Definition/General
Introduction:
Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare inherited bone marrow failure syndrome characterized by severe thrombocytopenia and absent or markedly reduced megakaryocytes in the bone marrow
It results from MPL gene mutations affecting the thrombopoietin receptor and progresses to pancytopenia and aplastic anemia.
Origin:
Results from mutations in MPL gene encoding the thrombopoietin receptor (c-Mpl)
Loss of function mutations lead to defective megakaryopoiesis
The disorder shows autosomal recessive inheritance
Thrombopoietin levels are elevated but ineffective due to receptor defects
Progressive bone marrow failure develops over time.
Classification:
Classified into two types based on severity: Type I CAMT (complete absence of megakaryocytes)
Type II CAMT (reduced but present megakaryocytes)
Type I has earlier progression to aplastic anemia
Type II has slower progression
Both types show MPL mutations but different severity.
Epidemiology:
Very rare disorder with less than 100 cases reported worldwide
Equal gender distribution
Presents in neonatal period or early infancy
Consanguinity common in affected families
Higher incidence in certain populations with founder effects.
Clinical Features
Presentation:
Severe thrombocytopenia from birth (platelet count <50,000/μL)
Bleeding manifestations (petechiae, bruising, mucosal bleeding)
No physical malformations (unlike TAR syndrome)
Normal birth weight and length
Progressive cytopenias develop over time.
Symptoms:
Bleeding tendency from birth
Petechiae and purpura
Mucosal bleeding (nosebleeds, gum bleeding)
Intracranial hemorrhage (life-threatening)
Gastrointestinal bleeding
Progressive fatigue (developing anemia)
Recurrent infections (neutropenia develops).
Risk Factors:
Consanguineous parents
Family history of thrombocytopenia
Sibling with CAMT
Ethnic predisposition in certain populations
Parental carrier status
No environmental risk factors identified.
Screening:
Complete blood count (severe thrombocytopenia)
Bone marrow examination (absent megakaryocytes)
Thrombopoietin levels (markedly elevated)
Genetic testing for MPL mutations
Family screening and genetic counseling.
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Gross Description
Appearance:
Bone marrow aspirate shows normal to increased cellularity initially
Absent or markedly reduced megakaryocytes
Normal erythropoiesis and granulopoiesis initially
Progressive hypocellularity develops over time.
Characteristics:
Selective megakaryocytic aplasia initially
Normal other lineages in early stages
Progressive pancytopenia develops
Fatty replacement in advanced stages
No abnormal cells or infiltrates.
Size Location:
Affects all hematopoietic sites
Uniform pattern of megakaryocyte absence
Progressive involvement of other lineages
No focal lesions
Spleen normal initially.
Multifocality:
Diffuse absence of megakaryocytes from birth
Progressive bone marrow failure
Age-related deterioration
Complete aplasia eventual outcome
Irreversible progression.
Microscopic Description
Histological Features:
Absent or markedly reduced megakaryocytes (<1% of expected)
Normal erythropoiesis initially
Normal granulopoiesis initially
Progressive hypocellularity develops
Increased fat content over time.
Cellular Characteristics:
Complete absence of megakaryocytes in Type I
Rare, dysplastic megakaryocytes in Type II
Normal morphology of other lineages initially
Progressive cytopenias all lineages
No abnormal cells.
Architectural Patterns:
Preserved bone marrow architecture initially
Selective megakaryocytic depletion
Progressive fatty replacement
Normal sinusoidal pattern
No fibrosis initially.
Grading Criteria:
Type I: Complete megakaryocyte absence
Type II: <10% expected megakaryocytes
Platelet count consistently <50,000/μL
Progressive severity over time
Thrombopoietin levels >10-fold elevated.
Immunohistochemistry
Positive Markers:
CD61 and CD41 highlight rare megakaryocytes (if present)
Factor VIII marks megakaryocytes
Glycophorin A shows normal erythropoiesis
MPO highlights normal granulopoiesis
CD34 shows stem cells.
Negative Markers:
Megakaryocyte markers essentially negative (CD61, CD41)
Platelet-specific markers absent
Viral markers negative
Abnormal cell markers negative
Lymphoid markers not increased.
Diagnostic Utility:
Confirms megakaryocyte absence
Quantifies residual megakaryocytes
Demonstrates normal other lineages
Excludes infiltrative processes
Monitors disease progression
Confirms selective defect.
Molecular Subtypes:
Type I CAMT (severe MPL mutations)
Type II CAMT (mild MPL mutations)
Different mutation types affect severity
Frameshift mutations more severe
Missense mutations milder phenotype.
Molecular/Genetic
Genetic Mutations:
MPL gene mutations (chromosome 1p34)
Biallelic mutations required (autosomal recessive)
Frameshift mutations (severe phenotype)
Nonsense mutations (severe phenotype)
Missense mutations (milder phenotype)
Over 30 mutations described.
Molecular Markers:
Elevated thrombopoietin levels (>10-fold)
Defective c-Mpl receptor
Normal megakaryocyte transcription factors
Absent platelet production
Normal stem cell markers
Progressive bone marrow failure.
Prognostic Significance:
Type I progresses to aplastic anemia within 5 years
Type II slower progression (>5 years)
Severe mutations earlier bone marrow failure
Bone marrow transplant curative
Without transplant fatal outcome
Gene therapy experimental.
Therapeutic Targets:
Bone marrow transplantation (curative therapy)
Platelet transfusions (supportive)
Thrombopoietin receptor agonists (ineffective)
Gene therapy (experimental)
Supportive care
Bleeding prevention.
Differential Diagnosis
Similar Entities:
Thrombocytopenia with absent radii (TAR syndrome)
Acquired amegakaryocytic thrombocytopenia
Wiskott-Aldrich syndrome
Immune thrombocytopenic purpura
Aplastic anemia (with thrombocytopenia)
Megakaryoblastic leukemia.
Distinguishing Features:
CAMT: No radial ray defects
CAMT: Absent megakaryocytes from birth
CAMT: MPL mutations
TAR: Bilateral radial aplasia
TAR: Megakaryocytes present
WAS: Small platelets
WAS: Immunodeficiency
ITP: Normal megakaryocytes
ITP: Antiplatelet antibodies.
Diagnostic Challenges:
Distinguishing from TAR syndrome
Confirming genetic etiology
Identifying carrier parents
Bone marrow timing for diagnosis
Genetic counseling complexity
Transplant timing decisions.
Rare Variants:
Atypical CAMT with delayed onset
CAMT with mild phenotype
Compound heterozygous mutations
Associated malformations (rare)
Familial clustering
Ethnic-specific mutations.
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
Congenital Amegakaryocytic Thrombocytopenia
Classification
Classification: [Type I/Type II] congenital amegakaryocytic thrombocytopenia
Bone Marrow Cellularity
Cellularity: [X]% for age, with selective megakaryocytic aplasia
Lineage Assessment
Megakaryopoiesis: absent/markedly reduced. Erythropoiesis: normal. Granulopoiesis: normal
Morphological Features
Shows absent or markedly reduced megakaryocytes with normal other lineages
Special Studies
CD61/CD41: confirms megakaryocyte absence
Genetic testing: recommend MPL gene analysis
Thrombopoietin level: [if available]
Clinical Correlation
Findings consistent with congenital amegakaryocytic thrombocytopenia
Final Diagnosis
Bone marrow showing congenital amegakaryocytic thrombocytopenia