Definition/General
Introduction:
Diamond-Blackfan anemia (DBA) is a rare congenital pure red cell aplasia characterized by ribosomal protein gene mutations
It presents with severe anemia in infancy and is associated with growth retardation and congenital malformations
The disorder affects erythropoiesis specifically while other cell lineages remain normal.
Origin:
Results from mutations in ribosomal protein genes leading to ribosomal dysfunction
The most common mutation is in RPS19 gene (25% cases)
Other genes include RPS26, RPS24, RPL5, RPL11
The ribosomal defect specifically affects erythroid progenitor cells leading to apoptosis of erythroid precursors.
Classification:
Classified based on genetic mutations: RPS19-associated DBA (most common)
RPS26-associated DBA
RPL5-associated DBA
Other ribosomal protein mutations
Classical DBA with typical features
Non-classical DBA with atypical presentation
Steroid-responsive vs steroid-resistant forms.
Epidemiology:
Rare disorder with incidence of 4-7 per million births
Typically presents in first year of life (90% by 1 year)
Equal male and female distribution
Autosomal dominant inheritance in 45% cases
De novo mutations in 55% cases
Associated with congenital malformations in 30-50% cases.
Clinical Features
Presentation:
Severe anemia presenting in infancy (usually <6 months)
Growth retardation and failure to thrive
Congenital malformations (30-50% cases)
Craniofacial abnormalities
Cardiac defects
Thumb and upper limb malformations
Pallor and fatigue in infants.
Symptoms:
Severe anemia symptoms in infancy
Feeding difficulties
Irritability and lethargy
Shortness of breath
Recurrent infections (mild)
Delayed developmental milestones
Growth retardation
Heart failure in severe cases.
Risk Factors:
Family history (45% inherited cases)
Parental consanguinity
Advanced maternal age
Genetic counseling indicated for affected families
Prenatal diagnosis available for known mutations
No environmental risk factors identified.
Screening:
Complete blood count in anemic infants
Reticulocyte count (markedly low)
Bone marrow examination
Genetic testing for ribosomal protein mutations
Family screening for known mutations
Fetal hemoglobin levels (elevated).
Master Diamond-Blackfan Anemia Pathology with RxDx
Access 100+ pathology videos and expert guidance with the RxDx app
Gross Description
Appearance:
Bone marrow aspirate shows reduced erythroid precursors
Normal myeloid and megakaryocytic elements
Aspirate may appear pale and hypocellular for erythroid lineage
No abnormal cells or infiltrates.
Characteristics:
Selective erythroid hypoplasia with normal other lineages
Increased bone marrow fat in erythroid areas
Normal trabecular architecture
No fibrosis or dysplastic changes
Normal sinusoidal pattern.
Size Location:
Affects all hematopoietic sites uniformly
Vertebral bodies and pelvic bones primarily affected
No focal lesions
Diffuse pattern of erythroid depletion
Normal splenic and lymph node architecture.
Multifocality:
Uniform involvement of all bone marrow sites
Consistent pattern across different bones
No geographic variation
Lifelong persistent pattern
Progressive fatty replacement in untreated cases.
Microscopic Description
Histological Features:
Marked reduction of erythroid precursors (<5% of nucleated cells)
Normal granulopoiesis with complete maturation
Normal megakaryopoiesis
Increased myeloid-to-erythroid ratio (>10:1)
No dysplastic changes in any lineage.
Cellular Characteristics:
Residual erythroid cells show normal morphology
Maturation arrest at pronormoblast stage
Giant pronormoblasts occasionally present
Normal granulocyte morphology
Normal megakaryocyte morphology and number
No abnormal cells.
Architectural Patterns:
Preserved bone marrow architecture
Selective erythroid depletion areas
Normal myeloid island distribution
Normal megakaryocyte distribution
Increased fatty tissue in erythroid zones
No fibrosis or infiltration.
Grading Criteria:
Severity assessed by erythroid percentage: Severe (<2% erythroid cells)
Moderate (2-5% erythroid cells)
Hemoglobin levels typically <6-8 g/dL
Reticulocyte count <1%
MCV often elevated for age.
Immunohistochemistry
Positive Markers:
Glycophorin A highlights residual erythroid cells
Hemoglobin F (elevated in residual cells)
CD71 marks early erythroid precursors
CD34 shows normal stem cell population
MPO highlights normal myeloid cells.
Negative Markers:
Viral markers typically negative
Lymphoid markers (CD20, CD3) negative in infiltrates
Plasma cell markers negative
Blastic markers negative except normal stem cells.
Diagnostic Utility:
Confirms selective erythroid aplasia
Quantifies residual erythroid cells
Demonstrates normal other lineages
Excludes viral etiology
Helps distinguish from aplastic anemia
Shows elevated HbF in residual cells.
Molecular Subtypes:
RPS19-associated DBA (25% cases)
RPS26-associated DBA (mild phenotype)
RPL5-associated DBA (craniofacial malformations)
Other ribosomal protein mutations
Genotype-phenotype correlations emerging.
Molecular/Genetic
Genetic Mutations:
RPS19 mutations (25% of DBA cases)
RPS26 mutations (7% cases)
RPS24, RPL5, RPL11 mutations
RPS17, RPS7, RPL35A mutations
Over 20 ribosomal protein genes implicated
Haploinsufficiency mechanism in most cases.
Molecular Markers:
Elevated adenosine deaminase (ADA) activity
Elevated fetal hemoglobin (HbF) levels
Elevated eADA/ADA ratio
Reduced ribosomal protein expression
p53 pathway activation
Impaired ribosome biogenesis.
Prognostic Significance:
RPS19 mutations often steroid-responsive
RPL5 mutations associated with malformations
RPS26 mutations milder phenotype
Steroid responsiveness predicts better outcome
Cancer predisposition (colorectal cancer risk)
Long-term complications with chronic transfusions.
Therapeutic Targets:
Corticosteroids (first-line therapy, 80% initial response)
Chronic transfusion therapy
Iron chelation for transfusion-dependent patients
Bone marrow transplantation for refractory cases
Gene therapy (experimental)
Leucine supplementation (investigational).
Differential Diagnosis
Similar Entities:
Transient erythroblastopenia of childhood (TEC)
Acquired pure red cell aplasia
Parvovirus B19 infection
Blackfan-Diamond syndrome variants
Congenital dyserythropoietic anemia
Thalassemia major.
Distinguishing Features:
DBA: Congenital presentation
DBA: Congenital malformations
DBA: Elevated ADA levels
TEC: Transient nature
TEC: Normal ADA levels
TEC: No malformations
Parvovirus: Giant pronormoblasts
Parvovirus: Viral serology positive
Acquired PRCA: Adult onset.
Diagnostic Challenges:
Distinguishing from TEC in infancy
Identifying underlying genetic mutations
Recognizing atypical presentations
Differentiating from other congenital anemias
Genetic counseling complexity
Steroid responsiveness assessment.
Rare Variants:
Non-classical DBA (late onset)
Steroid-resistant DBA
DBA with minimal malformations
Adult-onset DBA (rare)
Cancer-predisposition syndrome
Subclinical DBA in families.
Sample Pathology Report
Template Format
Sample Pathology Report
Complete Report: This is an example of how the final pathology report should be structured for this condition.
Specimen Information
Bone marrow aspirate and biopsy from [site], adequate for evaluation
Diagnosis
Diamond-Blackfan Anemia
Classification
Classification: Congenital pure red cell aplasia, [genetic subtype if known]
Bone Marrow Cellularity
Cellularity: [X]% for age, with selective erythroid hypoplasia
Lineage Assessment
Erythropoiesis: markedly reduced ([X]% of nucleated cells). Granulopoiesis: normal for age. Megakaryopoiesis: normal for age
Morphological Features
Shows selective erythroid aplasia with myeloid-to-erythroid ratio of [X]:1
Special Studies
Glycophorin A: highlights residual erythroid cells
ADA levels: [if performed]
Genetic testing: [recommend specific genes]
Clinical Correlation
Findings consistent with Diamond-Blackfan anemia. Recommend genetic testing and family counseling
Final Diagnosis
Bone marrow showing Diamond-Blackfan anemia (congenital pure red cell aplasia)