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A child with short stature, absent thumbs, and café-au-lait spots develops progressive pancytopenia at age 7. Chromosome breakage testing with DEB is positive.
AR (most) or XLR; 23+ genes
- FANCA most common (~60%)
- FA pathway: DNA interstrand crosslink repair
- Physical abnormalities: Radial ray (thumb, radius), café-au-lait spots, short stature, microcephaly, renal anomalies
- Hematologic: Progressive bone marrow failure (pancytopenia)
- Cancer predisposition: MDS, AML, squamous cell carcinomas (head/neck, anogenital)
- Chromosome breakage with DEB or MMC
- Chromosome breakage testing with diepoxybutane (DEB) or mitomycin C (MMC) is the gold standard: excessive chromosomal breaks and radial figures confirm the diagnosis
- CBC shows progressive pancytopenia; bone marrow evaluation assesses hypocellularity, MDS, and clonal cytogenetic changes
- Molecular testing of the FA gene panel (including FANCA) confirms the complementation group and enables carrier and prenatal testing; somatic mosaicism can cause false-negative blood breakage tests, so fibroblast testing may be needed
- HSCT (for marrow failure), cancer surveillance
Fanconi = Fingers (missing thumb): Imagine a fan shredding the entire bone marrow and thumbs. Radial ray anomalies (absent thumbs/radii) are a hallmark.
"Fanboni" anemia has bone marrow failure: First comes thrombocytopenia, then neutropenia, then anemia (pancytopenia). Distinguish from Diamond-Blackfan anemia (RBC aplasia only).
AR cancer genes causing Fanconi: Biallelic (AR) variants in BRCA2, BRIP1, PALB2, or RAD51C cause Fanconi anemia, while heterozygous (AD) variants in these same genes cause cancer predisposition.