Definition/General
Introduction:
Thrombocytopenia with absent radii (TAR syndrome) is a rare congenital disorder characterized by bilateral absence of radii and severe thrombocytopenia
Unlike other inherited thrombocytopenias, megakaryocytes are present in the bone marrow but show functional abnormalities
The condition shows autosomal recessive inheritance.
Origin:
Results from compound inheritance involving RBM8A gene and regulatory SNPs
The RBM8A gene deletion combined with hypomorphic alleles leads to disease
Nonsense-mediated decay pathway is affected
The disorder affects megakaryocyte function rather than number
Platelet production defect is the primary abnormality.
Classification:
Classified based on severity of thrombocytopenia: Severe TAR (platelet count <10,000/μL)
Moderate TAR (platelet count 10,000-50,000/μL)
Typical TAR with bilateral radial aplasia
Atypical TAR with partial radial defects
Early-onset vs late-improving forms.
Epidemiology:
Very rare disorder with incidence 1 in 240,000 births
Equal gender distribution
Bilateral radial defects in 100% cases
Severe thrombocytopenia in neonatal period
Improvement over time in many cases
Consanguinity increases risk.
Clinical Features
Presentation:
Bilateral absent radii (pathognomonic feature)
Severe thrombocytopenia at birth
Thumbs present (distinguishes from Fanconi anemia)
Bleeding manifestations in neonatal period
Growth retardation
Cow milk intolerance common.
Symptoms:
Bleeding tendency from birth
Petechiae and bruising
Intracranial hemorrhage (life-threatening)
Gastrointestinal bleeding
Feeding difficulties
Recurrent diarrhea (milk intolerance)
Joint contractures.
Risk Factors:
Consanguineous parents
Family history of limb defects
Carrier parents (both required)
Specific ethnic populations
Previous affected sibling
No environmental risk factors identified.
Screening:
Complete blood count (severe thrombocytopenia)
Bone marrow examination (normal/increased megakaryocytes)
Skeletal survey (bilateral radial aplasia)
Genetic testing for RBM8A deletions
Family screening and counseling.
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Gross Description
Appearance:
Bone marrow aspirate shows normal to increased cellularity
Normal or increased megakaryocytes
Megakaryocytes appear morphologically normal
Normal erythropoiesis and granulopoiesis
No abnormal cells.
Characteristics:
Normocellular bone marrow
Adequate megakaryocyte numbers
Normal megakaryocyte morphology
No dysplastic changes
Normal bone architecture
No fibrosis or infiltrates.
Size Location:
Normal bone marrow distribution
All hematopoietic sites show similar pattern
No focal abnormalities
Normal spleen and lymph nodes
Skeletal defects in radius and forearm.
Multifocality:
Uniform bone marrow pattern
Consistent findings across sites
No geographic variation
Stable over time in most cases
Improvement possible with age.
Microscopic Description
Histological Features:
Normal bone marrow cellularity for age
Normal or increased megakaryocytes (contrast to CAMT)
Morphologically normal megakaryocytes
Normal erythropoiesis
Normal granulopoiesis
No dysplastic changes.
Cellular Characteristics:
Megakaryocytes normal size and morphology
Normal nuclear segmentation
Adequate cytoplasm
Normal platelet budding (may be reduced functionally)
No abnormal megakaryocytes
Other lineages normal.
Architectural Patterns:
Normal bone marrow architecture
Appropriate megakaryocyte distribution
Normal sinusoidal pattern
No fibrosis
No abnormal infiltrates
Age-appropriate cellularity.
Grading Criteria:
Severity by platelet count: Severe (<10,000/μL)
Moderate (10,000-50,000/μL)
Megakaryocyte count normal or increased
Functional platelet defect primary issue
Improvement over time common.
Immunohistochemistry
Positive Markers:
CD61 and CD41 highlight normal megakaryocytes
Factor VIII marks megakaryocytes
Glycophorin A shows normal erythropoiesis
MPO highlights normal granulopoiesis
CD34 shows normal stem cells.
Negative Markers:
Viral markers negative
Abnormal cell markers negative
Dysplastic markers negative
Fibroblastic markers negative
Infiltrative markers negative.
Diagnostic Utility:
Confirms normal megakaryocyte presence
Demonstrates normal morphology
Excludes aplastic processes
Quantifies megakaryocyte numbers
Distinguishes from CAMT
Shows functional defect.
Molecular Subtypes:
RBM8A deletion with hypomorphic alleles
Different SNP combinations
Variable expressivity
Compound heterozygous patterns
Ethnic-specific variants.
Molecular/Genetic
Genetic Mutations:
RBM8A gene deletions (chromosome 1q21.1)
Compound inheritance with regulatory SNPs
Hypomorphic alleles required
Nonsense-mediated decay pathway affected
Two-hit model for disease development.
Molecular Markers:
Reduced RBM8A expression
Defective mRNA processing
Normal megakaryocyte numbers
Functional platelet defects
Normal coagulation studies
Thrombopoietin levels variable.
Prognostic Significance:
Neonatal period most dangerous
Improvement with age common
Platelet counts increase over time
Bleeding risk decreases
Good long-term prognosis if survive infancy
No malignancy predisposition.
Therapeutic Targets:
Platelet transfusions (neonatal period)
Avoid cow milk (intolerance common)
Supportive care
Orthopedic management for limb defects
No specific drug therapy
Genetic counseling.
Differential Diagnosis
Similar Entities:
Congenital amegakaryocytic thrombocytopenia
Fanconi anemia (with radial defects)
Wiskott-Aldrich syndrome
Immune thrombocytopenic purpura
VACTERL association
Holt-Oram syndrome.
Distinguishing Features:
TAR: Thumbs present
TAR: Normal megakaryocytes
TAR: Bilateral radial aplasia
CAMT: Absent megakaryocytes
FA: Thumbs absent
FA: Chromosomal instability
WAS: Small platelets
WAS: Immunodeficiency
Holt-Oram: Cardiac defects.
Diagnostic Challenges:
Distinguishing from Fanconi anemia
Confirming genetic diagnosis
Assessing megakaryocyte function
Family counseling complexity
Prognosis prediction
Treatment timing.
Rare Variants:
Atypical TAR with partial radial defects
Unilateral radial involvement (rare)
TAR with additional malformations
Late-improving phenotype
Mild thrombocytopenia variant.
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
Thrombocytopenia with Absent Radii (TAR Syndrome)
Classification
Classification: Congenital thrombocytopenia syndrome with limb defects
Bone Marrow Cellularity
Cellularity: [X]% for age (normal), with adequate megakaryopoiesis
Lineage Assessment
Megakaryopoiesis: normal/increased numbers with normal morphology. Erythropoiesis: normal. Granulopoiesis: normal
Morphological Features
Shows normal bone marrow with adequate megakaryocytes of normal morphology
Special Studies
CD61/CD41: highlights normal megakaryocytes
Genetic testing: recommend RBM8A analysis
Clinical correlation: bilateral radial aplasia
Clinical Correlation
Findings consistent with TAR syndrome. Recommend genetic counseling
Final Diagnosis
Bone marrow consistent with thrombocytopenia with absent radii (TAR syndrome)