Fanconi anemia and its diagnosis

Abstract

Fanconi anemia (FA) is a genetically and phenotypically heterogeneous recessive disorder characterized by diverse congenital malformations, progressive pancytopenia, and predisposition to both hematologic malignancies and solid tumors. Congenital anomalies vary from patient to patient and may affect skeletal morphogenesis as well as any of the major organ systems. Although this highly variable phenotype makes accurate diagnosis on the basis of clinical manifestations difficult in some patients, laboratory study of chromosomal breakage induced by diepoxybutane (DEB) or other crosslinking agents provides a unique cellular marker for the diagnosis of the disorder either prenatally or postnatally. Diagnosis based on abnormal response to DNA crosslinking agents can be used to identify the pre-anemia patient as well as patients with aplastic anemia or leukemia who may or may not have the physical stigmata associated with the syndrome. This overview will present our current knowledge regarding the varied phenotypic manifestations of FA and procedures for diagnosis based upon abnormal DNA damage responses.

Figure 1

Fifteen-year-old female monozygous twin pair homozygous for deletion of exons 30 and 31 of FANCA. In panel A, Twin A (on left) had a bifid right thumb (surgically repaired), hypoplastic left thumb and absent left clavicle. Twin B (on right) had unilateral absence of the radius, bilateral absent thumbs, and absent right clavicle. The hands of Twin A are seen in panel B; the hands of Twin B are seen in panel C.

Figure 2

A, Part of a metaphase spread of a Fanconi anemia (FA) lymphocyte showing spontaneous chromatid aberrations. B, Part of a metaphase spread of an FA lymphocyte treated with 0.1 μ/ml of diepoxybutane (DEB). Multiple complex chromatid exchange figures are seen. (From Auerbach et al. Pediatrics 67 (1981) 128–138, by permission).

Figure 3

Comparison of FA and non-FA cells. Data is expressed as breaks/cell (A) and breaks/aberrant cell (B). 98.9% of patients diagnosed as FA and none of the patients diagnosed as non-FA had greater than 0.65 mean breaks/cell. 96.6% of non-FA subjects and 0% of FA patients had less than 0.09 mean breaks/cell. Only a small number of affected individuals could not be discriminated on the basis of mean breaks/cell.

Figure 4

About 10% of FA patients have 50% or less of their cells exhibiting chromosomal abnormalities after treatment with 0.1 μ/ml of diepoxybutane (DEB). About 20% of FA patients have 75% or less aberrant cells with this treatment. Discrimination between FA subjects with very highly skewed mosaicism and non-FA subjects was uncertain in less than 2% of cases tested. It is recommended that retesting (or testing of another tissue such as skin fibroblasts) be performed in these cases.