Continuing Education Activity

Diamond-Blackfan anemia is a rare congenital red cell aplasia characterized by macrocytic anemia, reticulocytopenia, and a paucity of erythroid precursors in the bone marrow. While iron deficiency anemia remains the most common worldwide, Diamond-Blackfan anemia presents unique diagnostic and management challenges due to its genetic heterogeneity and frequent association with congenital abnormalities. This course explores the clinical presentation of Diamond-Blackfan anemia, which often begins in infancy with symptoms such as pallor and lethargy, and may also include physical anomalies (eg, craniofacial malformations, thumb abnormalities, and cardiac or renal defects).

Additionally, the course reviews diagnostic criteria, including elevated fetal hemoglobin, eADA activity, and erythropoietin levels, as well as treatment strategies for Diamond-Blackfan anemia to prevent the occurrence of tumors, organ failure, and other complications. This activity for healthcare professionals is designed to enhance the learner's competence in identifying Diamond-Blackfan anemia, performing the recommended evaluation, and implementing an appropriate interprofessional approach when managing this condition, enabling improved patient outcomes through early recognition and individualized care.

Objectives:

• Identify the genetic mutations in Diamond-Blackfan anemia.
• Evaluate the presentation of Diamond-Blackfan anemia.
• Identify the treatment of Diamond-Blackfan anemia.
• Assess the necessity of an integrated interprofessional team approach in managing Diamond-Blackfan anemia to achieve improved outcomes.

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Introduction

Anemia refers to a hemoglobin level below the normal range for a given age group. Classification typically falls into 3 categories based on the mean corpuscular volume (MCV) of red blood cells. Iron deficiency anemia remains the most prevalent type across all age groups worldwide.[1] In contrast, a rare anemia with a genetic origin—Diamond-Blackfan anemia is a congenital condition that features pure red cell aplasia and frequently accompanies congenital skeletal abnormalities. Diamond-Blackfan anemia presents as a chronic anemia, typically characterized by either macrocytic or normocytic features. In approximately 40% to 45% of cases, inheritance follows an autosomal dominant pattern, while 55% to 60% arise sporadically (see Image. Diamond-Blackfan Anemia).[2][3][4] A smaller subset of cases involves autosomal recessive inheritance. Although possible, the occurrence of hydrops remains exceedingly rare.[2]

Etiology

Often, Diamond-Blackfan anemia results from a genetic mutation. The most common mutation involves a ribosomal protein on chromosome 11. However, newer studies have also noted mutations of the transcription factor GATA1.[2][3][5][4] Ribosomal gene mutations are more common and present in about 60% to 70% of Diamond-Blackfan anemia cases.[2][3][5][4] It involves the gene that codes for both small and large ribosomal protein units, including but not limited to RPL5, RPL11, RPS7, RPS17, RPS24, RPS10, RPS19, and RPS26. In some families, mutations in RPL3, RPL7, RPL14, RPL19, RPL26, RPL36, RPL23A, RPL35, RPS 15, RPS 8, RPS27A, RPL35, and RPL18 gene has occurred.[2][3][6][4] Despite a significant genetic component to Diamond-Blackfan anemia, 30% to 35% of cases remain genetically indeterminate.[2][7][4] Defective ribosomal protein biosynthesis initiates apoptosis of erythroid progenitor cells through the activation and stabilization of p53, leading to erythroid failure. This mechanism is known as "ribosomal stress".[2] Up to 50% of Diamond-Blackfan anemia cases have a heterozygous mutation in the ribosomal gene, resulting in a loss of function.[2] 

Epidemiology

Diamond-Blackfan anemia is a rare disease with an incidence rate of 1 in 500,000 live births. The onset is generally within the first year of life. The incidence of Diamond-Blackfan anemia is similar among different ethnicities and genders.[2][7] In pregnant patients with Diamond-Blackfan anemia, relapse may occur, which is thought to be secondary to the hormonal stress of pregnancy.[8]

Pathophysiology

Diamond-Blackfan anemia is a chronic macrocytic-normochromic anemia characterized by low reticulocytes, normal platelets, and normal white blood cells (WBCs) in the bone marrow. In 25% of cases, a transient thrombocytopenia and neutropenia may be present.[9] Laboratory evaluation is significant for elevated MCV and erythrocyte adenosine deaminase (eADA). The eADA is elevated in 80% to 85% of patients.[8] Persistently elevated hemoglobin F is commonly seen in patients with Diamond-Blackfan anemia as well.[2][5][4]

Among all ribosomal protein genes, RPS19, which encodes a small subunit of the ribosome, represents the most frequently mutated gene in Diamond-Blackfan anemia, accounting for approximately 25% of cases.[2][4] More than 50% of mutations involving ribosomal protein genes affect RPS genes. These mutations include deletions, insertions, nonsense mutations, splice site alterations, and frameshift changes. Such alterations result in a deficiency of the RPS19 protein, a condition known as "haploinsufficiency."[2][4]

Up to 50% of Diamond-Blackfan anemia cases have a heterozygous mutation of the ribosomal gene, resulting in loss of function in a single copy of the gene.[2] RPS19 plays a crucial role in 18S rRNA maturation and 40S ribosome subunit synthesis. RPS19 mutation causes a decrease in the production of RPS19 and 40S ribosomal subunits by reducing translation initiation. This reduction disrupts the differentiation and production of normal primary hematopoietic progenitor cells and increases apoptosis.[2][4] The overexpression of exogenous RPS19 can compensate for the deficiency of RPS19, which helps explain the haploinsufficiency phenomenon and suggests that Diamond-Blackfan anemia might be treatable by augmenting the RPS gene.[2][4]

According to the "ribosomal stress" mechanism, ribosomal deficiency activates and stabilizes p53, subsequently initiating apoptosis to cause bone marrow failure by terminating cell lines. Murine double minute (MDM2) is a ringer figure ubiquitin ligase that controls the level and activity of p53. When interacting with the normal ribosomal protein, MDM2 enhances p53 degradation.[2] In Diamond-Blackfan anemia, ribosomal stress causes many free ribosomal proteins (RPS) to accumulate due to disrupted ribosomal biosynthesis. These free RPS, such as RPL5, RPL11, RPL23, RPS27, and RPS7, bind with MDM2 to stabilize p53, leading to apoptosis, cell cycle arrest, and eventually erythroid hypoplasia.[2] Diamond-Blackfan anemia also results from non-Rp gene mutations, eg, GATA1. GATA1 encodes for transcription factors.[2][5][4] It plays a crucial role in erythroid differentiation. GATA1 mutation of G to C transversion on the X chromosome leads to substituting leucine for valine. This mutation affects the splicing process of GATA1, leading to the termination of GATA1, which plays a crucial role in the differentiation of erythroid cells. GATA1 mutation ultimately acts by a global translation blockade.[2][5][4] 

History and Physical

Diamond-Blackfan Anemia Clinical Manifestations

In approximately 90% of patients, Diamond-Blackfan anemia typically begins before the age of 12 months. It commonly presents with congenital bony malformations (in 50% of cases) and growth retardation (in 30% of cases).[3] The median age of presentation and diagnosis is 2 months.[2][3] Children typically present with lethargy and pallor first. Patients usually present with severe macrocytic anemia and normochromic anemia, along with erythroid aplasia due to congenital bone marrow failure. Typically, platelet and leukocyte counts are within the normal range; however, some patients have been found to have low leukocyte and high platelet counts. Patients can have significantly low reticulocyte counts.[2] Diamond-Blackfan anemia is also associated with elevated fetal hemoglobin levels, erythropoietin, and eADA activities.[2][7][5][4]

Diamond-Blackfan anemia presents a broad spectrum of phenotypes, from mild to severe. Physical abnormalities are present in 50% of cases.[2][3][9] The most common congenital physical abnormalities are thumb and upper extremity malformations, craniofacial anomalies (eg, microtia), and short stature. RPL26 favors variable radial ray anomalies.[10] The patient may also have a snub nose and wide-spaced eyes. They may manifest congenital glaucoma or cataracts, and strabismus. The characteristic Diamond-Blackfan anemia anomalies include a distinct facial appearance along with triphalangeal thumbs.[2][3][4] The PRL5 mutation is associated with cleft lip or soft palate, while RPL11 largely correlates with thumb abnormalities but is also observed in cases of cleft lip or palate.[2][3][4] Other physical anomalies include urogenital (eg, absence of or horseshoe kidney), atrial septal, and ventricular septal defects as well as aortic coarctation.[2][3][7] Due to cervical spine anomalies, patients may manifest Klippel-Feil deformity.

Diagnostic Criteria for Classical Diamond-Blackfan Anemia

The following criteria identify classic Diamond-Blackfan anemia

• Age of onset less than 12 months
• Macrocytic anemia without other significant cytopenias
• Reticulocytopenia
• Bone marrow with normal cellularity with a lack of erythroid precursors [3][7][11] 

Major supporting criteria include:

• Gene mutation described in Diamond-Blackfan anemia
• Positive family history

Minor supporting criteria include:

• Elevated ADA activity
• Congenital anomalies described in classical Diamond-Blackfan anemia
• Elevated HbF
• There is no evidence of another inherited bone marrow failure syndrome

Evaluation

After meeting the clinical criteria for diagnosis, laboratory tests help physicians make a correct diagnosis. Erythropoietin (EPO) levels are elevated in Diamond-Blackfan anemia due to a lack of EPO receptors in the setting of erythroid aplasia. Other biological tests may include immune phenotyping and titers of IgG and IgA agglutinins.[12] For molecular diagnosis, the first step is to characterize the phenotype with a bone marrow evaluation. Molecular tests are performed to identify a heterozygous pathogenic variant in genes commonly associated with Diamond-Blackfan anemia.

The types of molecular testing include serial single-gene testing and multigene panels. Parvovirus B19 is a common cause of bone marrow failure, making it mandatory to have parvovirus B19 serology or blood parvovirus B19 PCR done in patients where Diamond-Blackfan anemia is suspected.[12] A common hematological workup includes a complete blood count with differential, hemoglobin F, eADA, erythropoietin level, reticulocyte count, and a peripheral blood smear. 

Treatment / Management

Corticosteroid Therapy

Corticosteroids are the first-line treatment of Diamond-Blackfan anemia. However, despite the efficacy of corticosteroids, patients with Diamond-Blackfan anemia often require chronic blood transfusions (90% of patients before the age of 1 year) and concurrent iron chelation therapy.[2][3][5] A patient who is responsive to steroid therapy but with intolerable adverse effects requires chronic blood transfusions with a hemoglobin goal of 8 g/dL and requires a blood transfusion usually every 35 weeks.[2] Approximately 40% of patients became steroid dependent, while steroid resistance occurred in 35%.[9][8] Frequent monitoring of serum ferritin levels helps determine if iron chelation therapy is necessary.

Clinicians should bear in mind that ferritin is an "acute-phase reactant" (ie, phase reactant protein) and can be elevated in conditions of inflammation, infarction, ischemia, and infection, thereby giving a false impression of the iron level. Generally, iron chelation is started after 12 to 15 units of blood transfusions if serum ferritin concentration increases to 1000 to 1500 µg/L or if hepatic iron concentration increases to 6 to 7 mg of the dry weight of liver tissue.[2][3][5] When iron chelation is required, deferasirox and desferrioxamine are the therapeutic choices. Deferiprone is not a recommendation due to its adverse effect of neutropenia.

The mechanism of action of corticosteroids remains obscure, but it seems to have a nonspecific anti-apoptotic effect on erythroid progenitors.[2] Metoclopramide can be used as a supplement to steroid therapy to decrease steroid dose and, therefore, the adverse effects.[4] Clinical trials have also suggested leucine as a supplemental therapy to steroids.[4] For patients on chronic steroids, vitamin D supplementation and regular bone density checks are recommended.[8]

Hematopoietic Stem Cell Transplantation

Diamond-Blackfan anemia may also receive treatment with hematopoietic stem cell transplantation (HSCT). This approach is the only treatment that cures the hematological manifestation of Diamond-Blackfan anemia; the procedure proves to be risky if a matched sibling donor is not available.[3][7][6][4] HSCT has a high success rate in patients younger than 10 treated with an HLA-identical donor. HSCT is indicated as an alternative to chronic blood transfusions if the patient becomes nonresponsive to chronic blood transfusions or develops adverse effects of iron overload.[2][3][8] However, HSCT also has adverse effects to consider, including infection and graft-versus-host disease.[2][6] The indications for HSCT are resistance to chronic steroids, transfusion dependency, and steroid toxicity.[8] Stem cells from the bone marrow are preferred over those from the peripheral blood. Total body irradiation is not recommended as a preconditioning component, as Diamond-Blackfan anemia patients are already predisposed to cancer.

Gene Therapy

According to recent literature, gene therapy and gene editing may be potential future treatments for Diamond-Blackfan anemia.[6][13] The primary difference between gene therapy and allogeneic HSCT lies in the source of stem cells. In gene therapy, the source of stem cells is the patient's normal HSCs; then, a normal copy of the mutated gene can be inserted into the patient's cells. In allogeneic HSCT, normal stem cells are obtained from a donor.[13] Since the RPS19 gene is present in 25% of Diamond-Blackfan anemia cases, gene therapy may benefit patients with the mutation, which involves replacing the normal copy of the RPS19 gene to alleviate symptoms of Diamond-Blackfan anemia in the patient.[2][13][4] The viral vector system is the most common method for gene therapy, achieving a high success rate and safety profile.[6][13] Approximately 20% to 25% of Diamond-Blackfan anemia patients experience spontaneous remission.[5] 

Differential Diagnosis

Diamond-Blackfan anemia has a unique quantitative defect in erythropoiesis rather than hematopoiesis, as seen in other bone marrow failure syndromes (BMF).[12] Various BMF syndromes include: 

• Transient erythroblastopenia of childhood is a type of acquired anemia of unknown etiology, which typically (over 80%) presents at 1 year of age. In contrast, Diamond-Blackfan anemia usually (90%) presents before the age of 1. Another distinguishing feature of transient erythroblastopenia of childhood is that only 10% of patients have elevated eADA, and anemia is normocytic.[14]

• Fanconi anemia is a bone marrow failure syndrome characterized by pancytopenia and physical abnormalities, typically presenting within the first decade of life.[15]

• Shwachman-Diamond syndrome is a clinical syndrome characterized by exocrine pancreatic dysfunction with malabsorption, single or multi-lineage cytopenia, growth failure, bone abnormalities, and susceptibility to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).[16][17]

• Pearson syndrome is a maternally inherited mDNA mutation characterized by sideroblastic anemia of childhood, exocrine pancreatic failure, liver failure, renal tubular defects, and pancytopenia. Death generally occurs in infancy due to progressive liver failure and severe metabolic acidosis.[18][19]

• Dyskeratosis congenita is a genetically inherited disorder with a wide spectrum of severity. Dyskeratosis congenita is a telomere biology disorder characterized by the classic triad of lacy reticular pigmentation on the upper chest and neck, dysplastic nails, and oral leukoplakia. These patients have an increased risk of MDS, BMF, or AML.[20][21]

• Cartilage-hair dysplasia is an autosomal recessive inherited disorder with a high incidence in the Amish and Finnish populations. This condition is characterized by anemia, macrocytosis, defective T cell-mediated immune response, short tubular bones, and fine, sparse blond hair.[22][23]

• Thrombocytopenia absent radii syndrome presents in the neonatal period or infancy with thrombocytopenia, absent radii, and the presence of bilateral thumbs. Other physical findings include rib, cervical, ulnar, and humeral deformities, cardiac septal defects, gastrointestinal abnormalities, and genitourinary abnormalities. In rare cases, aplastic anemia, multilineage cytopenia, or leukemia have been clinical features.[24][25]

• Congenital amegakaryocytic thrombocytopenia usually presents at birth or in the neonatal period with severe thrombocytopenia, petechiae, and intracranial or intestinal mucosal bleeding. No congenital physical findings are associated with this disease. In childhood, these patients may develop pancytopenia, MDS, or leukemia.[3][5][26][27]

Acquired conditions with BMF include viral infections (eg, parvovirus B19, viral hepatitis and mononucleosis, and human T-cell lymphotropic virus type 1, HIV-associated pure red cell aplasia), immune-mediated diseases (myasthenia gravis, thymoma, multiple endocrinopathy, and systemic lupus erythematosus), and drugs (eg, antiepileptic drugs, sulfonamide, isoniazid, chloramphenicol, procainamide, azathioprine, and thiamphenicol).[3][4]

Prognosis

The prognosis is relatively good; however, complications related to treatment may impact the patient's quality of life.[2] Severe complications as a result of treatment or the development of cancer may reduce life expectancy.[2] Disease severity is determined by the quality of life and response to treatment.[2]

Complications

Diamond-Blackfan anemia patients are at a high risk of developing hematological complications in the first year of life. Diamond-Blackfan anemia has a high risk of developing AML, MDS, and solid tumors. Other complications like growth failure, organ failure, and infection are related to iron overload due to blood transfusion, chronic steroid use, and HSCT.

Deterrence and Patient Education

Patients with Diamond-Blackfan anemia should have their complete blood counts monitored frequently.[3] Periodic bone marrow biopsy or aspiration to evaluate cellularity and morphology helps diagnose any new cytopenia or bone marrow failure.[3] Patients who are steroid-dependent or transfusion-dependent should be monitored for blood pressure and growth as they are at high risk of organ failure; often, an endocrinology consult is necessary.[3] Healthy Diamond-Blackfan anemia patients must follow up every 4 to 6 months with history, physical examination, and complete blood count for cancer surveillance.[3] The rapid decline of any cell line indicates bone marrow failure, and bone marrow biopsy with cytogenetic studies is required to diagnose chromosomal abnormalities associated with cancer.[3]

Relatives of individuals with Diamond-Blackfan anemia are at risk of developing the condition, as approximately 40% to 45% of autosomal dominant Diamond-Blackfan anemia patients have inherited a pathognomonic variant from 1 parent. Additionally, X-linked inheritance has been noted.[3] Offering genetic testing if a pathognomonic variant is known is appropriate. The patient may receive an offer for other hematological tests for early diagnosis of Diamond-Blackfan anemia and cancer.[3] Approximately 55% to 60% of cases of Diamond-Blackfan anemia are found to have a de-novo pathognomonic variant; this may be a result of alternate paternity or maternity, including assisted reproduction or adoption.[3] 

An international consensus advocates for a maximum prednisone dose of 0.3 mg/kg/d, increasing the pretransfusion threshold to a hemoglobin level of 9 to 10 g/dL (regardless of age), early chelation, and a greater focus on stem cell transplantation, as well as early cancer detection.[28] Young adults with Diamond-Blackfan anemia are at an increased risk of early cancers, especially colorectal and osteogenic sarcoma.

Enhancing Healthcare Team Outcomes

Effective management of Diamond-Blackfan anemia demands a cohesive, interprofessional strategy that prioritizes patient-centered care, safety, and long-term outcomes. Given the chronic nature and complexity of Diamond-Blackfan anemia, physicians, advanced practitioners, nurses, pharmacists, and other health professionals must collaborate closely to implement evidence-based treatment strategies. Physicians and hematology specialists bear primary responsibility for diagnosis, initiating corticosteroid therapy, coordinating blood transfusion schedules, and considering hematopoietic stem cell transplantation when necessary. Pharmacists contribute to patient care by educating patients about corticosteroid therapy, monitoring for adverse effects, ensuring accurate dosing, and performing comprehensive medication reconciliation to prevent harmful drug interactions. Nurses play a pivotal role in administering transfusions, monitoring clinical responses, and educating patients about iron overload, a common complication of repeated transfusions.[29][30][31] Obstetricians and labor and delivery nurses must provide high-risk counseling, as pregnancy can exacerbate or trigger relapses in Diamond-Blackfan anemia, requiring specialized prenatal and genetic care.

In addition to clinical management, supporting patients holistically requires integration of mental health, genetic counseling, and social services. Mental health nurses should offer counseling to address the psychological burden associated with chronic treatment and poor quality of life. Social workers assist patients in navigating financial challenges and accessing necessary care resources. Genetic counselors play a critical role in prenatal screening and education, particularly given the autosomal dominant inheritance pattern of Diamond-Blackfan anemia, which carries a 50% transmission risk.[3] Coordination of imaging studies and cardiac evaluations by radiology and cardiology teams enables early detection of renal, hepatic, or cardiac complications. Open, consistent communication among all team members enhances care continuity, reduces medical errors, and improves patient satisfaction. Through shared responsibilities and mutual respect across disciplines, the interprofessional team can optimize treatment efficacy, ensure patient safety, and promote long-term wellness in individuals living with Diamond-Blackfan anemia.

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Disclosure: Robert Killeen declares no relevant financial relationships with ineligible companies.

Disclosure: Christina Wills declares no relevant financial relationships with ineligible companies.