cells and platelets) in the peripheral blood, and an increased risk of transformation to acute myeloid leukemia (AML). MDS arise when some of the stem cells (progenitor cells) suffer changes, which include mutations and chromosome abnormalities. These aberrant cells form clones within the blood forming tissues and trigger activation of the immune system which affects the survival of these cells.  Patient disease course, progression, and survival rates are highly variable, and the disease is divided into Low, Intermediate and High-risk categories; the higher-risk subtypes are associated with higher aberrant progenitor cell counts, increased risk of leukaemic transformation, and shorter median overall survival. Even though MDS affect children, frequency increases with age and so MDS is the most frequent hematological disease in the elderly. The only curative treatment is by HSCT, which is not possible in all patients, especially the elderly with co-morbidities which do not allow the necessary immunosuppression. Alternative treatments are often required. Most available are cytotoxic agents however, half of the patients do not respond to these treatments and many eventually acquire resistance leading to relapse. Combining therapies (e.g. venetoclax and azacitidine combination) is a promising strategy to overcome or avoid the problem of acquired resistances. New approaches are currently in various stages of development (including luspatercept). Supportive therapy with blood transfusions, with or without oral iron chelators, may also be necessary.


  • Hatzimichael E, Timotheatou D, Koumpis E, Benetatos L, Makis A. Luspatercept: A New Tool for the Treatment of Anemia Related to β-Thalassemia, Myelodysplastic Syndromes and Primary Myelofibrosis. Diseases. 2022 Oct 9;10(4):85. doi: 10.3390/diseases10040085. PMID: 36278584
  • Sekeres MA, Taylor J. Diagnosis and Treatment of Myelodysplastic Syndromes: A Review. JAMA. 2022;328(9):872–880. doi:10.1001/jama.2022.14578

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5. Sideroblastic Anaemias

Hereditary Sideroblastic Anaemias

This is a group of anaemias in which the common feature is the appearance of ring sideroblasts when the bone marrow cells are stained for iron. The mitochondria (organelles of the cytoplasm) are loaded with iron. This is due to mutations in genes encoding for mitochondrial proteins, causing a reduction in erythroblast heme, while iron continues to enter the cells and precipitates in the mitochondria. While normal amounts of iron are present, the iron is not adequately incorporated into haemoglobin – the molecule needed to transport oxygen effectively around the body. This causes ineffective erythropoiesis and the patients may present as anaemia or iron overload. Other cells may be involved, so the patient may present with pancytopenia, neutropenia or thrombocytopenia. Other tissues may also be affected (multisystem mitochondrial diseases) such as the inner ear, the pancreas, the cerebellum, endocrine glands and muscle (causing a myopathy). All patterns of inheritance are encountered. Diagnosis is by examination of the bone marrow with a special iron stain which will detect ring sideroblasts. Different genes are involved and molecular studies are needed especially when there are multi-organ manifestations.

Acquired Sideroblastic Anaemias

These can be caused by myelodysplasia with ring sideroblasts and neoplasms with ring sideroblasts and thrombocytosis. Also there is toxic or metabolic acquired sideroblastic anaemia.

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6. Non-sideroblastic anaemias due to iron metabolism defects

This is a group of disorders in which there is mild to severe anaemia, but without ring sideroblasts, and there is a disturbed regulation of iron metabolism.

Disorders of this group are extremely rare, with perhaps Iron-refractory Iron-deficiency anaemia (IRIDA) being the least rare. In IRIDA there is an increased amount of the hormone hepcidin, which inhibits the absorption of iron and so leads to iron deficiency. In other members of this group there is iron overload.

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7. Hereditary disorders of folic acid and cobalamin defects

Deficiency of folate or cobalamin during pregnancy can cause severe malformation in the central nervous system such as neural tube defects. After birth, folate and cobalamin deficiency can cause anaemia, failure to thrive, recurrent infections, psychiatric and neurological symptoms.

Several inherited disorders of folate metabolism and transport[1] have been described, including Hereditary folate malabsorption, Cerebral folate deficiency and others.

Cobalamin Defects. Cobalamin (vitamin B12) is a water soluble vitamin from the B-group. It is essential for cell growth and division. Vitamin B12 deficiency can cause severe haematological and/or neurological manifestations. Low serum levels are also associated with pregnancy loss. Inherited defects in vitamin B12 metabolism are associated with failure to thrive, irritation, feeding problems, and neurological or neurodevelopmental disorders in children.

Hematological and neurological symptoms of folate and cobalamin deficiency are similar.

[1] Kirsch SH, Herrmann W, Obeid R. Genetic defects in folate and cobalamin pathways affecting the brain. Clin Chem Lab Med. 2013 Jan;51(1):139-55. doi: 10.1515/cclm-2012-0673. PMID: 23183749

8. Paroxysmal nocturnal haemoglobinuria (PNH)

This disease is characterised by destruction (haemolysis) of red cells in the circulation (intravascular haemolysis) and bone marrow failure, causing anaemia and organ dysfunction (renal failure, pulmonary hypertension and others) due to a propensity to thrombosis (thrombophilia). PNH is caused by somatic mutations in PIG-A gene in one or more blood forming stem cell clones. This gene codes for a protein which is important for stem cell development and deficiency of the protein defines the severity of the disease. PNH erythrocytes are susceptible to haemolysis, which can lead to thrombosis. Diagnosis is by a test called Flow cytometry. Treatment is by bone marrow transplantation. Eculizumab, a monoclonal antibody complement inhibitor, is highly effective in reducing complications.

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9. Anaemias due to rare complex mechanisms

Autoimmune haemolytic anaemia (AIHA)

The patient’s immune system acts against its own red cell antigens, forming autoantibodies. Other factors, such as the complement system, come into play and complicate the pathophysiology. In other words, the red cells are tagged by antibodies and then destroyed by other cells of the immune system The direct anti-globulin test (DAT or Coomb’s test) is positive. There is a genetic background since AIHA has been associated with HLA-B8 and BW6 locus of the HLA system.

AIHAs may be primary (idiopathic) or associated with several conditions (lymphomas, infections immunodeficiencies, drug induced haemolysis, transfusion reactions, allo-immune reaction to HSCT, haemolytic disease of the newborn, liver disease and many others). Most cases are mild/moderate but acute, severe cases are also described[1].

Most cases are due to the presence a warm antibody (i.e. an IgG autoantibody) that binds to red cells at 37oC (warm autoimunne haemolytic anaemia – wAIHA). Others are due to an IgM antibody that causes clumping (agglutination) of red cells at cold temperatures (3-4°C) (causing cold agglutinin disease – CAD). In wAIHA haemolysis is mainly in the spleen and so splenectomy may be effective, whereas in CAD haemolysis is in the liver and in the blood stream. Also, CAD may signal a lymphoma or an infection and it mostly affects people between the ages of 40 and 80 years.

Treatment is by identifying and managing the underlying condition, which must be have a timely recognition, compatibility testing and detecting antibodies to the red cell blood groups (ABO, CcDEe and Kell), folic acid supplements and preventing thrombosis. Steroids are used in wAIHA whereas in CAD rituximab is the first line of treatment. In both cases, the response is temporary. A series of novel therapies are becoming available in both forms of AIHA. In CAD, for example sutimlimab (Enjaymo) has been FDA approved to decrease the need for blood transfusion and EMA approval is pending. Specific situations, such as paediatric acute disease triggered usually by virus infections, pregnancy, the presence of other congenital anaemias, must be considered in deciding treatment[2].

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[1] Hill A, Hill QA. Autoimmune hemolytic anemia. Hematology Am Soc Hematol Educ Program. 2018 Nov 30;2018(1):382-389. doi: 10.1182/asheducation-2018.1.382. PMID: 30504336

[2] Barcellini W, Fattizzo B. Diagnosis and Management of Autoimmune Hemolytic Anemias. J Clin Med. 2022 Oct 13;11(20):6029. doi: 10.3390/jcm11206029. PMID: 36294350

10. Anaemias of unknown origin (AUO)

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