Diamond-Blackfan anemia

INTRODUCTION — Diamond-Blackfan anemia (DBA) is a congenital erythroid aplasia that classically presents in infancy. It is characterized by a progressive normochromic, usually macrocytic, anemia; congenital malformations (in approximately 50 percent of patients); and predisposition to cancer (table 1).

The genetics, pathophysiology, clinical features, diagnosis, and management of DBA will be reviewed here. The use of hematopoietic cell transplantation (HCT) for treatment of DBA is discussed in greater detail separately. (See "Hematopoietic cell transplantation (HCT) for inherited bone marrow failure syndromes (IBMFS)", section on 'Diamond-Blackfan anemia'.)

Other congenital and acquired pure red blood aplasias are reviewed separately. (See "Overview of causes of anemia in children due to decreased red blood cell production".)

EPIDEMIOLOGY — Approximately 90 percent of patients with DBA are diagnosed within the first year of life, with 35 percent diagnosed within the first month [1,2]. In general, patients are significantly anemic at the time of presentation. Based on a report from the United Kingdom's registry, which identified 80 patients with DBA in a 20-year birth cohort, the estimated incidence of DBA is 5 cases per 1 million live births [3]. Males and females appear to be equally affected. Although most case reports are of White patients, the syndrome has been noted in different races and ethnic groups [3-5].

GENETICS AND PATHOGENESIS

Pathogenesis — DBA is a ribosomopathy caused by genetic mutations affecting ribosome synthesis and processing. This results in stabilization and activation of the tumor protein p53 (TP53) tumor suppressor pathway, which is thought to be one of the causes of the clinical manifestations, including impaired erythropoiesis [1,2,6,7]. The erythropoietin level is consistently elevated in DBA because of ineffective erythropoiesis. However, relatively few erythropoietin receptors are available to bind erythropoietin, given the lack of erythroid precursors [4]. No evidence has been found for abnormalities in other regulators of erythropoiesis (eg, interleukin-3, granulocyte-macrophage colony-stimulating factor, or c-Kit or its ligand steel factor [also called stem cell factor]) [8-10]. (See "Regulation of erythropoiesis".)

Causative genetic variants — Approximately 45 percent of DBA cases are familial, usually displaying autosomal dominant inheritance but with a wide range of severity within a family (ie, variable penetrance) [11]. Therefore, some cases that appear to be sporadic may prove to be familial if genetic testing is performed. In one series of 219 patients with DBA, 129 distinct mutations were found, 64 percent of which were de novo and 35 percent were inherited [12].

●Variants in genes encoding ribosomal proteins – The most common cause of DBA is a mutation in the gene encoding ribosomal protein 19 (RPS19), which is identified in approximately 25 percent of patients with DBA [13]. Other pathologic variants include mutations, deletions, and copy number variations in genes encoding the large (RPL35A, RPL5, RPL11, RPL26, RPL15, RPL19) and small (RPS24, RPS17, RPS7, RPS10, RPS26, RPS29) ribosomal subunits [14-22]. However, the list of potential candidate genes is ever evolving. Deletions and copy number variations may not be detected by sequencing [23,24].

●Other less common variants – While most cases of DBA are associated with variants in genes encoding ribosomal proteins, other genes have been implicated in a minority of cases:

•Mutations in the gene GATA1 and the related chaperone gene, HSP70, have been reported to cause a DBA-like phenotype in a few patients [1]. GATA1 is a transcription factor necessary for erythroid differentiation. One report identified GATA1 mutations in three male patients with DBA [25,26]. Because two of the patients were siblings and the parents were unaffected, this suggests X-linked or autosomal recessive inheritance (in contrast with the ribosomal mutations described above, which typically have autosomal dominant inheritance). Notably, an identical mutation in GATA1 can cause an X-linked form of dyserythropoietic anemia, as described separately. (See "Overview of causes of anemia in children due to decreased red blood cell production", section on 'Congenital dyserythropoietic anemia'.)

•Mutations and deletions in the CECR1 gene and the related chaperone gene, TSR2, have been associated with a DBA-like phenotype [21,27]. CECR1 encodes the growth factor adenosine deaminase 2 (ADA2), and mutations and deletions in this gene are known to cause vasculopathy and inflammation [28]. (See "Deficiency of adenosine deaminase 2 (DADA2)".)

Genotype-phenotype correlation — Genotype-phenotype correlations exist [12,29,30]. In a series of 74 patients with DBA, of whom 45 (61 percent) were identified as having ribosomal gene mutations, patients with RPS19 mutations were more likely to maintain long-term steroid responsiveness without needing chronic transfusions [30]. The frequency and type of associated birth defects also varied depending on the genotype, with RPL5 and RPL11 mutations having a higher rate of birth defects compared with RPS19 mutations. In a study of 45 patients with DBA, those with large deletions in RPL35A had a more severe phenotype (ie, more likely to have steroid-resistant anemia, neutropenia, craniofacial abnormalities, chronic gastrointestinal problems, and intellectual disabilities) compared with other pathogenic variants [31]. In another series of 24 patients with DBA associated with cleft palate, RPL5 mutations were identified in 88 percent, whereas no patients had RPS19 mutations [12].

Patients with combined features of DBA and mandibulofacial dysostosis (Treacher Collins syndrome) may have pathogenic mutations in a single gene; however, this phenotype appears to be genetically heterogeneous [27]. (See "Syndromes with craniofacial abnormalities", section on 'Treacher Collins syndrome'.)

CLINICAL MANIFESTATIONS — DBA usually presents in infancy. It is characterized by the following features [32,33]:

●Progressive anemia with onset in infancy or early childhood; anemia is normochromic (usually macrocytic) and is associated with reticulocytopenia

●Normal cellularity of the bone marrow with markedly decreased or absent erythroid precursors

●Congenital malformations (table 2)

●Increased risk of malignancies (see 'Predisposition to cancer' below)

●Increased risk of endocrine dysfunction (see 'Endocrine dysfunction' below)

Physical features — Thirty to 50 percent of patients with DBA have associated congenital abnormalities [3,4,13]. These findings occur mainly in the head and upper limb area and include (table 2):

●Craniofacial abnormalities

●Neck anomalies

●Thumb anomalies

●Urogenital anomalies

●Cardiac anomalies (atrial and ventricular septal defects)

●Hypogonadism

●Intellectual disability

●Other skeletal abnormalities

Children with DBA sometimes have characteristic facial features with hypertelorism, flat nasal bridge, ear anomalies, and high-arched or cleft palate, similar to the features of Treacher Collins syndrome [34,35]. However, these features are quite variable. The name "Aase syndrome" has been used to describe patients with congenital anemia, triphalangeal thumbs, cleft lip-palate, and cardiac defects [36,37]. However, Aase syndrome is probably a variant of DBA rather than a distinct clinical entity [38-40].

The presence of physical anomalies does not reliably predict the severity of the hematologic disease [3,5]. However, as the understanding of genotype-phenotype correlations improves, this may change. (See 'Genotype-phenotype correlation' above.)

Growth failure or short stature occurs in >30 percent of affected patients and may progress with age [3,41,42]. It is often associated with other congenital abnormalities. Primary growth failure is uncommon in children with RPS19 gene mutations [42]. However, secondary growth failure can occur as a consequence of chronic glucocorticoid therapy. (See 'Endocrine dysfunction' below.)

Laboratory findings — Laboratory findings in DBA include:

●Anemia – The anemia is generally normochromic and macrocytic (ie, elevated red blood cell mean corpuscular volume) and is usually profound at diagnosis. In one study, the mean hemoglobin (Hgb) was 6.5 g/dL in infants ≤2 months old and 4 g/dL in infants >2 months old [4,5]. However, patients with nonclassical DBA may have only mild anemia or subtle erythroid abnormalities.

●Reticulocytopenia.

●White blood cell count is typically normal. Platelet counts are generally normal but can be increased or decreased.

●Evidence of stress erythropoiesis – Patients with DBA usually have an elevated fetal Hgb, and their red cells have increased expression of the i antigen beyond the first year of life. These fetal-like red blood cell features are indicative of stress erythropoiesis and persist even in patients with spontaneous remissions [5].

●Normal bone marrow cellularity – Bone marrow examination shows normal overall cellularity with decreased or absent erythroid precursors. However, a report of 28 patients with steroid-refractory DBA who were followed for up to 13 years found that 75 percent ultimately developed moderate to severe bone marrow hypoplasia, with bone marrow cellularity ranging between 0 and 30 percent [43]. This hypoplasia correlated with the development of neutropenia and thrombocytopenia in 43 and 29 percent of the patients, respectively. None of the patients who were studied had cytogenetic abnormalities noted at the time of hypoplasia.

●Elevated erythrocyte adenosine deaminase (eADA) activity – eADA activity is elevated in approximately 75 percent of patients with DBA who undergo such testing [44-47]. Although the significance of this finding is unclear, it may be useful in differentiating between DBA and transient erythroblastopenia of childhood (TEC) in ambiguous cases (table 1). It may also be a useful marker to differentiate from other inherited bone marrow failure syndromes, in which eADA is not elevated [48]. (See 'Differential diagnosis' below and "Overview of causes of anemia in children due to decreased red blood cell production", section on 'Transient erythroblastopenia of childhood'.)

DIAGNOSIS — DBA should be suspected in infants and children presenting with severe anemia and reticulocytopenia during the first year of life.

Diagnostic approach — While DBA is classically described as a progressive, severe anemia with onset in infancy, it is increasingly recognized that there is a wide phenotypic spectrum and more patients are being diagnosed at a later age. Thus, the diagnosis of DBA should be considered in any patient with an unexplained macrocytic anemia with reticulocytopenia after other etiologies have been ruled out. In addition, the diagnosis of DBA may be suspected based upon the presence of craniofacial or thumb abnormalities (table 2) in association with anemia.

The following sections review the approach to confirming the diagnosis of DBA. The diagnostic approach to evaluating anemia in children more broadly is discussed in a separate topic review. (See "Approach to the child with anemia".)

Laboratory evaluation — The laboratory evaluation for a patient with suspected DBA should include:

●A complete blood count with red blood cell indices and review of the peripheral blood smear

●Reticulocyte count

●Measurement of fetal hemoglobin (Hgb F; eg, by Hgb electrophoresis)

●Erythrocyte adenosine deaminase (eADA) activity

For patients requiring transfusion for the management of anemia, the above tests should be performed prior to transfusion.

This initial evaluation will help to establish whether the anemia is due to decreased red blood cell production and will help to distinguish between DBA, transient erythroblastopenia of childhood (TEC), and other causes of red cell aplasia. It also informs decisions about additional testing to perform (eg, genetic testing, bone marrow examination).

Genetic testing — For patients with a high clinical suspicion of DBA, we suggest genetic testing for mutations in the genes associated with DBA. A list of laboratories that can perform this testing is available at the Genetic Testing Registry website. The available panels for DBA gene testing differ slightly regarding which genes are tested and the methodology used. The choice among them is dependent on clinician preference and insurance considerations. If a disease-causing mutation is found, the parents and siblings of the proband should be screened for the same mutation and should have routine laboratory testing (ie, complete blood count and reticulocyte count). Testing first-degree relatives is warranted even if they are asymptomatic to guide genetic counseling and determine the need for routine screening, given the increased risk for malignancy [40].

Bone marrow examination — A bone marrow examination may be included in the diagnostic evaluation for suspected DBA; however, this practice is not standardized and varies from center to center. In some cases, the diagnosis of DBA can be made based upon a classic clinical history, consistent laboratory studies, and an identified RP gene mutation. In such cases, bone marrow examination adds little to the diagnostic evaluation, and some centers do not perform it unless the diagnosis is uncertain. The advantage of this approach is that it avoids procedure- and anesthesia-related risks in some patients. By contrast, other centers routinely perform bone marrow examination in all patients with suspected DBA to provide additional confirmation of the diagnosis and to serve as a baseline if concerns arise later for myelodysplastic syndrome (MDS).

If bone marrow examination is performed, the characteristic findings in DBA include normal bone marrow cellularity with markedly decreased or absent erythroid precursors. It is important to exclude the presence of ringed sideroblasts, which are seen in Pearson syndrome. (See 'Differential diagnosis' below.)

Diagnostic criteria — Diagnostic criteria for DBA were established by an international clinical consensus group in 2008 [49]. It should be noted that there have been substantial advances in the understanding of the genetics of DBA and in genetic testing since the initial consensus document. Nevertheless, these diagnostic criteria and categories remain the established tool for the diagnosis of DBA. Based on these criteria, the diagnosis of DBA can be established as follows (table 3):

●Classic DBA – Classic DBA is diagnosed if all four diagnostic criteria are present:

•Onset of anemia at age <1 year

•Macrocytic anemia with no other significant cytopenias

•Reticulocytopenia

•Normal marrow cellularity with a paucity of erythroid precursors

●Nonclassical DBA – A diagnosis of nonclassical DBA can be made if the patient has a DBA-associated genetic variant but does not meet all four diagnostic criteria for classic DBA.

●Probable DBA – A probable diagnosis of DBA can be made based upon any of the following:

•Three of the four diagnostic criteria above plus a positive family history

•Two of the four diagnostic criteria above plus at least three minor criteria:

-Elevated eADA activity

-Congenital anomalies associated with DBA

-Elevated fetal Hgb

-No evidence of another inherited bone marrow failure syndrome

•Three or more minor criteria plus a positive family history

Additional testing — Once the diagnosis of DBA is confirmed, kidney ultrasound and echocardiography should be performed as a part of the initial evaluation because of the association of cardiac and kidney/urinary tract abnormalities in patients with DBA [49]. If there is clinical evidence of bony abnormalities, radiographs should be performed, but they are not otherwise routinely required. An ophthalmologic examination and an initial evaluation for endocrinopathies are appropriate prior to initiation of glucocorticoid therapy to establish a baseline.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis includes other causes of anemia due to decreased red blood cell production:

●Transient erythroblastopenia of childhood (TEC) is the most common cause of pure red blood cell aplasia in children and should be suspected in an otherwise healthy child with anemia and reticulocytopenia. TEC is a self-limited illness and typically presents between the ages of one and four years. Features that distinguish DBA from TEC are summarized in the table (table 1). TEC is discussed in greater detail separately. (See "Overview of causes of anemia in children due to decreased red blood cell production", section on 'Transient erythroblastopenia of childhood'.)

●Other genetic conditions characterized by bone marrow failure, including Fanconi anemia, Shwachman-Diamond syndrome, and dyskeratosis congenita, which usually have additional cytopenias. Routine testing for other bone marrow failure syndromes is not required unless there is diagnostic uncertainty, although evaluation for Fanconi anemia and dyskeratosis congenita is often done prior to possible hematopoietic stem cell transplant. (See "Aplastic anemia: Pathogenesis, clinical manifestations, and diagnosis", section on 'Inherited genetic abnormalities'.)

●Pearson marrow pancreas syndrome is a relatively rare condition that shares a number of overlapping features with DBA. This condition can be diagnosed via mitochondrial DNA deletion testing. Clinical features are not always sufficient to distinguish these disorders. In a series of 173 genetically uncharacterized patients who were presumed to have DBA, eight patients (5 percent) harbored large mitochondrial deletions consistent with Pearson syndrome [50]. (See "Causes and pathophysiology of the sideroblastic anemias", section on 'Pearson syndrome (large deletion of mitochondrial DNA)'.)

TREATMENT

Approach to treatment — The mainstays of therapy for DBA are glucocorticoids and blood transfusion [49]. Hematopoietic cell transplantation (HCT) has been employed with success in steroid-refractory patients.

The general approach is as follows (algorithm 1):

●Infants <1 year old – Infants are maintained with transfusion therapy. Glucocorticoid therapy is generally deferred until after the age of one year because of the high risk of adverse effects of glucocorticoids in young infants. (See 'Transfusion therapy' below.)

●Children ≥1 year old – For children ≥1 year old, we suggest glucocorticoid therapy as the first-line treatment. (See 'Glucocorticoids' below.)

●Steroid-resistant patients – For patients who do not respond to or have unacceptable side effects from glucocorticoids, we suggest chronic transfusion therapy. HCT has been employed with success in steroid-refractory patients, as discussed separately. (See 'Transfusion therapy' below and "Hematopoietic cell transplantation (HCT) for inherited bone marrow failure syndromes (IBMFS)", section on 'Diamond-Blackfan anemia'.)

Other agents previously used to treat patients with DBA (eg, androgens, metoclopramide, cyclosporine, other immunosuppressive agents) are generally not effective in steroid-resistant patients and are no longer routinely used. (See 'Therapies not routinely used' below.)

Glucocorticoids — Glucocorticoids are the first-line therapy for DBA in children ≥1 year old. This therapy is generally deferred until after the age of one year because of the high risk of adverse effects of glucocorticoids in young infants [49]. The exact mechanism by which glucocorticoids stimulate erythropoiesis in DBA remains unknown. This is an area of ongoing investigation.

●Dose – We usually begin with oral prednisolone at a dose of 2 mg/kg per day, administered as one or two daily doses.

●Response to treatment – In steroid-responsive patients, reticulocytes typically begin to appear within one to two weeks in responders [51]. If there is no response after a four-week trial, glucocorticoid therapy should be discontinued [49]. The response rate to glucocorticoids in DBA ranges from 50 to 75 percent [4,41]. Factors associated with steroid responsiveness include [41]:

•Older age at presentation

•Family history of DBA

•Normal platelet count at the time of diagnosis

●Tapering – Once the hemoglobin (Hgb) has increased to ≥10 g/dL, a tapering schedule may be instituted, starting with a reduction in the number of daily doses. The steroid dose should be reduced slowly until a minimum effective dose is reached. Such minimally effective doses are highly variable, and many children who respond to steroids cannot be completely weaned [4,5]. The taper should be over an 8- to 12-week time period, with a goal of reaching a dose ≤0.5 mg/kg/day or ≤1 mg/kg every other day and a target Hgb between 8 and 10 g/dL [49].

●Infection prophylaxis – Patients receiving prolonged steroid therapy should receive prophylaxis with sulfamethoxazole-trimethoprim. Live-virus vaccination should be avoided while the patient remains on high or moderate doses of corticosteroid therapy [49]. (See "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Prophylaxis' and "Measles, mumps, and rubella immunization in infants, children, and adolescents", section on 'Contraindications'.)

●Refractory patients – Steroid-resistant patients are generally managed with transfusion therapy (see 'Transfusion therapy' below). Other immunosuppressive agents (eg, cyclosporin) are generally not effective in steroid-resistant patients [52,53]. (See 'Therapies not routinely used' below.)

Investigational therapies are discussed below (see 'Investigational therapies' below). The role of HCT in steroid-resistant transfusion-dependent patients is discussed separately. (See "Hematopoietic cell transplantation (HCT) for inherited bone marrow failure syndromes (IBMFS)", section on 'Diamond-Blackfan anemia'.)

Transfusion therapy — Transfusion therapy is the mainstay of treatment for infants ≤12 months and patients who are refractory to or who have unacceptable side effects from glucocorticoid therapy. Patients are transfused to maintain Hgb levels 8 to 10 g/dL, which typically requires transfusion every four to six weeks [49]. Transfusions can also be used intermittently to support patients who are maintained on lowered doses of steroids as needed.

To avoid red cell sensitization and transfusion reactions, complete red cell typing should be performed and blood should be leukoreduced. (See "Red blood cell transfusion in infants and children: Selection of blood products", section on 'Leukoreduced red blood cells' and "Pretransfusion testing for red blood cell transfusion".)

Immediate family members should not be used as blood donors, to avoid allosensitization, which might jeopardize future HCT [54]. (See "Hematopoietic cell transplantation (HCT) for inherited bone marrow failure syndromes (IBMFS)", section on 'Donor'.)

The major complication of transfusion therapy is iron overload, as discussed below. (See 'Transfusional iron overload' below.)

Hematopoietic cell transplantation — HCT has been employed with success in steroid-refractory patients. The outcomes and timing of HCT for the treatment of this disease are discussed in a separate topic review. (See "Hematopoietic cell transplantation (HCT) for inherited bone marrow failure syndromes (IBMFS)", section on 'Diamond-Blackfan anemia'.)

Investigational therapies

●L-leucine – Limited data on L-leucine in children with DBA suggest that it is safe and may increase weight and linear growth velocity in a subset of patients, though a hematologic response was less frequently observed [55]. The proposed mechanism is that L-leucine upregulates messenger RNA (mRNA) translation.

●Ongoing clinical trials – There are several ongoing clinical trials investigating the following agents:

•Sotatercept – Sotatercept acts as a ligand trap for members of the transforming growth factor-beta superfamily and inhibits negative regulators of late-stage erythropoiesis [56].

•Trifluoperazine – Trifluoperazine is a calmodulin inhibitor that is approved for use as an antipsychotic. It has been shown to increase Hgb levels in a mouse model of DBA, and it improved erythroid differentiation in human CD34+ cells in in vitro testing [57,58].

•Eltrombopag – It is postulated that the thrombopoietin receptor agonist eltrombopag may improve production of red blood cells in DBA patients via chelation of iron and subsequent reduction in heme synthesis, resulting in decreased toxicity to bone marrow stem cells and developing erythroid cells [59].

●Gene therapy – Gene therapy and gene editing have been proposed as possible future treatments for DBA, with some promising initial results in a mouse model [60].

Therapies not routinely used — Several drugs were previously used to treat DBA with limited effect and are no longer routinely used. These include:

●Androgens (which are occasionally used in Fanconi anemia and dyskeratosis congenita) (see "Management and prognosis of Fanconi anemia", section on 'Androgens')

●Metoclopramide [61-63]

●Cyclosporine and other immunosuppressive agents [52]

LONG-TERM COMPLICATIONS

Predisposition to cancer — DBA is associated with a predisposition to cancer. Associated malignancies include myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML). There is also an increased risk of solid tumors including colon cancer, female genital cancers, and osteogenic sarcoma [49,64].

The risk of solid tumors in nontransplanted patients begins to rise around 30 years of age. The cancer risk is substantially higher than in a healthy population but is lower than that for Fanconi anemia or dyskeratosis congenita. However, the degree of risk for cancer has not been fully established and the optimal approach to cancer surveillance in this population is uncertain.

Our general approach is as follows:

●Surveillance for MDS and AML – We monitor complete blood counts every three to six months (this is usually done in conjunction with monitoring of steroid therapy and/or chronic transfusions). If there are any changes in the complete blood count and/or a loss of response to therapy, we consider performing flow cytometry, including an MDS panel. Based on this and other clinical and laboratory findings, we determine if bone marrow examination is warranted. We do not routinely perform bone marrow surveillance in patients with DBA.

●Surveillance for solid tumors – We advise patients to undergo routine cancer screening, as recommended for all adults. We do not suggest more frequent or additional screening; however, we do counsel patients to maintain a high level of vigilance if any concerning symptoms arise. We encourage adult patients to establish appropriate specialty care (eg, with orthopedics, gastroenterology, and obstetrics/gynecology), ideally in the setting of a comprehensive bone marrow failure clinic.

●Patients who have undergone hematopoietic cell transplantation (HCT) – The risk of cancer in patients who undergo HCT is discussed separately. (See "Hematopoietic cell transplantation (HCT) for inherited bone marrow failure syndromes (IBMFS)", section on 'Cancer risk'.)

In a report from a registry that included follow-up data on 608 patients with DBA, the cumulative incidence of malignancy (solid tumor or leukemia) was approximately 20 percent by age 46 years [64]. Four cases of MDS and two cases of AML were reported; solid tumors included colon cancer (n = 3), osteogenic sarcoma (n = 2), female genital cancers (n = 3), melanoma (n = 1), breast cancer (n = 2), non-Hodgkin lymphoma (n = 1), soft tissue sarcoma (n = 1), testicular cancer (n = 1), and choroid meningioma of the lung (n = 1).

Endocrine dysfunction — Endocrine dysfunction is common in patients with DBA, occurring in approximately 50 percent of patients [32]. Some of these complications are inherent to the disease, and some are secondary to chronic glucocorticoid therapy. Endocrine dysfunction may include:

●Short stature – For children with DBA who have short stature, treatment with growth hormone may improve growth velocity and height for age [65]. However, there is some controversy about this, given the increased risk of osteosarcoma in these patients. There are no consensus guidelines, and decisions are ultimately made between the family, patient, and provider. This therapy is discussed separately. (See "Treatment of growth hormone deficiency in children".)

●Adrenal insufficiency – Adrenal insufficiency is particularly common in patients who are chronically steroid dependent. Management of adrenal insufficiency is discussed separately. (See "Treatment of adrenal insufficiency in children".)

●Hypogonadism. (See "Clinical features and diagnosis of male hypogonadism".)

●Hypothyroidism. (See "Acquired hypothyroidism in childhood and adolescence".)

●Vitamin D deficiency and bone disease. (See "Vitamin D insufficiency and deficiency in children and adolescents".)

Given the frequency of endocrine abnormalities, we suggest that patients with DBA be seen annually by an endocrinologist for monitoring of growth velocity, pubertal development, vitamin levels, and thyroid function and other monitoring if on chronic steroids (eg, dual-energy x-ray absorptiometry [DXA] scans to screen for osteopenia).

In a report of 57 patients from the North American DBA registry, 53 percent of patients had at least one endocrine disorder, including adrenal insufficiency (32 percent), short stature (33 percent), hypogonadism (29 percent), hypothyroidism (14 percent), growth hormone dysfunction (7 percent), diabetes mellitus (2 percent), and diabetes insipidus (2 percent) [32]. Low levels of 25-hydroxyvitamin D were noted in one-half of the cohort. Adrenal insufficiency most commonly occurred in steroid-dependent patients, whereas other endocrinopathies were more often observed in chronically transfused patients.

Transfusional iron overload — Patients managed with chronic transfusion therapy are at risk for transfusional iron overload, which may result in significant morbidity and mortality. Patients with DBA appear to deposit iron differently compared with other patients who require chronic transfusions. For example, patients with DBA tend to develop earlier and more severe iron overload compared with patients with transfusion-dependent beta-thalassemia [66]. Thus, patients with transfusion-dependent DBA should be carefully monitored for this complication and iron chelation therapy should be instituted in patients with evidence of significantly increased iron stores. Iron chelation therapy is discussed in detail separately. (See "Approach to the patient with suspected iron overload", section on 'Transfusional iron overload' and "Iron chelators: Choice of agent, dosing, and adverse effects".)

PROGNOSIS — Spontaneous remissions have been reported in as many as 25 percent of patients with DBA [51]. Overall, approximately 40 percent of patients are steroid dependent, 40 percent are transfusion dependent, and 20 percent go into remission by age 25 years [42,49]. In most cases, the remission is stable.

The prognosis for patients who undergo hematopoietic cell transplantation (HCT) is discussed separately. (See "Hematopoietic cell transplantation (HCT) for inherited bone marrow failure syndromes (IBMFS)", section on 'Post-HCT care'.)

SUMMARY AND RECOMMENDATIONS

●Incidence – Diamond-Blackfan anemia (DBA) is a congenital red cell aplasia that usually presents in infancy or early childhood. It is a rare disorder with an estimated incidence of 5 cases per 1 million live births. (See 'Epidemiology' above.)

●Genetics – The most common cause of DBA is a mutation in the gene encoding ribosomal protein 19 (RPS19), which is identified in approximately 25 percent of patients with DBA. Other pathologic variants have been identified, including mutations, deletions, and copy number variations in genes encoding the large and small ribosomal subunits. Other genes have been implicated in a minority of cases. (See 'Genetics and pathogenesis' above.)

●Laboratory findings – The following laboratory findings are characteristic of DBA (see 'Laboratory findings' above):

•Normochromic and usually macrocytic anemia associated with reticulocytopenia

•White blood cell and platelet counts are typically normal

•Evidence of stress erythropoiesis (ie, elevated fetal hemoglobin [Hgb F] and increased expression of i red blood cell antigen)

•Elevated erythrocyte adenosine deaminase (eADA)

•Bone marrow with normal cellularity with markedly decreased or absent erythroid precursors

●Physical findings – Associated congenital abnormalities occur in up to 50 percent of patients with DBA, including (table 2) (see 'Physical features' above):

•Craniofacial abnormalities

•Neck anomalies

•Thumb anomalies

•Urogenital anomalies

•Cardiopulmonary anomalies

•Hypogonadism

•Intellectual disability

•Other skeletal abnormalities

●Diagnostic evaluation – The initial laboratory evaluation for a patient with suspected DBA includes the following and should be obtained prior to transfusion (see 'Laboratory evaluation' above):

•A complete blood count with red blood cell indices and smear review

•Reticulocyte count

•Measurement of fetal Hgb (eg, by Hgb electrophoresis)

•eADA activity

For patients with a high clinical suspicion of DBA, we suggest genetic testing for mutations in the genes associated with DBA. (See 'Genetic testing' above.)

●Diagnosis – Classic DBA is diagnosed if all of the following are present (see 'Diagnostic criteria' above):

•Onset of anemia at age <1 year

•Macrocytic anemia with no other significant cytopenias

•Reticulocytopenia

•Normal marrow cellularity with a paucity of erythroid precursors

A diagnosis of nonclassical DBA can be made if the patient has a DBA-associated gene mutation but does not meet diagnostic criteria for classic DBA. A probable diagnosis can be made based upon other supporting features, as summarized in the table (table 3). (See 'Diagnostic criteria' above.)

Once the diagnosis of DBA is confirmed, additional testing includes kidney ultrasound and echocardiography to assess for associated congenital abnormalities. (See 'Additional testing' above.)

●Differential diagnosis – The differential diagnosis includes transient erythroblastopenia of childhood (TEC) (table 1); other genetic bone marrow failure syndromes (eg, Fanconi anemia, Shwachman-Diamond syndrome, and dyskeratosis congenita), which usually have additional cytopenias; and Pearson marrow pancreas syndrome. (See 'Differential diagnosis' above.)

●Treatment – The mainstays of therapy for DBA are glucocorticoids and blood transfusion. Hematopoietic cell transplantation (HCT) has been employed with success in steroid-resistant patients. The general approach is as follows (algorithm 1) (see 'Treatment' above):

•Infants <1 year old - Infants are maintained with transfusion therapy. Glucocorticoid therapy is generally deferred until after the age of one year because of the high risk of adverse effects of glucocorticoids in young infants. (See 'Transfusion therapy' above.)

•Children ≥1 year old - For children ≥1 year old, we suggest glucocorticoid therapy as the first-line treatment (Grade 2C). The usual starting dose of oral prednisolone is 2 mg/kg per day, administered as one or two doses. In steroid-responsive patients, the response is usually apparent within one to two weeks, at which point, a tapering schedule can be started. Glucocorticoids are then tapered over 8 to 12 weeks, with a goal of reaching a dose ≤0.5 mg/kg/day or ≤1 mg/kg every other day and a target Hgb between 8 and 10 g/dL. (See 'Glucocorticoids' above.)

•Steroid-resistant patients – For patients who do not respond to or have unacceptable side effects from glucocorticoids, we suggest chronic transfusion therapy (Grade 2C). Patients are transfused to maintain Hgb levels ≥8 g/dL, which typically requires transfusion every four to six weeks. To avoid red cell sensitization and transfusion reactions, complete red cell typing should be performed and blood should be leukoreduced. HCT has been employed with success in steroid-resistant patients, as discussed separately. (See 'Transfusion therapy' above and "Hematopoietic cell transplantation (HCT) for inherited bone marrow failure syndromes (IBMFS)", section on 'Diamond-Blackfan anemia'.)

●Prognosis – Approximately 40 percent of patients are steroid dependent, 40 percent are transfusion dependent, and 20 percent go into remission by age 25 years. In most cases, the remission is stable. (See 'Prognosis' above.)

Long-term complications may include (see 'Long-term complications' above):

•Malignancy – DBA is associated with a predisposition to cancer. Associated malignancies include acute myelogenous leukemia (AML); myelodysplastic syndrome (MDS); and solid tumors including colon cancer, female genital cancers, and osteogenic sarcoma. (See 'Predisposition to cancer' above.)

•Endocrine dysfunction – Endocrine dysfunction is common in patients with DBA, including short stature, adrenal insufficiency, hypogonadism, hypothyroidism, vitamin D deficiency, and bone disease. Some of these complications are inherent to the disease, while others are caused by chronic glucocorticoid therapy. (See 'Endocrine dysfunction' above.)

•Iron overload – Patients managed with chronic transfusion therapy are at risk for transfusional iron overload. (See "Approach to the patient with suspected iron overload", section on 'Transfusional iron overload' and "Iron chelators: Choice of agent, dosing, and adverse effects".)