Definition/General
Introduction:
Fanconi anemia (FA) is a rare inherited bone marrow failure syndrome characterized by progressive pancytopenia, congenital malformations, and cancer predisposition
It results from defects in DNA repair pathway leading to chromosomal instability
The disorder shows autosomal recessive or X-linked inheritance patterns.
Origin:
Results from mutations in DNA repair genes (FANC genes) involved in homologous recombination repair
Over 22 complementation groups (FANC-A to FANC-W) identified
The most common mutations are in FANCA (60-70%), FANCC (10-15%), and FANCG (10%) genes
DNA repair defect leads to chromosomal instability and cellular apoptosis.
Classification:
Classified by complementation groups: FANC-A (most common, 60-70%)
FANC-C (10-15% cases)
FANC-G (10% cases)
FANCD1/BRCA2 (severe phenotype)
FANCN/PALB2 (cancer predisposition)
Classical FA with typical features
Variant FA with atypical presentations.
Epidemiology:
Rare disorder with incidence of 1 in 160,000 births
Higher prevalence in certain populations (Ashkenazi Jews, South Africans)
Male predominance in some subtypes
Bone marrow failure typically develops in first decade
Cancer risk significantly elevated (500-700 fold for AML).
Clinical Features
Presentation:
Progressive bone marrow failure (pancytopenia)
Congenital malformations (60-75% cases)
Growth retardation and short stature
Skin pigmentation abnormalities (cafe-au-lait spots)
Skeletal malformations (radial ray defects)
Microcephaly and intellectual disability.
Symptoms:
Fatigue and weakness (anemia)
Bleeding tendency (thrombocytopenia)
Recurrent infections (neutropenia)
Growth retardation
Delayed sexual development
Feeding difficulties in infancy
Developmental delays.
Risk Factors:
Consanguineous parents
Family history of bone marrow failure
Ethnic predisposition (certain populations)
Sibling with FA
Parental carrier status
No environmental risk factors identified.
Screening:
Complete blood count (progressive cytopenias)
Chromosomal breakage test (gold standard)
DEB or MMC stress test
Bone marrow examination
Genetic testing for FANC mutations
Family screening and genetic counseling.
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Gross Description
Appearance:
Bone marrow aspirate shows progressive hypocellularity
Fatty replacement of hematopoietic tissue
Decreased cellularity affecting all lineages
Pale, hypocellular aspirate in advanced cases.
Characteristics:
Progressive pancytopenia with hypocellular marrow
Fatty infiltration replacing hematopoietic cells
Reduced megakaryocytes and erythroid precursors
Normal bone architecture initially
Complete aplasia in end-stage disease.
Size Location:
Affects all hematopoietic sites progressively
Axial skeleton primarily involved
Peripheral bones show fatty conversion early
Spleen and lymph nodes typically normal
No focal lesions or masses.
Multifocality:
Diffuse, progressive involvement of all bone marrow sites
Age-related progression from normocellular to hypocellular
Uniform pattern across different bones
Complete replacement by fat in severe cases.
Microscopic Description
Histological Features:
Progressive hypocellularity affecting all lineages (10-30% cellularity for age)
Decreased erythropoiesis with maturation defects
Reduced granulopoiesis and megakaryopoiesis
Increased fat cells and stromal elements
No dysplastic changes initially.
Cellular Characteristics:
Cytopenia in all lineages
Morphologically normal residual cells initially
Possible megaloblastic changes in erythroid cells
Decreased megakaryocytes
Stress hematopoiesis features may be present
No abnormal cells or infiltrates.
Architectural Patterns:
Preserved bone marrow architecture initially
Progressive fatty replacement
Reduced cellularity in all areas
Normal sinusoidal pattern
No fibrosis in early stages
Complete aplasia in advanced cases.
Grading Criteria:
Severity graded by cellularity percentage: Mild (30-50% cellularity)
Moderate (15-30% cellularity)
Severe (<15% cellularity)
Progression over time is characteristic
Pancytopenia severity correlates with cellularity.
Immunohistochemistry
Positive Markers:
CD34 highlights residual stem cells (decreased)
Glycophorin A marks residual erythroid cells
MPO highlights myeloid cells
CD61 identifies megakaryocytes
Reticulin stain shows normal pattern initially.
Negative Markers:
Viral markers typically negative
Lymphoid infiltrates usually absent
Plasma cells not increased
Fibroblastic markers negative initially
Abnormal cell markers negative.
Diagnostic Utility:
Quantifies residual hematopoietic cells
Assesses stem cell compartment
Excludes infiltrative processes
Demonstrates architectural preservation
Helps stage disease progression
Monitors treatment response.
Molecular Subtypes:
FANC-A subtype (most common)
FANC-C subtype (founder mutations)
FANC-D1/BRCA2 (severe phenotype)
FANC-G subtype
Rare complementation groups
Genotype-phenotype correlations.
Molecular/Genetic
Genetic Mutations:
FANCA mutations (60-70% cases)
FANCC mutations (10-15% cases)
FANCG mutations (10% cases)
FANCD1/BRCA2 mutations (severe phenotype)
FANCN/PALB2 mutations
22 complementation groups identified
Biallelic mutations in autosomal recessive forms.
Molecular Markers:
Chromosomal instability (hallmark feature)
Increased chromosomal breaks with DNA cross-linking agents
G2/M cell cycle arrest
Defective DNA repair
Increased sister chromatid exchanges
p53 pathway activation.
Prognostic Significance:
FANCD1/BRCA2 mutations have worst prognosis
FANCC mutations associated with earlier bone marrow failure
FANCA mutations variable severity
Cancer predisposition varies by subtype
Bone marrow transplant outcomes depend on subtype
Conditioning regimen sensitivity varies.
Therapeutic Targets:
Bone marrow transplantation (curative but risky)
Androgens (temporary improvement)
Growth factors (limited efficacy)
Gene therapy (experimental)
Reduced-intensity conditioning for transplant
Cancer surveillance protocols.
Differential Diagnosis
Similar Entities:
Aplastic anemia (acquired form)
Dyskeratosis congenita (telomere disorder)
Shwachman-Diamond syndrome (pancreatic insufficiency)
Constitutional aplastic anemia (other forms)
Myelodysplastic syndrome (dysplastic changes)
Paroxysmal nocturnal hemoglobinuria.
Distinguishing Features:
FA: Congenital malformations
FA: Chromosomal instability
FA: DNA cross-linker sensitivity
Aplastic anemia: No malformations
Aplastic anemia: Normal chromosomal stability
DC: Telomere defects
DC: Different clinical features
SDS: Pancreatic insufficiency
MDS: Dysplastic changes.
Diagnostic Challenges:
Distinguishing from acquired aplastic anemia
Identifying subtle malformations
Recognizing variant presentations
Chromosomal breakage testing technical requirements
Genetic counseling complexity
Cancer surveillance protocols.
Rare Variants:
FA without malformations (25-40% cases)
Late-onset FA (adult presentation)
Mosaic FA (somatic reversion)
FA with isolated thrombocytopenia
FA with malignancy at presentation
Atypical complementation groups.
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
Fanconi Anemia
Classification
Classification: Inherited bone marrow failure syndrome, [complementation group if known]
Bone Marrow Cellularity
Cellularity: [X]% for age (hypocellular), affecting all lineages
Lineage Assessment
Erythropoiesis: reduced. Granulopoiesis: reduced. Megakaryopoiesis: reduced
Morphological Features
Shows hypocellular bone marrow with fatty replacement and preserved architecture
Special Studies
Chromosomal breakage test: [result]
Genetic testing: recommend FANC gene panel
Immunohistochemistry: confirms reduced hematopoiesis
Clinical Correlation
Findings consistent with Fanconi anemia. Recommend genetic counseling and family screening
Final Diagnosis
Bone marrow showing changes consistent with Fanconi anemia