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Sideroblastic anemias: Diagnosis and management

Sideroblastic anemias: Diagnosis and management
Literature review current through: Jan 2024.
This topic last updated: Nov 07, 2023.

INTRODUCTION — The sideroblastic anemias comprise a wide spectrum of relatively uncommon heritable and acquired erythropoietic disorders that are due to various abnormalities in heme synthesis and mitochondrial function (table 1).

In many of these disorders, the severity of the anemia is quite variable; it is uncommon for the peripheral blood findings to be characteristic. Thus, sideroblastic anemia should be considered in all children and adults with anemia of any severity when it is unexplained by the patient's history, clinical examination, and basic laboratory data.

The singular feature that typifies all forms of sideroblastic anemia is the presence of ring sideroblasts in the bone marrow aspirate.

The clinical course and management of these heterogeneous disorders are highly dependent on the underlying cause.

An approach to the patient with evident sideroblastic anemia is discussed here, along with distinguishing clinical features, diagnostic evaluation, and management. Comprehensive discussions of the inherited and acquired sideroblastic anemias, including genetic defects and pathophysiology, are presented separately. (See "Causes and pathophysiology of the sideroblastic anemias".)

CONGENITAL SIDEROBLASTIC ANEMIAS

Overview of inherited disorders — The congenital sideroblastic anemias are inherited diseases of mitochondrial dysfunction and can be attributed to pathogenic variants in genes involved in three interrelated mitochondrial pathways:

Heme biosynthesis

Iron-sulfur cluster biogenesis

Mitochondrial protein synthesis and respiration

The incidence of congenital sideroblastic anemias is unknown. While they usually present in childhood, there may be cases in which these conditions are not diagnosed until adolescence or adulthood, owing to a wide spectrum of manifestations in some disease types, especially if their presentation is mild and thus delayed. (See 'Diagnostic approach' below.)

Inherited sideroblastic anemias include nonsyndromic and syndromic disorders (table 1).

Nonsyndromic – The nonsyndromic forms present with anemia but lack other clinical manifestations. X-linked sideroblastic anemia (XLSA) is the most common (see 'X-linked sideroblastic anemias' below), followed in prevalence by the autosomal nonsyndromic SLC25A38 anemia [1]. (See 'Autosomal recessive forms' below.)

Syndromic – The syndromic inherited sideroblastic anemias are rare and include XLSA with ataxia (XLSA/A) and an X-linked MLASA variant, several autosomal recessive disorders, and two mitochondrially inherited forms.

Children with severe disease may have impaired growth and development. Many patients eventually develop systemic iron overload, management of which is discussed below. (See 'Iron overload' below.)

The inherited sideroblastic anemias are not associated with a predisposition to leukemia.

X-linked sideroblastic anemias — X-linked sideroblastic anemia (XLSA) is the most common congenital sideroblastic anemia. A typical presentation is of a young boy, perhaps slightly small for age, with no other clinical features and no family history of anemia, who presents with a hemoglobin of 7 g/dL, mean corpuscular volume (MCV) of 65 fL, and a red cell distribution width (RDW) of 30. He has no evidence of iron deficiency or thalassemia. The peripheral smear shows marked hypochromia and microcytosis occasionally with inclusions. The bone marrow aspirate shows abundant ring sideroblasts.

XLSA is viewed as an X-linked recessive disorder. However, in contrast to many X-linked disorders that present predominantly in males, up to one-third of cases of XLSA occur in females, with anemia onset typically at middle age or later. This high incidence in females relative to other X-linked disorders is attributed to acquired skewed X-chromosome inactivation in hematopoietic cells with advancing age. Some experts have suggested that the terms dominant and recessive not be used for X-linked disorders because of their extraordinarily variable expressivity and the multiple mechanisms that can result in expression of X-linked traits in females, including cell autonomous expression, skewed X-inactivation, clonal expansion, and somatic mosaicism [2].

XLSA is caused by heterozygous pathogenic variants in the ALAS2 gene, which encodes the erythroid-specific form of the heme biosynthetic enzyme 5-aminolevulinate synthase (also called delta-aminolevulinic acid synthase [ALAS]) (figure 1). Because vitamin B6 is the essential cofactor of this enzyme, the anemia may respond to vitamin B6 supplements by enhancing the impaired function of certain ALAS2 variants. Among all types of sideroblastic anemia, this response to vitamin B6 is thus unique to XLSA. The pathophysiology of XLSA is discussed in more detail separately.

The anemia in XLSA is of quite variable severity. It is always microcytic in males but normocytic or macrocytic in most females. The explanation for this difference is that in females, skewed X-chromosome inactivation in hematopoietic cells in the bone marrow leads to predominantly nonviable red blood cell (RBC) precursors usually bearing a severe mutant ALAS2 allele (that succumb to intramedullary hemolysis), while the peripheral blood RBCs represent the progeny of the RBC precursors bearing the normal ALAS2 allele, which undergo accelerated release from the bone marrow, mediated by increased erythropoietin drive of anemic hypoxia. This often produces macrocytosis [3,4].

In cases where the anemia is mild, the condition may not be discovered until later in life and may be attributed to a myelodysplastic syndrome (MDS) or thalassemia [5-7].

The severity of the anemia usually remains stable over many years; however, in some individuals, it worsens over time. Disease worsening over time may be attributed to one or more of the following, several of which relate to reduced vitamin B6 (pyridoxine) availability (for XLSA that responds to vitamin B6 supplementation):

Discontinuation of vitamin B6 that had been part of a multivitamin preparation the patient no longer takes

Changes in dietary habits that lead to reduced intake of vitamin B6

Age-associated alterations in pyridoxine metabolism

Age-associated skewing of the X chromosome inactivation pattern (lyonization) in hematopoietic cells in women, leading to progressive inactivation of the normal ALAS2 allele and greater relative expression of the allele bearing the pathogenic variant [3,8-11]

The commonly associated iron overload, which may further impair erythroblast mitochondrial function and heme synthesis [12]

XLSA with ataxia (XLSA/A) is a syndromic X-linked disorder caused by pathogenic variants in a different gene, ABCB7, which encodes an ATP-binding cassette with a postulated role in exporting iron-sulfur clusters (ISC) from mitochondria for cytosolic ISC-containing proteins [13]. The anemia is microcytic and relatively mild. Neurologic findings include delayed motor and cognitive development, incoordination, and nonprogressive cerebellar atrophy [13-16]. (See "Overview of the hereditary ataxias", section on 'X-linked sideroblastic anemia with ataxia'.)

A second syndromic X-linked congenital sideroblastic anemia is associated with a mutation in NDUFB11, which encodes a mitochondrial respiratory complex I associated protein [17,18]. The anemia is normocytic and moderately severe. Associated features have been variable among patients, such as short stature or developmental delay or myopathy.

Autosomal recessive forms — Autosomal recessive congenital sideroblastic anemias (ARCSA) include nonsyndromic and syndromic forms.

Nonsyndromic forms

ARCSA due to pathogenic variants in SLC25A38, which encodes the mitochondrial glycine transporter protein

ARCSA due to variants in HSPA9, which encodes a mitochondrial protein involved in iron-sulfur cluster (ISC) production

ARCSA due to variants in HSCB, which encodes a mitochondrial co-chaperone protein for HSPA9 involved in ISC production

ARCSA due to variants in GLRX, which encodes glutaredoxin 5, a mitochondrial enzyme required for ISC formation

Erythropoietic protoporphyria (EPP) due to variants in FECH, which encodes the terminal enzyme of heme biosynthesis

Syndromic forms

Sideroblastic anemia, B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD), due to pathogenic variants in TRNT1

Myopathy, lactic acidosis, and sideroblastic anemia (MLASA), due to variants in PUS1 or YARS2; and three clinical variants due to pathogenic variants in LARS2, IARS1, or SARS2

Thiamine-responsive megaloblastic anemia (TRMA), associated with diabetes mellitus and deafness, due to pathogenic variants in SLC19A2

TRNT1, PUS1, YARS2, LARS2, IARS1, and SARS2 encode components of the mitochondrial protein translation apparatus. SLC19A2 encodes the high-affinity thiamine transporter. The roles of these proteins in the pathogenesis of anemia and other disease manifestations are discussed separately. (See "Causes and pathophysiology of the sideroblastic anemias".)

Patients with pathogenic variants of SLC25A38 invariably have severe microcytic anemia that presents in early childhood, or occasionally in young adults, and nearly always requires chronic transfusion support [1]. While patients with variants in TRNT1 were all first noted to present with severe microcytic, transfusion-dependent anemia, subsequent experience has revealed a much wider spectrum of clinical manifestations as well as disease severity including absence of anemia [19]. Moreover, this syndrome can be considered the third most prevalent among the inherited sideroblastic anemias.

Patients with HSPA9 and HSCB pathogenic variants have mild or moderate microcytic anemia. Variants in GLRX5, PUS1, YARS2, LARS2, IARS2, SARS2, and SLC19A2 cause moderate to severe anemia. Variants in FECH cause EPP, which is associated with mild microcytic anemia, but the incidence of the ring sideroblast feature is not known as it was observed in only a small series of patients and not in others. As the name implies, TRMA responds to thiamine supplementation. (See 'Treatments for anemia' below.)

Mitochondrially inherited forms — Two of the syndromic forms follow a mitochondrial inheritance pattern:

Pearson marrow-pancreas syndrome, associated with acidosis and pancreatic insufficiency, due to large-scale mitochondrial DNA (mtDNA) deletions

Mitochondrial myopathy, lactic acidosis, and sideroblastic anemia variant (MLASA-plus), due to heteroplasmic pathogenic variant in MTATP6

In both of these syndromes, the anemia is normocytic or macrocytic, usually but not always severe, and typically transfusion dependent.

Pearson marrow-pancreas syndrome is discussed in more detail separately. (See "Mitochondrial myopathies: Clinical features and diagnosis", section on 'Pearson syndrome' and "Causes and pathophysiology of the sideroblastic anemias", section on 'Pearson syndrome (large deletion of mitochondrial DNA)' and "Overview of the causes of chronic diarrhea in children in resource-abundant settings", section on 'Pancreatic exocrine insufficiency' and "Causes of cholestasis in neonates and young infants", section on 'Mitochondrial disorders'.)

ACQUIRED SIDEROBLASTIC ANEMIAS

Overview of acquired disorders — Acquired sideroblastic anemias may be discovered incidentally or may come to medical attention in the setting of nonspecific symptoms of anemia or neurologic findings. There are two principal categories (table 1):

Clonal sideroblastic anemias, which are bone marrow stem cell disorders that are classified within the broad rubric of myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN). (See 'MDS/MPN variants' below.)

In sideroblastic anemia attributed to copper deficiency, certain medications, or excessive alcohol use, the anemia is fully reversible upon removal of the cause. In the reversible forms of acquired sideroblastic anemia, the clinical setting characterizes the problem. The prevalence of these disorders is not well characterized. (See 'Copper deficiency' below and 'Medications' below and 'Excessive alcohol' below.)

Additional information about the mechanisms of these disorders is presented separately.

MDS/MPN variants — Clonal sideroblastic anemias, also referred to as MDS/MPN variants, are the most common sideroblastic anemias in clinical practice, almost always occur in individuals over age 40, and fall into the lower-risk MDS categories in the International Prognostic Scoring System (IPSS). Other causes of acquired sideroblastic anemia should be excluded (eg, copper deficiency, medications), as well as X-linked sideroblastic anemia (XLSA) in females that is nearly always indistinguishable from the MDS/MPN variants. (See 'Diagnostic approach' below.)

Three of the MDS or MPN variants are associated with ring sideroblasts. Their names were updated in the 2016 World Health Organization (WHO) classification of hematopoietic neoplasms as follows [20]:

MDS-RS-SLD – MDS with ring sideroblasts and single lineage dysplasia (MDS-RS-SLD); this was previously called refractory anemia with ring sideroblasts (RARS). These individuals have normal white blood cell (WBC) and platelet counts.

MDS-RS-MLD – MDS with ring sideroblasts and multilineage dysplasia (MDS-RS-MLD); this was previously called refractory cytopenia with multilineage dysplasia and ring sideroblasts (RCMD-RS). These individuals have low WBC and/or platelet counts and may have the pseudo-Pelger-Huët anomaly (picture 1) or immature WBCs in the peripheral blood.

MDS/MPN-RS-T – MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T); this was previously called refractory anemia with ring sideroblasts and thrombocytosis (RARS-T). These patients have thrombocytosis with or without leukocytosis and frequently have the JAK2 V617F mutation that is found in other myeloproliferative neoplasms [21,22]. MDS/MPN-RS-T is the least common of the clonal sideroblastic anemias.

The anemia typically develops insidiously and may present as an incidental finding or when the individual develops symptoms of anemia such as fatigue, dyspnea, or reduced exercise tolerance. Older adults, especially those with coexisting coronary artery disease, may present with angina or other symptoms of myocardial ischemia. On examination, patients may have pallor and/or hepatosplenomegaly (found in up to one-third to one-half of patients). With advanced iron overload, often accentuated by repeated transfusions, symptoms and signs of liver decompensation, as well as heart failure and arrhythmia, may occur.

The anemia is usually moderate and normocytic or macrocytic, with a variable population of hypochromic cells on the peripheral blood smear. Particularly characteristic are occasional siderocytes (hypochromic red cells with basophilic granules that stain positive for iron); the granules are referred to as Pappenheimer bodies (picture 2). The WBC and platelet counts may be normal, increased, or reduced, depending on the MDS variant.

The principal clinical problem in these clonal disorders is anemia when it progresses. Its management is discussed below and in a separate topic review. (See 'Agents for MDS/MPN variants' below and "Treatment of lower-risk myelodysplastic syndromes (MDS)".)

Acquired heterozygous missense mutations in splicing factor 3B, subunit 1 (SF3B1), which encodes a constituent of the messenger RNA (mRNA) spliceosome, are found in up to 85 percent of patients with any of the three MDS/MPN variants. Their presence confirms the diagnosis of one of these variants and excludes XLSA in women; it also appears to impart a favorable clinical outcome [22,23]. How the SF3B1 mutations lead to the ring sideroblastic phenotype remains to be elucidated. Evidence shows that only the MDS-RS-MLD variant is at risk of transformation to acute leukemia [23-25]. (See "Prognosis of myelodysplastic neoplasms/syndromes (MDS) in adults", section on 'Others'.)

Copper deficiency — Copper deficiency can cause sideroblastic anemia that may be misdiagnosed as an MDS variant. The deficiency may develop in a number of clinical settings:

Malabsorption – Typically malabsorption occurs in the setting of small bowel disorders or gastrointestinal surgery [26-32].

Lack of supplementation – Deficiency can develop with prolonged parenteral nutrition or forced enteral feeding if copper is not included in the formulations [33-37].

Zinc ingestion – Causes of zinc-induced copper deficiency include prolonged ingestion of zinc supplements, use of large amounts of denture cream containing zinc, or massive and prolonged ingestion of zinc-containing coins associated with psychiatric illness (metal pica) [38-46].

Chelation – Use of the copper-chelating agent trientine (triethylene tetramine dihydrochloride; TTH) can cause copper deficiency [47]. (See 'Medications' below.)

The mechanism of copper deficiency after ingestion of excess zinc has been attributed to induction of the intestinal metal-binding protein metallothionein by zinc [48]. Metallothionein preferentially binds copper in the gut and prevents its absorption, thereby enhancing its excretion in sloughed intestinal cells and leading to clinical copper deficiency. A case report has also described copper deficiency in an infant with a familial nephrotic syndrome associated with an NPHS2 mutation (see "Steroid-resistant nephrotic syndrome in children: Etiology"). The presumed mechanism was attributed to urinary losses of ceruloplasmin and copper.

The anemia due to copper deficiency is progressive and may be profound, with hemoglobin levels as low as 3.5 g/dL [38]. The anemia typically is normocytic or slightly macrocytic, but hypochromic and microcytic red cells are detectable on the blood smear.

In addition to anemia, copper deficiency can cause neutropenia and is often (if not invariably) accompanied by neurologic manifestations. Absolute neutrophil counts are generally strikingly reduced to less than 1000/microL, while the platelet count is usually normal. Pancytopenia has been reported in some cases. Neurologic manifestations are varied; myeloneuropathy is commonly seen [49-53]. Other neurologic findings are related to demyelination; peripheral and optic neuropathy have also been reported. (See "Copper deficiency myeloneuropathy" and 'Differential diagnosis' below and "Treatment of vitamin B12 and folate deficiencies".)

Diagnosis of suspected copper deficiency is confirmed by serum copper and ceruloplasmin levels, which are uniformly low. In cases of zinc-induced copper deficiency, serum zinc levels are typically increased two- to threefold. Serum and urine zinc concentrations were also increased in some patients with copper deficiency and neurologic disease without identifiable excess zinc intake [49,53].

Upon bone marrow examination, some individuals with copper deficiency were misdiagnosed as having clonal sideroblastic anemia [28,31,53]. Moderate numbers of ring sideroblasts are observed, and plasma cells often contain prominent hemosiderin [31]. (See 'Bone marrow examination' below.)

The copper deficit is readily corrected with parenteral or oral copper preparations that provide 2 mg of elemental copper per day, and the hematologic abnormalities return to normal in less than two months [31,34,38,49,53]. However, this usual dose of copper may not be sufficient for all patients as relapse has occurred [54], and long-term follow-up is advised for all patients. Hematologic recovery may occur following discontinuation of excess zinc intake alone. Neurologic deficits may improve or only stabilize with continued copper supplementation [31,49,53].

Medications — The antibiotics isoniazid (INH), linezolid, and chloramphenicol are the most commonly reported causes of drug-induced sideroblastic anemia.

Isoniazid – The incidence of anemia caused by INH appears to be quite low. However, certain individuals seem more susceptible to INH-induced anemia (eg, concomitant folate deficiency). In a series of 63 patients undergoing treatment for tuberculosis (most with INH), one had ring sideroblasts in the bone marrow but was not anemic, and an additional 19 (30 percent) had excess hemosiderin granules [55]. Occasional cases of INH-related sideroblastic anemia continue to be reported [56,57]. The mechanism of the anemia involves interference of vitamin B6 metabolism by the drug, depriving the delta-aminolevulinic acid (ALA) synthase enzyme of its essential cofactor [58].

In patients with INH-induced sideroblastic anemia, anemia typically occurs within 1 to 10 months after initiation of the drug when vitamin B6 is not coadministered. It may be mild or moderate (eg, hemoglobin 7 to 8 g/dL). There is prominent hypochromia and microcytosis, with dimorphic red blood cell morphology [59]. Ring sideroblasts are present in the bone marrow. Serum vitamin B6 concentrations were subnormal in most patients [60,61].

Chloramphenicol and linezolid – The use of chloramphenicol has declined in many settings due to availability of other effective antibiotics and the known risk of potentially serious and fatal aplastic anemia, for which the drug carries a Boxed Warning. Earlier use of chloramphenicol documented that the drug regularly produced sideroblastic anemia, with moderately severe reductions in hemoglobin level, increased serum iron level, and ring sideroblasts in the bone marrow [62,63]. The drug impairs mitochondrial protein synthesis (similar to its bacteriostatic mechanism of action) [64]. Linezolid has subsequently been shown to cause a similar sideroblastic anemia [65-67].

Others – A number of other drugs have been implicated in causing sideroblastic anemia in a few cases [47,58,68-71]:

Busulfan

Cycloserine

Fusidic acid

Melphalan

Penicillamine

Pyrazinamide

Trientine (triethylene tetramine dihydrochloride [TTH]), a copper chelating agent (see 'Copper deficiency' above)

Excessive alcohol — Anemia in the setting of chronic excessive alcohol use is often multifactorial. Possible contributing factors such as associated liver disease, portal hypertension with splenomegaly, gastrointestinal bleeding with or without iron deficiency, nutritional folate deficiency, infection, and direct bone marrow toxicity by ethanol with decreased erythropoiesis are discussed in detail separately. (See "Hematologic complications of alcohol use", section on 'Anemia'.)

Approximately one-third of patients with alcohol-induced anemia have sideroblastic changes, with occasional siderocytes in the peripheral blood [72]. Bone marrow examination shows ring sideroblasts, which typically represent late erythroblasts. Iron studies usually show increased iron stores (eg, high ferritin, high transferrin saturation), unless there is concomitant iron deficiency (eg, due to gastrointestinal bleeding).

Withdrawal of alcohol is followed by recovery from the anemia over several weeks. The rate of improvement of the anemia depends on whether other alcohol-induced defects or associated medical illnesses (eg, bleeding, infection) are contributing to the anemia. A more prompt recovery may be associated with a brisk reticulocytosis, which might be otherwise mistaken as an episode of hemolytic anemia. Follow-up bone marrow examination would show disappearance of ring sideroblasts and increased erythropoiesis within a few days to two weeks [73].

DIAGNOSTIC APPROACH

Overview of diagnostic issues — Sideroblastic anemia is often considered in the differential diagnosis of unexplained anemia after more common causes have been excluded. (See "Approach to the child with anemia" and "Diagnostic approach to anemia in adults".)

The diagnosis of all sideroblastic anemias is made by identifying the telltale ring sideroblasts on the bone marrow aspirate smear. Distinction among the specific forms of sideroblastic anemia, which determines management, involves evaluation of clinical features and laboratory testing, often followed by genetic testing. The algorithm summarizes the diagnostic approach (algorithm 1).

It is worth noting that the associated clinical features in some syndromic congenital sideroblastic anemias occur variably or are not yet fully manifest at presentation to be recognized, and thus some of the inherited forms may not be correctly identified until later in life.

The causes of sideroblastic anemia are listed in the tables, categorized by whether the cause is congenital or acquired (table 1) and by whether the red blood cells (RBCs) are microcytic or normocytic/macrocytic (table 2). Details of the diagnostic approach according to the age range of the patient are presented in the following sections. (See 'Child/young adult (<20 years) evaluation' below and 'Adult evaluation' below.)

Child/young adult (<20 years) evaluation — A congenital sideroblastic anemia may be suspected based on a known family history, clinical features that suggest a syndromic condition, or lack of another diagnosis. (See 'Overview of inherited disorders' above.)

Microcytic anemia (anemia with a low mean corpuscular volume [MCV]) in the absence of iron deficiency or thalassemia is highly suggestive of a common congenital sideroblastic anemia such as X-linked sideroblastic anemia (XLSA) or SLC25A38 anemia (table 2). Much less common are other autosomal recessive forms and several syndromic forms of congenital sideroblastic anemia that are microcytic or normocytic/macrocytic, while a reversible sideroblastic anemia would be extremely rare and unlikely to be encountered in a child.

The mode of transmission (X-linked or autosomal) may be helpful if it is clearly X-linked (no transmission to sons from fathers), but it is worth keeping in mind that the X-linked sideroblastic anemias can be transmitted to daughters from mothers or fathers.

Nonsyndromic findings

Microcytic anemia – The most frequent inherited sideroblastic anemia syndrome appears to be the sideroblastic anemia with immunodeficiency, periodic fevers, and developmental delay (SIFD; due to pathogenic variants in TRNT1). XLSA with ataxia (XLSA/A; due to pathogenic variants in ABCB7) is very rare, with only six families reported since the syndrome was first described. (See 'X-linked sideroblastic anemias' above and 'Autosomal recessive forms' above.)

Normocytic or macrocytic anemia – The candidate inherited sideroblastic anemia syndromes are myopathy, lactic acidosis, and sideroblastic anemia (MLASA) or variants thereof (due to pathogenic variants in PUS1, YARS2, MT-ATP6, LARS2, IARS1, SARS2, or NDUFB11); Pearson marrow-pancreas syndrome (mitochondrial DNA deletions), which is associated with lactic acidosis and pancreatic insufficiency; or thiamine-responsive megaloblastic anemia (TRMA; due to pathogenic variants in SLC19A2), which is associated with diabetes mellitus and deafness. (See 'X-linked sideroblastic anemias' above and 'MDS/MPN variants' above and 'Copper deficiency' above and 'Medications' above.)

Syndromic findings

Microcytic anemia – Although uncommon, the most frequent inherited sideroblastic anemia syndrome probably is sideroblastic anemia with immunodeficiency, periodic fevers, and developmental delay (SIFD; due to pathogenic variants in TRNT1). XLSA with ataxia (XLSA/A; due to pathogenic variants in ABCB7) is very rare, with only six families reported since the syndrome was first described. (See 'Overview of inherited disorders' above.)

Normocytic or macrocytic anemia – The candidate inherited sideroblastic anemia syndromes are myopathy, lactic acidosis, and sideroblastic anemia (MLASA) or variants thereof (due to pathogenic variants in PUS1, YARS2, MT-ATP6, LARS2, IARS1, SARS2, or NDUFB11); Pearson marrow-pancreas syndrome (mitochondrial DNA deletions), which is associated with lactic acidosis and pancreatic insufficiency; or thiamine-responsive megaloblastic anemia (TRMA; SLC19A2 mutations), which is associated with diabetes mellitus and deafness. (See 'Overview of inherited disorders' above.)

These genetic disorders are ultimately confirmed by DNA analysis (algorithm 1). The clinical phenotype, including the presence of marrow ring sideroblasts, dictates which gene to prioritize for mutation analysis. Depending on the result, other likely candidate genes can be sequentially tested. (See 'Molecular (genetic) testing' below.)

However, failure to find a pathogenic variant in the known relevant genes does not eliminate the possibility of a congenital sideroblastic anemia, as causative variants have not yet been identified in up to one-third of cases [74-76]. (See "Causes and pathophysiology of the sideroblastic anemias", section on 'Congenital sideroblastic anemias'.)

Adult evaluation — In adults, an acquired sideroblastic anemia is much more common than an inherited form, although the diagnosis of a congenital type has often been delayed until adulthood. The algorithm summarizes the approach (algorithm 1).

The presentations in adults are those with a clue from the history, or those for whom the bone marrow aspirate performed for unexplained anemia reveals ring sideroblasts:

A clue from the history, such as gastrointestinal surgery, enteral or parenteral feedings without copper supplementation, or excessive zinc ingestion, suggests copper deficiency. Use of an implicated medication or evidence of excessive alcohol use may also be helpful in suggesting the cause. Uncommonly, unexplained chronic anemia may be reported in multiple family members. In these situations, the clinical setting defines which laboratory tests are performed. (See 'Overview of acquired disorders' above.)

In an adult over the age of 40 with ring sideroblasts in the bone marrow aspirate, the most likely diagnosis is a myelodysplastic syndrome (MDS). These conditions are diagnoses of exclusion, and reversible causes such as copper deficiency, implicated medications, and excessive alcohol use should be eliminated before the diagnosis of MDS is established. It is also prudent to exclude XLSA in all women with ring sideroblasts who are considered to have MDS, as their phenotype of XLSA is indistinguishable from MDS. An exception is an individual with one of the commonly acquired mutations in the SF3B1 and/or the JAK2 gene, which confirms an MDS or myeloproliferative neoplasm (MPN) and excludes a congenital sideroblastic anemia. (See 'MDS/MPN variants' above and 'Copper deficiency' above and 'Medications' above and 'Excessive alcohol' above and 'X-linked sideroblastic anemias' above.)

Laboratory and bone marrow findings

CBC and blood smear — Patients being evaluated for sideroblastic anemia may have prior complete blood counts (CBCs) and blood smears available for review. The white blood cell (WBC) and platelet counts are typically normal; if these are low, an explanation should be sought, such as splenomegaly with hypersplenism or MDS. The platelet count is increased in myeloproliferative neoplasms (MPN). (See 'MDS/MPN variants' above.)

Hemoglobin – The hemoglobin level is variable among the sideroblastic anemias; in the inherited forms, the hemoglobin for a given patient tends to remain constant for long periods of time. In the autosomal recessive congenital sideroblastic anemias due to pathogenic variants in SLC25A38 or TRNT1, the hemoglobin is usually below 7 g/dL at diagnosis (table 1).

RBC indices – The mean corpuscular volume (MCV) is often helpful in distinguishing among the sideroblastic anemias (table 2). Diagnosis stratified by MCV is illustrated in the algorithm (algorithm 1).

The anemia is microcytic (low MCV) in all nonsyndromic forms of congenital sideroblastic anemia (XLSA in males and those due to pathogenic variants in SLC25A38, HSPA9, HSCB, and GLRX5) and two of the syndromic forms (XLSA/A and SIFD). The anemia is also microcytic in sideroblastic anemia due to isoniazid. The degree of microcytosis and hypochromia (reflected in the MCV and mean corpuscular hemoglobin [MCH]) generally parallels the severity of the anemia (picture 3).

The anemia is normocytic to macrocytic (normal to high MCV) in females with XLSA and in most of the syndromic forms of congenital sideroblastic anemia (MLASAs, Pearson marrow-pancreas syndrome, and TRMA). The anemia is normocytic to macrocytic in nearly all of the acquired forms, including MDS, copper deficiency, and most medication-induced cases.

In many sideroblastic anemias, a large variation in RBC size is reflected in an abnormally high red cell volume distribution width (RDW) (figure 2).

RBC morphology – In severe cases of sideroblastic anemia, striking anisocytosis, poikilocytosis, target cells, and occasional siderocytes are prominent findings on blood smear, as depicted in the lower panel of the figure (picture 3). This can lead to mistaken impression of other disorders with similar findings, such as iron deficiency or thalassemia. (See 'Differential diagnosis' below.)

Siderocytes are essentially pathognomonic of sideroblastic anemia. They are hypochromic RBCs with distinctive coarse basophilic granules, usually in pairs, which can be seen on the standard Wright or Wright-Giemsa stain (picture 2). These granules are residual iron-laden mitochondria, and they will stain positive for iron as Pappenheimer bodies. They represent the mature RBC counterpart of ring sideroblasts seen in the bone marrow. Siderocytes are always numerous in the unlikely event that the patient has had a splenectomy, although splenectomy is not recommended in the sideroblastic anemias. (See 'Avoidance of splenectomy' below.)

RBC dimorphism is common, particularly in females with milder XLSA when the anemia may be microcytic by MCV [9]. This is depicted in the upper panel of the figure (picture 3).

Reticulocyte count – The reticulocyte count is normal to low, which is consistent with the associated ineffective erythropoiesis in most cases.

Bone marrow examination — The bone marrow aspirate smear in sideroblastic anemia usually shows normoblastic erythroid hyperplasia and often poorly hemoglobinized cytoplasm in the RBC precursors. Dysplastic changes are common in the MDS disorders. The Prussian blue-stained smear reveals the presence of ring sideroblasts (picture 4 and picture 5), the diagnostic hallmark of all sideroblastic anemias. In the common congenital sideroblastic anemias, the ring sideroblast finding is prominent in late, nondividing erythroblasts, while in the MDS disorders it is evident at all stages of erythroid maturation. (See 'Overview of diagnostic issues' above.)

Ring sideroblasts are RBC precursors (erythroblasts) in which numerous coarse siderotic (iron-containing) granules tend to surround (form a ring around) the nucleus (picture 4 and picture 5). These granules represent pathologic iron deposits in mitochondria due to various aberrations in the processing of iron in the developing RBC [77,78]. This diagnostic feature became the basis for the heterogeneous sideroblastic anemias being lumped together as a group of diseases after they were recognized in the 1960s [79]. The amount of iron in bone marrow macrophages is often strikingly increased due to the presence of ineffective erythropoiesis with intramedullary hemolysis.

The ring sideroblast abnormality may be masked in the exceptional case of sideroblastic anemia with concomitant iron deficiency, most commonly encountered in young females with excess menstrual blood losses [28,80]. In such cases, iron studies show a reduced or normal serum iron and a low ferritin concentration, consistent with a concomitant iron deficiency state. Occasionally, technical reasons in performing the Prussian blue stain may account for not detecting ring sideroblasts.

It is important to recognize that ring sideroblasts are not detectable in iron-stained bone marrow biopsy sections, as the erythroblast iron becomes leeched out during the tissue processing. Thus, a simple needle aspirate of bone marrow for smears (for Wright-Giemsa and iron staining) fully suffices for the diagnostic procedure; a biopsy is unnecessary and not helpful.

Other morphologic abnormalities in the bone marrow can provide a diagnostic clue for certain sideroblastic anemias:

Dyserythropoietic changes such as a left shift of erythroid precursors, megaloblastoid changes, chromatin clumping, and binuclearity are common in MDS variants but not in most other sideroblastic anemias, and these are associated with certain cellular marker changes detectable by flow cytometry [81].

Cytoplasmic vacuolization in early myeloid and erythroid precursors is common in Pearson syndrome (picture 6) and is found in MLASA due to pathogenic variants in YARS2 (picture 7) [82,83].

Vacuoles in erythroid and myeloid precursors are also a common finding in copper deficiency, and there may be hyperplasia of hematogones (lymphoid precursor cells) [31,36,53]. These changes are depicted in the figure (picture 8).

Iron studies — Iron studies will often have been obtained as part of the initial anemia evaluation, and they should be obtained in individuals for whom they are not available. (See 'Additional post-diagnosis testing' below.)

At presentation (before transfusions) the serum transferrin saturation and serum ferritin are typically increased in most congenital sideroblastic anemias and in patients with MDS disorders with ring sideroblasts.

These tests are important both to assess the degree of excess iron before clinical manifestations of iron overload develop and to guide management in preventing tissue damage and associated symptoms if these are not already evident. (See 'Management' below.)

Hepcidin and erythroferrone — These hormonal mediators of intestinal iron absorption are relevant to the pathophysiology of the iron overload in anemias with ineffective erythropoiesis. Whether their measurement is clinically useful in sideroblastic anemias remains to be established.

Erythrocyte protoporphyrin — The erythrocyte protoporphyrin (PP) measurement has not been systematically examined in the majority of sideroblastic anemia types and has limited value in diagnosis. RBC PP values have been established in a few forms:

In X-linked sideroblastic anemia (XLSA) and with defects in SLC25A38, the erythrocyte PP level is uniformly low because heme synthesis and hence protoporphyrin production are reduced

In XLSA with ataxia (XLSA/A), erythrocyte PP is increased (mainly as zinc protoporphyrin) [13,14]

In MDS disorders with ring sideroblasts, erythrocyte PP is characteristically increased up to 300 mcg/dL (normal: 20 to 80 mcg/dL)

A markedly elevated RBC PP is diagnostic in the rare case of late-onset erythropoietic protoporphyria (EPP) in the setting of an MDS-RS-SLD diagnosis, regardless of whether or not the patient exhibits photosensitivity associated with EPP [77,84]. The diagnostic evaluation of EPP is presented separately. (See 'MDS/MPN variants' above and "Erythropoietic protoporphyria and X-linked protoporphyria", section on 'Erythrocyte protoporphyrin'.)

Copper levels — Serum copper and ceruloplasmin levels are determined in individuals with suspected copper deficiency due to one of the conditions described above. In some cases, the serum zinc level may also be tested. (See 'Copper deficiency' above.)

Molecular (genetic) testing — In congenital sideroblastic anemias, genetic testing is the most definitive means of establishing the specific diagnosis and characterizing the pathogenic variant [85]. Genetic testing is performed by DNA sequence analysis using leukocytes from peripheral blood.

According to the patient's phenotype and its prevalence, single-gene Sanger sequencing can suffice. In other uncommon forms, given their clinical heterogeneity selection of genes to sequence is often difficult and becomes labor intensive. For these, next-generation sequencing tools (ie, custom targeting gene panels and/or whole exome sequencing [WES]) are time-efficient and have entered clinical practice [86,87]. (See "Next-generation DNA sequencing (NGS): Principles and clinical applications", section on 'Whole genome, exome, or gene panel'.)

Accurate genetic diagnosis is important for management, such as for determining specific therapies or evaluations for other organ involvement in the syndromic conditions as well as genetic counseling and testing of first-degree relatives. (See 'Congenital sideroblastic anemias' above and 'Genetic counseling and testing of first degree relatives' below.)

The genes that are known to have pathogenic variants in the congenital sideroblastic anemias are as follows:

ALAS2 – X-linked sideroblastic anemia (XLSA)

SLC25A38, HSPA9, HSCB, and GLRX5 – Autosomal recessive nonsyndromic sideroblastic anemias

ABCB7 – XLSA with ataxia (XLSA/A)

NDUFB11 – X-linked sideroblastic anemia with variable syndromic features such as short stature, developmental delay, or myopathy

TRNT1 – Sideroblastic anemia with immunodeficiency, periodic fevers, and developmental delay (SIFD)

PUS1, YARS2, NDUFB11, MT-ATP6, LARS2, IARS2, and SARS2 – Myopathy, acidosis, and sideroblastic anemia (MLASA) and MLASA variants

SLC19A2 – Thiamine-responsive megaloblastic anemia (TRMA)

FECH – Erythropoietic protoporphyria (EPP)

Mitochondrial DNA deletions and rearrangements – Pearson marrow-pancreas syndrome

In the MDS disorders with ring sideroblasts, acquired mutations in two genes that tend to confer a favorable prognosis are very common (see 'MDS/MPN variants' above):

SF3B1 – All three MDS/MPN disorders with ring sideroblasts

JAK2 V617F mutation – MPN with ring sideroblasts and thrombocytosis

Moreover, combining next-generation DNA sequencing with conventional sequencing methodology has allowed identification of spliceosome mutations in almost all MDS patients with ring sideroblasts [88].

Molecular analysis of the above-listed genes is available in various commercial or academic laboratories that are listed on the Genetic Testing Registry website. Some may be available in certain research laboratories.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of sideroblastic anemia includes other inherited and acquired anemias: the common microcytic anemias, several that are associated with neurologic findings, and other causes of abnormal red blood cell (RBC) inclusions that resemble Pappenheimer bodies.

Other microcytic anemias – The most common microcytic anemias worldwide are iron deficiency anemia, thalassemia, and anemia of chronic disease/anemia of inflammation (ACD/AI). These would always first be excluded by assessing clinical findings and appropriate laboratory studies documenting (or excluding) these conditions before considering the microcytic sideroblastic anemias and performing bone marrow examination (table 2). (See "Microcytosis/Microcytic anemia", section on 'Causes of microcytosis'.)

Megaloblastic anemias – Megaloblastic anemias are anemias in which DNA synthesis is impaired in developing RBC precursors, leading to anemia with an inappropriately low reticulocyte count, macrocytosis and multilobed neutrophils in the peripheral blood, and megaloblastic changes in the bone marrow (see "Evaluation of bone marrow aspirate smears", section on 'Megaloblastic changes'). Common causes include deficiency of vitamin B12 or folate, and certain medications. Like sideroblastic anemias, megaloblastic anemias present with anemia, low reticulocyte count, and sometimes neurologic findings, which may be quite variable. Unlike sideroblastic anemia, megaloblastic anemia is associated with megaloblastic changes rather than ring sideroblasts in the bone marrow, although ferritin sideroblasts (sideroblasts in which the granules are cytosolic, non-mitochondrial ferritin aggregates and do not encircle the nucleus) may be seen. If vitamin B12 or folate deficiency is responsible, laboratory testing in megaloblastic anemia shows the deficiency, whereas in sideroblastic anemia, deficiency of copper may be found. The drugs implicated in megaloblastic anemia differ from those implicated in sideroblastic anemia. (See "Treatment of vitamin B12 and folate deficiencies" and "Macrocytosis/Macrocytic anemia", section on 'Drug-induced macrocytosis' and 'Medications' above and "Clinical manifestations and diagnosis of vitamin B12 and folate deficiency".)

Wilson disease – Wilson disease results from mutations in the ATP7B gene, which encodes an ATPase in hepatic cells responsible for copper transport. Like sideroblastic anemia, Wilson disease may be associated with anemia and neurologic findings. Unlike sideroblastic anemia, in Wilson disease, the anemia is due to hemolysis and the neurologic features are usually associated with the presence of Kayser-Fleischer rings. Like in sideroblastic anemia due to copper deficiency, in Wilson disease, the serum copper and ceruloplasmin levels are often low, but urinary copper excretion is high and diagnostic of the disease. (See "Wilson disease: Clinical manifestations, diagnosis, and natural history".)

Lead poisoning – Lead poisoning is often listed in textbooks as a cause of sideroblastic anemia. It is the author's experience, however, that lead poisoning is not associated with sideroblastic changes [84]. Like sideroblastic anemia, lead poisoning can cause anemia, a low reticulocyte count, and neurologic changes. Like sideroblastic anemia, lead poisoning is associated with disordered heme synthesis. Unlike sideroblastic anemia, lead poisoning typically produces heavy basophilic stippling rather than Pappenheimer bodies in RBCs or ring sideroblasts. Unlike sideroblastic anemia, lead poisoning is associated with elevated blood lead levels. (See "Childhood lead poisoning: Clinical manifestations and diagnosis" and "Lead exposure, toxicity, and poisoning in adults".)

Other RBC inclusions – Basophilic stippling and other RBC inclusions may be confused with Pappenheimer bodies. Like sideroblastic anemias, these inclusions may be seen in the setting of various anemias. Unlike sideroblastic anemia, these inclusions are not iron-positive or associated with ring sideroblasts in the bone marrow. (See "Evaluation of the peripheral blood smear", section on 'Red cell inclusions and other changes'.)

Beta thalassemia – A 2017 report described a series of individuals with beta thalassemia whose definitive diagnosis was delayed, in whom bone marrow examinations documented ring sideroblasts [89]. Thus, in individuals with ring sideroblasts who lack congenital sideroblastic anemia mutations or causes of acquired sideroblastic anemia, beta thalassemia should be considered in the differential diagnosis. (See "Diagnosis of thalassemia (adults and children)".)

MANAGEMENT

Management overview — Management of sideroblastic anemias depends on the severity of the anemia, whether reversible abnormalities are present, and whether the sideroblastic anemia is responsive to a specific agent.

Nonsyndromic congenital sideroblastic anemias – For patients with nonsyndromic forms of congenital sideroblastic anemia, the treatment program must be aimed at prevention of organ damage from the associated iron overload, as well as control of the symptoms of anemia, to improve outcomes and reach close to normal survival. (See 'Treatments for anemia' below and 'Iron overload' below.)

Vitamin B6 (pyridoxine) supplements are often effective in X-linked sideroblastic anemia (XLSA). (See 'Vitamins' below.)

Luspatercept, an erythroid maturation agent, may be useful in congenital sideroblastic anemias with prominent ineffective erythropoiesis. (See 'Treatments for anemia' below.)

Syndromic sideroblastic anemias – In most syndromic forms of congenital sideroblastic anemia, the clinical course is largely dominated by the nonhematologic features and their care. Thiamine is used to treat thiamine-responsive megaloblastic anemia (TRMA). (See 'Vitamins' below.)

Reversible sideroblastic anemias – In copper deficiency, the hematologic abnormalities are promptly corrected by copper replacement. In drug-induced sideroblastic anemia, the anemia and associated morphologic abnormalities (siderocytes in the peripheral blood, ring sideroblasts in the bone marrow) are reversible and disappear upon drug withdrawal. For isoniazid (INH), the anemia can also be reversed by administering large doses of vitamin B6 (up to 200 mg/day orally) while continuing the INH, if needed.

MDS – Management of myelodysplastic syndrome (MDS) is summarized below and discussed in more detail separately. (See 'Treatments for anemia' below and 'Iron overload' below and "Overview of the treatment of myelodysplastic syndromes" and "Treatment of lower-risk myelodysplastic syndromes (MDS)".)

Additional post-diagnosis testing — For patients with congenital and acquired clonal sideroblastic anemia, the following laboratory studies are appropriate:

Iron studies (serum transferrin saturation, ferritin), to determine the degree of iron overload, which will in turn guide the need for phlebotomy or iron chelation, and subsequent monitoring. For those with laboratory evidence of iron overload, the degree of iron deposition in tissues is best assessed using magnetic resonance imaging (MRI; using the T2* method) or by obtaining a liver biopsy, as serum ferritin values afford only a rough indication of the iron burden present [90]. The liver biopsy may also provide additional prognostic information through demonstration of any liver damage and/or cirrhosis. (See "Approach to the patient with suspected iron overload".)

Erythrocyte folate level (also called RBC folate), to identify a deficiency occasionally associated with ineffective erythropoiesis. This may be seen mainly in patients with XLSA or an autosomal recessive congenital sideroblastic anemia (ARCSA) and severe anemia.

Plasma copper and ceruloplasmin levels, mainly in the clonal sideroblastic anemias to exclude copper deficiency, particularly if neutropenia or neurologic deficits are present.

Genetic testing is advised in all irreversible sideroblastic anemias (algorithm 1). A gene (or genes) is selected for analysis that is consistent with the patient's phenotype as discussed previously (See 'Congenital sideroblastic anemias' above and 'MDS/MPN variants' above.)

Treatments for anemia — Treatment of anemia depends on its severity and associated symptoms. The goal should be to obtain a safe hemoglobin level and reduce symptoms, not to normalize the hemoglobin level.

Transfusions — For symptomatic anemic individuals, periodic transfusions are necessary to relieve symptoms, and, for children, to allow normal growth and development. Transfusion of red blood cells (RBCs) should be kept to a minimum as the iron contained in the transfused RBCs accelerates the degree of iron overload that is often already present. (See 'Iron overload' below.)

Vitamins — In specific disorders, the anemia may be responsive to a vitamin supplementation:

Vitamin B6 (pyridoxine) is used in XLSA and drug-induced sideroblastic anemia from isoniazid.

XLSA may respond to vitamin B6 (pyridoxine) supplements in up to two-thirds of cases; hemoglobin concentrations return to normal in about one-third of the responders. The morphologic red cell abnormalities improve variably, but very rarely completely disappear [77,91]. It is prudent in all patients with congenital microcytic/hypochromic sideroblastic anemias to give a therapeutic trial of vitamin B6 for three months or until a specific genetic diagnosis other than XLSA is established. In XLSA, oral doses of vitamin B6 of 50 to 100 mg/day (over and above the estimated adult daily requirement of 1.5 to 2 mg/day) are sufficient for a maximal response; in one case, only 2 to 4 mg/day were found to be effective [92]. In responders, maintenance treatment with vitamin B6 is necessary, as relapse follows within several months after discontinuing treatment.

In isoniazid-induced sideroblastic anemia, the vitamin B6 dosing is similar, but the isoniazid should be discontinued if possible (with substitution of another agent). If this is not advisable, vitamin B6 can be administered while continuing the isoniazid.

Thiamine is used to treat TRMA. In addition to clinical improvement of the anemia, the other clinical features (diabetes mellitus and deafness) may respond to thiamine to a lesser extent. Supraphysiologic oral doses of thiamine (ie, 25 to 75 mg/day) are necessary for an effect, but during puberty, supplements seem to become ineffective [93].

In a report of a single patient with the syndromic form of congenital sideroblastic anemia and mitochondrial myopathy, treatment with coenzyme Q10 at an oral dose of 400 mg/day was associated with a dramatic decrease in red cell transfusion requirement and improvement in muscle strength [94]. (See "Mitochondrial disorders: Treatment", section on 'Specific supplements'.)

Luspatercept for congenital sideroblastic anemias with ineffective erythropoiesis — A case report described use of luspatercept to treat an adult with X-linked sideroblastic anemia due to a germline pathogenic variant in ALAS2; the patient had increasing anemia-related symptoms and a doubling in transfusion requirements (from 10 units per year to >21 units per year) [95]. After six months of treatment, symptoms improved dramatically and baseline hemoglobin level increased from 7 g/dL to 9 g/dL, without significant adverse effects.

Given this case experience and observations that luspatercept is effective in transfusion-dependent beta-thalassemia and MDS variants with ring sideroblasts, luspatercept is likely of value in congenital sideroblastic anemias associated with ineffective erythropoiesis, including XLSA, SLC25A38 anemia, and SIFD [96]. As with MDS variants, its use is individualized. (See 'Maturation promotors (luspatercept)' below.)

Anti-TNF agents for SIFD — In a preliminary report of four individuals with sideroblastic anemia with immunodeficiency, periodic fevers, and developmental delay (SIFD), anti-tumor necrosis factor (TNF) therapy with infliximab or etanercept was effective in suppressing fevers, decreasing the need for transfusions, and improving laboratory markers of inflammation [97]. Although data are extremely limited, we would use this approach in severely affected individuals, initiating it early in life. The rationale for this approach is discussed separately. (See "Causes and pathophysiology of the sideroblastic anemias", section on 'Sideroblastic anemia, B cell immunodeficiency, periodic fevers, and developmental delay (TRNT1 mutation)' and "Autoinflammatory diseases mediated by miscellaneous mechanisms", section on 'SIFD syndrome'.)

Agents for MDS/MPN variants — For management of symptomatic anemia of the MDS/myeloproliferative neoplasm (MPN) variants with ring sideroblasts, guidelines for treatment of low-risk MDS would apply [98]. Agents used over the years, namely erythropoietins and/or granulocyte colony-stimulating factor (G-CSF), hypomethylating agents (azacitidine, decitabine), immunosuppressive therapy (antithymocyte globulin [ATG]), and imetelstat, are options for averting RBC transfusions with at best 50 percent response rates [99,100]. These therapies are discussed in more detail separately. (See "Overview of the treatment of myelodysplastic syndromes" and "Treatment of lower-risk myelodysplastic syndromes (MDS)".)

Newer options include luspatercept, which promotes erythroid maturation, and splicing modulators, which remain investigational. (See 'Maturation promotors (luspatercept)' below and 'Splicing modulators' below.)

Maturation promotors (luspatercept) — In the randomized, double-blind MEDALIST trial, luspatercept, a first-in-class erythroid maturation agent that promotes late-stage erythropoiesis, significantly reduced the need for RBC transfusions and led to hematologic improvement in patients with lower-risk MDS and ring sideroblasts who were transfusion-dependent [101].

Therapy was well-tolerated with rare drug discontinuation due to adverse effects. These results have generated considerable enthusiasm for use of luspatercept in patients with the MDS/MPN variants with ring sideroblasts unresponsive to erythropoietin [102]. The decision to use luspatercept initially or after a trial of an erythropoiesis-stimulating agent is individualized.

Luspatercept was approved by the US Food and Drug Administration (FDA) for this indication in April 2020 [103]. Follow-up data indicate sustained benefits of its use [104].

Splicing modulators — The use of splicing inhibitors or modulators to target the spliceosome harboring the mutations in MDS is another unique approach being investigated [105]. These therapies are not clinically available.

Role of hematopoietic stem cell transplant — Definitive cure for some nonsyndromic forms of inherited sideroblastic anemia has been documented in an increasing number of patients treated with allogeneic hematopoietic stem cell transplantation (HSCT), although the number of transplanted patients remains small [1,106-114]. For individuals in whom the genetic cause was identified, 20 patients had SLC25A38 anemia and one had XLSA. Among 32 patients who were transplanted, approximately 84 percent had apparent cure. However, out of five patients with SIFD who were transplanted, only two survived [115]. HSCT can thus be considered in young, transfusion-dependent patients with appropriate donors before developing sequelae of chronic transfusions. Existing iron overload should be controlled prior to transplantation for optimal outcomes.

With effective HSCT using gene therapy in curing beta-thalassemia, a similar commitment marshaled for selected, transfusion-dependent patients with genetic sideroblastic anemia could also become a reality. (See "Overview of gene therapy, gene editing, and gene silencing", section on 'Inherited single gene disorders' and "Management of thalassemia", section on 'Gene therapy and other stem cell modifications'.)

HSCT is rarely used for MDS/MPN variants with ring sideroblasts, as discussed separately. (See "Treatment of lower-risk myelodysplastic syndromes (MDS)", section on 'Intensive therapies'.)

Iron overload — Many patients with sideroblastic anemia develop iron overload as a result of the ineffective erythropoiesis and/or transfusions [6,116,117]. Mild to moderate degrees of hepatosplenomegaly are common, but liver function is usually normal or only mildly disturbed at presentation. Liver biopsy reveals a pattern of iron deposition that is indistinguishable from that of hereditary hemochromatosis (picture 9). In XLSA patients, well-established but asymptomatic micronodular cirrhosis may be discovered by the third or fourth decade, which does not correlate with severity of the anemia (picture 10) [116,118,119]. Hepatocellular carcinoma developed in two reported cases with XLSA [120,121].

Cardiac complications (arrhythmia, heart failure) occur with advanced iron overload in the heart (picture 11) and are the usual cause of a fatal outcome.

Control of iron overload in sideroblastic anemias is an important aspect of management. Even patients with several common forms of sideroblastic anemia who do not receive transfusions develop systemic iron overload over time because ineffective erythropoiesis leads to increased iron absorption. Necessary chronic transfusions predictably add to the body iron burden and its consequences. Removal of excess iron has also improved the anemia in some cases. Ideally, development of any iron overload in the sideroblastic anemias should be prevented prospectively, although usually not achieved. (See "Regulation of iron balance" and "Approach to the patient with suspected iron overload", section on 'Ineffective erythropoiesis'.)

Severity of iron overload is best assessed by T2* MRI or liver biopsy (see 'Additional post-diagnosis testing' above). An iron depletion program is initiated if the serum ferritin exceeds 500 to 1000 ng/mL, or after transfusion of 20 to 25 units of RBCs (in adults), or if liver iron content is over 3 mg iron/g dry weight. Iron depletion is accomplished in one of two ways: therapeutic phlebotomy or iron chelation.

Therapeutic phlebotomy – Iron depletion is best performed by phlebotomy when the anemia is mild or moderate (ie, hemoglobin >9 g/dL) or when a patient with XLSA has had a sufficient response to pyridoxine, provided there are no contraindications to therapeutic phlebotomy such as congestive heart failure [122,123]. Half-unit phlebotomies may be carried out initially in order for the anemic patient to adjust to this regimen. Once the serum ferritin level has been reduced sufficiently, maintenance phlebotomies are continued on a regular basis for life, to prevent re-accumulation of iron. (See "Management and prognosis of hereditary hemochromatosis" and "Management and prognosis of hereditary hemochromatosis", section on 'Phlebotomy'.)

Iron chelation therapy – In patients who have more severe anemia, and in those who require regular RBC transfusions and thus cannot undergo phlebotomy, iron chelation is used. The available agents in the United States are deferoxamine (Desferal) for parenteral administration and deferasirox (Exjade) as the oral preparation. Details of specific chelating agents are presented separately. (See "Iron chelators: Choice of agent, dosing, and adverse effects", section on 'Available chelating agents'.)

For the congenital sideroblastic anemias, owing to their uncommon occurrence, a large patient series describing results of iron chelation is not available. However, clinical experience over the past 50 years in this young population has demonstrated that, much like extensively shown in thalassemia, effective iron chelation therapy provides for normal growth and development as well as significantly reduces or averts morbidity and mortality due to iron overload. The first detailed guidelines on monitoring and management of iron overload in hemoglobinopathies and rare anemias were published in 2021 from the British Society for Haematology [124]. These guidelines for the first time interpret the available evidence on chelation as best applied to each type of anemia.

In the clonal sideroblastic anemias (MDS/MPN variants), in which iron overload often develops well before transfusion dependence but is greatly accentuated by eventual chronic transfusions, iron chelation has provided favorable supportive therapy for many patients, despite some individuals debating its clinical utility [125]. In this group of older patients, we use an individualized approach for managing iron overload by also considering the patient's clinical status and life expectancy.

The benefit of iron chelation in reducing morbidities associated with iron overload in transfusion-dependent, lower-risk MDS was demonstrated in the first prospective, placebo-controlled trial, TELESTO. In TELESTO, 225 individuals with low-risk MDS and transfusional iron overload were assigned to receive deferasirox or placebo for at least one year [126]. Patients treated with deferasirox had longer event-free survival (no cardiac or liver dysfunction or transformation to acute myeloid leukemia [AML]) of 3.9 years versus 3.0 years with placebo (hazard ratio [HR] 0.64 [95% CI 0.42-0.96]). Median overall survival in the deferasirox group showed a trend towards improvement (5.2 versus 4.1 years; HR 0.83 [95% CI 0.54-1.28]). Serious adverse events were somewhat greater with deferasirox (54 versus 50 percent). The trial size was hampered by slow enrollment.

An investigational approach to managing the iron overload due to ineffective erythropoiesis involves use of an antibody to the iron-regulatory erythrokine erythroferrone (ERFE), which mediates the increased iron absorption via suppression of hepcidin production by the liver. Preclinical studies in a murine model of beta thalassemia have shown that an anti-ERFE monoclonal antibody increased hemoglobin levels and decreased serum iron levels and systemic iron overload [127].

Avoidance of splenectomy — There has been a temptation to perform splenectomy in patients with severe anemia and a significant degree of splenomegaly with suspected splenic sequestration of RBCs. However, this procedure is almost invariably complicated by postoperative thromboembolic events and often a fatal outcome [128-131]. Factors other than persistent thrombocytosis appear to play a role; control of the platelet count and anticoagulant therapy usually are not effective. Thus, splenectomy is considered to be contraindicated in the congenital sideroblastic anemias save for a case of clinical urgency such as traumatic splenic rupture or otherwise untreatable splenic abscess. We also suggest avoiding splenectomy in individuals with the long-lived myelodysplastic syndrome variants MDS-RS-SLD (previously called RARS) and MDS/MPN-RS-T (previously called RARS-T). (See 'MDS/MPN variants' above.)

Genetic counseling and testing of first degree relatives — For patients with inherited sideroblastic anemia, we educate the patient or family about the disease and relevant inheritance pattern. We also obtain a full family history and a complete blood count (CBC) on each parent and sibling. When the genetic defect has been identified in the index case, it can be easily confirmed in any affected family members by genetic (DNA) testing.

In the X-linked anemias, we advise all young women who are candidates for having a pathogenic variant to be tested for carrier status. Testing of the parents can be used to determine whether the defect in the proband has been transmitted or is a de novo mutation.

In autosomal recessive forms, the genetic status of the parents of an affected and genetically identified offspring can be confirmed and used for counseling regarding future pregnancies, including consideration of prenatal testing or preimplantation genetic testing (PGT). In one family, preimplantation diagnosis was used and resulted in unaffected twin offspring [132]. (See "Preimplantation genetic testing".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Anemia in adults".)

SUMMARY AND RECOMMENDATIONS

Inherited – Inherited sideroblastic anemias include nonsyndromic and syndromic disorders (table 1). These can also be categorized by red blood cell (RBC) size (microcytic or normocytic/macrocytic) (table 2) and by inheritance pattern (X-linked, autosomal, or mitochondrial). X-linked sideroblastic anemia (XLSA) is the most common congenital sideroblastic anemia. Although it is X-linked, up to one-third of cases occur in females. (See 'Congenital sideroblastic anemias' above.)

Acquired – Acquired sideroblastic anemias include clonal bone marrow disorders that are classified within the rubric of myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN), as well as reversible conditions attributed to copper deficiency, certain medications, or excessive alcohol use. (See 'Acquired sideroblastic anemias' above.)

Evaluation – Sideroblastic anemia is often considered in the differential diagnosis of unexplained anemia after more common causes have been excluded. The diagnosis of all sideroblastic anemias is made by identifying the telltale ring sideroblasts on the bone marrow aspirate smear. Distinction among the specific forms of sideroblastic anemia involves evaluation of clinical features and laboratory testing, often followed by genetic testing (algorithm 1). (See 'Overview of diagnostic issues' above.)

Children and young adults – In a child or young adult, congenital sideroblastic anemia may be suspected from known family history, clinical features that suggest a syndromic condition, or lack of another diagnosis. The spectrum of associated clinical features in some syndromic congenital sideroblastic anemias is wide and may not fully manifest at presentation; thus, some of the inherited forms may not be correctly diagnosed until later in life. (See 'Child/young adult (<20 years) evaluation' above.)

Adults – In adults, acquired sideroblastic anemia is more common than inherited, although there are often delays in diagnosis of congenital types until adulthood. The two typical presentations are a clinical history consistent with a reversible cause and a bone marrow aspirate showing ring sideroblasts. Almost all of the acquired sideroblastic anemias produce normocytic or macrocytic RBCs. For individuals with suspected MDS/MPN variants, other causes of sideroblastic anemia must be excluded, such as copper deficiency, medications, and XLSA in females. (See 'Adult evaluation' above.)

Laboratory – Testing involves review of the complete blood count (CBC), peripheral blood smear, and bone marrow aspirate smear, including iron stain. Patients may require additional testing such as iron studies. Molecular/genetic testing is appropriate when the bone marrow shows ring sideroblasts or when a congenital sideroblastic anemia or MDS/MPN variant is suspected. (See 'Laboratory and bone marrow findings' above.)

Differential – The differential diagnosis includes inherited and acquired anemias, several of which have neurologic findings (megaloblastic anemias, Wilson disease, lead poisoning), and causes of RBC inclusions that resemble Pappenheimer bodies. Iron deficiency and thalassemia should be excluded in individuals with microcytosis and/or poikilocytosis. (See 'Differential diagnosis' above.)

Management – Management depends on the severity of the anemia, whether reversible abnormalities are present, and whether the anemia is responsive to a specific agent such as vitamin B6. Management of anemia and iron overload are critical. Splenectomy is avoided. Genetic counseling and testing of first-degree relatives is appropriate with inherited forms. (See 'Management' above.)

Luspatercept for selected individualsLuspatercept is an erythroid maturation agent; it is an option for individuals with MDS/MPN variants with ring sideroblasts who have transfusion-dependent anemia. The decision to use luspatercept initially or after a trial of an erythropoiesis-stimulating agent is individualized. A case report indicates that luspatercept may be effective in the common congenital sideroblastic anemias; this is also an individualized decision. (See 'Treatments for anemia' above and "Treatment of lower-risk myelodysplastic syndromes (MDS)".)

ACKNOWLEDGMENT — UpToDate gratefully acknowledges Stanley L Schrier, MD (deceased), who contributed as Section Editor on earlier versions of this topic and was a founding Editor-in-Chief for UpToDate in Hematology.

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Topic 7123 Version 58.0

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