The sideroblastic anemias are a heterogeneous group of inherited and acquired disorders characterised by anaemia of varying severity and the presence of ring sideroblasts in the bone marrow.¹ According to the World Health Organization (WHO) classification, sideroblastic anaemia shows anaemia, no blasts in the peripheral blood, isolated erythroid dysplasia with <5% blasts and >15% ringed sideroblasts in the bone marrow.² The International Working Group on Morphology of Myelodysplastic Syndrome (IWGM-MDS) has recommended that ring sideroblasts be defined as erythroblasts in which there are a minimum of five siderotic granules covering at least one third of the circumference of the nucleus.³

The sideroblasts form due to reduced haemoglobin synthesis, resulting in the accumulation of iron within red blood cell precursors. Cases may be congenital or acquired. Cases are more often acquired and sometimes represent a stage in the development of myelodysplastic syndromes (MDS).

Epidemiology

Refractory anaemia with ringed sideroblasts (RARS) may account for 5-15% of all myelodysplastic syndrome (MDS) cases.⁴

Aetiology

Congenital

• The most common inherited sideroblastic anaemia is X-linked sideroblastic anaemia (XLSA) caused by mutations of the erythroid-specific delta-aminolevulinic acid synthase 2 gene (ALAS2).⁵ Sideroblastic anaemia due to SLC25A38 gene mutations is the next most common inherited sideroblastic anaemia.^6,7
• Congenital causes of sideroblastic anaemia also include Wolfram's syndrome (DIDMOAD = Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy and Deafness).⁸

Acquired

In addition to the myelodysplastic syndromes (MDS), sideroblastic anaemia can also occur in other bone marrow diseases including:

• Myeloma
• Polycythaemia rubra vera
• Myelosclerosis
• Leukaemias

Secondary causes include:⁸

• Inflammatory conditions, e.g. rheumatoid arthritis.
• Systemic lupus erythematosus.
• Chronic infections.
• Drug toxicity, e.g. chloramphenicol, cycloserine, antituberculous agents.
• Chronic alcoholism.
• Haemolytic anaemia.
• Nutritional deficiencies, e.g. copper, vitamin B6; malabsorption syndromes.
• Hypothyroidism.
• Hypothermia.
• Lead poisoning.
• Zinc overdose.
• Haemodialysis.⁹
• Pregnancy.

Presentation

• Clinical features are those related to anaemia in general. Symptoms reflect the cytopenias, i.e. anaemia, infection, bruising and haemorrhage.
• There are no specific signs or symptoms related to sideroblastic anaemia alone.

Investigations

Diagnosis is made from bone marrow examination demonstrating the presence of ring sideroblasts with a generalised increase in iron stores.

• FBC usually shows a moderate degree of anaemia.⁸
• The mean corpuscular volume (MCV) is normal or increased, but can be low.
• High serum iron and transferring saturation also occur.
• The blood film shows a dimorphic population of both normal and hypochromic red blood cells.

Management

General measures

• Treatment is mainly supportive.
• Red cell transfusion is given for symptomatic anaemia.
• Iron chelation with desferrioxamine should be considered after 20-25 units of red cells have been received.¹⁰
• Avoid alcohol and reduce vitamin C intake, as these increase iron absorption.

Pharmacological

• The use of erythropoietin ± granulocyte colony-stimulating factor has been demonstrated to reduce the need for red cell transfusion in some patients with myelodysplastic syndrome (MDS) but the studies were small.¹⁰
• Patients with hereditary sideroblastic anaemia may respond to pyridoxine.¹⁰
• Ciclosporin has been shown to give a response rate (i.e. alteration of disease progression or remission) of 62.5% in patients with MDS including sideroblastic anaemia.¹¹
• New therapies are emerging, e.g. azacitidine.¹²

Surgical

• Allogenic peripheral stem cell transplantation has been used with success in pyridoxine refractory hereditary sideroblastic anaemia. Few patients are eligible for transplant.¹¹

Prognosis⁸

• The prognosis is very variable.
• Reversible causes (e.g. alcohol or drugs) appear to have no long-term effects if the underlying cause is successfully treated or removed.
• Patients continuing to need regular blood transfusions, those who have conditions unresponsive to treatment, and those with myelodysplastic syndrome (MDS) often have a much worse prognosis.
• Patients with idiopathic sideroblastic anaemia and MDS have a median survival of 38 months. Those with pure sideroblastic anaemia (abnormal erythropoiesis only) have a median survival of 60 months.
• Favourable prognostic indicators include thrombocytosis and needing fewer blood transfusions.¹³
• Causes of death include haemochromatosis, resulting from transfusions, and leukaemia.

Document references

1. Cazzola M, Invernizzi R; Ring sideroblasts and sideroblastic anemias. Haematologica. 2011 Jun;96(6):789-92.
2. Vardiman JW, Harris NL, Brunning RD; The World Health Organization (WHO) classification of the myeloid neoplasms. Blood. 2002 Oct 1;100(7):2292-302. [abstract]
3. Mufti GJ, Bennett JM, Goasguen J, et al; Diagnosis and classification of myelodysplastic syndrome: International Working Group on Morphology of myelodysplastic syndrome (IWGM-MDS) consensus proposals for the definition and enumeration of myeloblasts and ring sideroblasts. Haematologica. 2008 Nov;93(11):1712-7. Epub 2008 Oct 6. [abstract]
4. Refractory anemia with ringed sideroblasts (RARS), Atlas of Genetics and Cytogenetics in Oncology and Haematology
5. Anemia, Sideroblastic, X-linked; XLSA, Online Mendelian Inheritance in Man (OMIM)
6. Camaschella C; Recent advances in the understanding of inherited sideroblastic anaemia. Br J Haematol. 2008 Sep;143(1):27-38. Epub 2008 Jul 14. [abstract]
7. Harigae H, Furuyama K; Hereditary sideroblastic anemia: pathophysiology and gene mutations. Int J Hematol. 2010 Oct;92(3):425-31. Epub 2010 Sep 17. [abstract]
8. Mir MA et al, Sideroblastic Anemias, Medscape, Jul 2011
9. Furuyama K, Harigae H, Kinoshita C, et al; Late-onset X-linked sideroblastic anemia following hemodialysis. Blood. 2003 Jun 1;101(11):4623-4. Epub 2003 Jan 16. [abstract]
10. Bowen D, Culligan D, Jowitt S, et al; Guidelines for the diagnosis and therapy of adult myelodysplastic syndromes. Br J Haematol. 2003 Jan;120(2):187-200.
11. Chen S, Jiang B, Da W, et al; Treatment of myelodysplastic syndrome with cyclosporin A. Int J Hematol. 2007 Jan;85(1):11-7. [abstract]
12. Steensma DP, Tefferi A; Risk-based management of myelodysplastic syndrome. Oncology (Williston Park). 2007 Jan;21(1):43-54; discussion 57-8, 62. [abstract]
13. Palmer SR, Tefferi A, Hanson CA, et al; Platelet count is an IPSS-independent risk factor predicting survival in refractory anaemia with ringed sideroblasts. Br J Haematol. 2008 Mar;140(6):722-5. Epub 2008 Jan 29.

Internet and further reading

• Mufti GJ, Bennett JM, Goasguen J, et al; Diagnosis and classification of myelodysplastic syndrome: International Working Group on Morphology of myelodysplastic syndrome (IWGM-MDS) consensus proposals for the definition and enumeration of myeloblasts and ring sideroblasts. Haematologica. 2008 Nov;93(11):1712-7. Epub 2008 Oct 6. [abstract]
• Moyo V, Lefebvre P, Duh MS, et al; Erythropoiesis-stimulating agents in the treatment of anemia in myelodysplastic syndromes: a meta-analysis. Ann Hematol. 2008 Jul;87(7):527-36. Epub 2008 Mar 20. [abstract]