Definition/General
Introduction:
Dyskeratosis congenita (DC) is a rare inherited bone marrow failure syndrome caused by defects in telomere maintenance
It is characterized by the mucocutaneous triad of abnormal skin pigmentation, nail dystrophy, and oral leukoplakia
The disorder shows premature aging and high cancer predisposition.
Origin:
Results from mutations in telomerase complex genes leading to shortened telomeres
Key genes include TERC, TERT, DKC1, TINF2
Telomerase dysfunction causes premature cellular senescence
Affects highly proliferative tissues including bone marrow, skin, and mucosa
Progressive telomere shortening with each cell division.
Classification:
Classified by inheritance pattern: X-linked DC (DKC1 mutations)
Autosomal dominant DC (TERC, TERT mutations)
Autosomal recessive DC (multiple genes)
Classical DC with typical triad
Hoyeraal-Hreidarsson syndrome (severe form)
Revesz syndrome (with retinal changes).
Epidemiology:
Very rare disorder with incidence 1 in 1 million
Male predominance in X-linked form
Usually presents in childhood or adolescence
Bone marrow failure develops in 80-90% cases
Cancer risk significantly elevated (1000-fold increase).
Clinical Features
Presentation:
Mucocutaneous triad: abnormal skin pigmentation, nail dystrophy, oral leukoplakia
Progressive bone marrow failure
Growth retardation and short stature
Pulmonary fibrosis
Liver cirrhosis
Premature graying and hair loss.
Symptoms:
Fatigue and weakness (anemia)
Bleeding tendency (thrombocytopenia)
Recurrent infections (neutropenia)
Dyspnea (pulmonary fibrosis)
Developmental delays
Premature aging features
Gastrointestinal bleeding.
Risk Factors:
Family history of bone marrow failure
Consanguineous parents
Early onset cytopenias
Mucocutaneous features
Pulmonary complications
Cancer family history.
Screening:
Complete blood count (progressive cytopenias)
Telomere length measurement
Bone marrow examination
Genetic testing for telomerase genes
Pulmonary function tests
Cancer surveillance protocols.
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Gross Description
Appearance:
Bone marrow aspirate shows progressive hypocellularity
Fatty replacement of hematopoietic tissue
All lineages affected
Pale, hypocellular aspirate in advanced cases.
Characteristics:
Progressive pancytopenia with hypocellular marrow
Fatty infiltration replacing normal hematopoiesis
Preserved bone architecture initially
No dysplastic changes initially
Complete aplasia in end-stage.
Size Location:
Affects all hematopoietic sites progressively
Axial skeleton primarily involved
Peripheral bones show early changes
Diffuse pattern
No focal lesions.
Multifocality:
Progressive, uniform involvement
Age-related deterioration
Earlier onset than other bone marrow failure syndromes
Irreversible progression
Complete marrow failure eventual outcome.
Microscopic Description
Histological Features:
Progressive hypocellularity affecting all lineages
Cellularity <20% for age in advanced cases
Increased fat cells and stromal tissue
Reduced stem cell population
Normal morphology of residual cells initially.
Cellular Characteristics:
Morphologically normal hematopoietic cells initially
Decreased cell numbers in all lineages
Possible megaloblastic changes
Premature cellular senescence features
No abnormal infiltrates.
Architectural Patterns:
Preserved bone marrow architecture
Progressive fatty replacement
Reduced cellularity uniformly
Normal sinusoidal structure
No fibrosis initially
Complete aplasia in severe cases.
Grading Criteria:
Severity by cellularity percentage: Mild (30-50% cellularity)
Moderate (15-30% cellularity)
Severe (<15% cellularity)
Telomere length <1st percentile for age
Progressive deterioration over time.
Immunohistochemistry
Positive Markers:
CD34 shows decreased stem cells
Glycophorin A marks residual erythroid cells
MPO highlights myeloid cells
CD61 identifies megakaryocytes
Ki-67 shows low proliferation.
Negative Markers:
Viral markers typically negative
Abnormal cell markers negative
Lymphoid infiltrates usually absent
Blast markers negative initially
Fibroblastic markers negative.
Diagnostic Utility:
Quantifies residual hematopoietic cells
Assesses stem cell depletion
Demonstrates low proliferation
Excludes other disorders
Monitors disease progression
Confirms aplastic pattern.
Molecular Subtypes:
TERC-associated DC (autosomal dominant)
TERT-associated DC (autosomal dominant)
DKC1-associated DC (X-linked)
TINF2-associated DC (severe phenotype)
Other telomerase genes.
Molecular/Genetic
Genetic Mutations:
DKC1 mutations (X-linked form, 35% cases)
TERC mutations (autosomal dominant, 15% cases)
TERT mutations (autosomal dominant, 10% cases)
TINF2 mutations (severe phenotype)
Other genes: NOP10, NHP2, WRAP53
Haploinsufficiency mechanism.
Molecular Markers:
Short telomeres (<1st percentile for age)
Reduced telomerase activity
Premature cellular senescence
DNA damage response activation
p53 pathway upregulation
Chromosomal instability.
Prognostic Significance:
TINF2 mutations worst prognosis
DKC1 mutations variable severity
TERC/TERT mutations later onset
Telomere length correlates with severity
Earlier bone marrow failure worse outcome
Cancer risk very high.
Therapeutic Targets:
Androgens (temporary hematologic improvement)
Bone marrow transplantation (high risk procedure)
Reduced-intensity conditioning
Gene therapy (experimental)
Supportive care
Cancer surveillance.
Differential Diagnosis
Similar Entities:
Aplastic anemia (acquired)
Fanconi anemia (DNA repair defect)
Shwachman-Diamond syndrome (pancreatic insufficiency)
Diamond-Blackfan anemia (pure red cell aplasia)
Telomerase RNA component disorders
Idiopathic pulmonary fibrosis.
Distinguishing Features:
DC: Mucocutaneous triad
DC: Short telomeres
DC: Pulmonary fibrosis
AA: No distinctive features
AA: Normal telomeres
FA: Chromosomal instability
FA: DNA cross-linker sensitivity
SDS: Pancreatic insufficiency
SDS: Skeletal abnormalities.
Diagnostic Challenges:
Recognizing mucocutaneous features
Telomere length testing availability
Distinguishing from acquired aplastic anemia
Identifying variant presentations
Genetic testing complexity
Family screening issues.
Rare Variants:
Hoyeraal-Hreidarsson syndrome (severe, early onset)
Revesz syndrome (with retinal changes)
Coats plus syndrome
Atypical DC without full triad
Late-onset DC
Pulmonary fibrosis predominant form.
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
Dyskeratosis Congenita
Classification
Classification: Inherited bone marrow failure syndrome with telomere defect
Bone Marrow Cellularity
Cellularity: [X]% for age (hypocellular), affecting all lineages
Lineage Assessment
Pancytopenia with reduced erythropoiesis, granulopoiesis, and megakaryopoiesis
Morphological Features
Shows hypocellular bone marrow with fatty replacement and preserved architecture
Special Studies
Telomere length: [if performed]
Genetic testing: recommend telomerase gene panel
Clinical correlation: mucocutaneous features
Clinical Correlation
Findings consistent with dyskeratosis congenita. Recommend genetic counseling
Final Diagnosis
Bone marrow showing changes consistent with dyskeratosis congenita