Fanconi Anemia
Epidemiology and Etiology:
- Rare
- Autosomal recessive
- Defects in a component of a multiprotein
complex required for DNA repair (Fanconi anemia
complex)
- Ashkenazi Jews (FANCC mutation)
Common sites:
- Kidney
- Spleen
- Bone (often thumbs, radii)
- Bone marrow
- Failure / hypoplasia
- Malignancies (10-33%)
- Skin
- Abnormal skin pigmentation
- malignancies
- H&N:
- Malignancies (squamous cell)
- Eyes
- Ear
- Oral cavity
- Urinary tract
- Heart
- GI
- Malformations
- Malignancies (squamous cell)
- CNS
- GU
- Hypogonadism
- Renal hypoplasia
- Malignancies
- Facies
- Characteristic “crowded” appearance
Gross features:
- Short stature / growth retardation
Histologic features:
Immunophenotype:
Marker:
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Sensitivity:
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Specificity:
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Molecular features:
- Fanconi
anemia complex of proteins (13 genes)
- BRCA2 is one of them (FANCD1)
- Spontaneous chromosomal aberrations:
- Chromatid breaks
- Exchanges
- Dicentrics
- Rings
- Premature chromosome condensation (PCC) maybe
- Micronuclei maybe
- High level of chromosomal damage in cultures
exposed to alkylating agents (ex. Mitomycin C (MMC),
diepoxybutane (DEB), HN2)
- Chromosome breakage study (peripheral blood)
- Culture cells with and without DNA interstrand cross-linking agent (ex. MMC, DEB)
- Solid stsaining
- 50 mets analyzed
- Chromosomal breakage and radials counted,
compared to control culture
- Chromatid breaks
- Chromosome breaks
- Exchanges
- Dicentrics
- If test is negative and FA is still clinically
suspected, should redo on another tissue (ex. skin fibroblasts) to rule
out mosaicism which can occur in the blood
- Also analyze 5 G-banded metaphases
- Cytogenetic findings in bone marrow may increase
over time
- Clonal 3q26-29 amplifications are associated
with a significantly increased risk for progression to MDS or AML
- Gene mutation analysis is difficult due to
number of possible genes involved
- G2 phase transit delay and blockage
- Flow cytometry can be
used for diagnosis
- Somatic mosaicism in
~25%
- Induced SCE frequencies are not grossly abnormal
usually
- AML in FA:
- Monosomy 7
- Translocations or duplications of 1q
Other features:
- Hypersensitivity to DNA cross-linking agents
- Hearing loss
- Hypogonadism
- Developmental delay
- Pancytopenia (presents within 1st
decade) (significant cause of mortality)
- Thrombocytopenia
- Leucopenia
- anemia
- Malignancy risk
- Hematologic (10-33%)
- Solid (28-29%)
- Difficult to treat due to chemo sensitivity in
FA
- Shortened life span (in the past survival was
rare beyond 20y)
- Mosaics have better prognosis
References:
·
Kumar V, Fausto
N, Abbas A. Robbins & Cotran Pathologic Basis of
Disease, Seventh Edition. 7th ed. Saunders; 2004.