Positive diepoxybutane test in only one of two brothers found to be compound heterozygotes for Fanconi's anaemia complementation group C mutations

Fanconi's anaemia (FA) is an autosomal recessive disorder characterized by diverse congenital abnormalities, the development of progressive bone marrow failure, and an increased predisposition to malignancy, particularly acute leukaemia. The FA phenotype is so variable that diagnosis on the basis of clinical manifestations alone can be difficult. The modern diagnosis of FA no longer rests entirely on the constellation of clinical and haematological abnormalities first described by Fanconi, but depends on finding elevated chromosomal breakage after incubation of peripheral blood lymphocytes with the chemical clastogens diepoxybutane (DEB) or mitomycin-C (MMC). The cloning of the gene for FA complementation group C [ FAC ] provides an opportunity to test the validity of the 'DEB test' which in recent times has become the main arbiter as to whether a patient is classified as FA or non-FA.
We report on two brothers with similar clinical and haematological features who have both been identified as compound heterozygotes for the FAC mutations L554P and ΔG322, but only one of the brothers has a positive DEB test. On the basis of the DEB test one would be classified as FA and the other as non-FA. The time has come to re-evaluate the diagnostic criteria of 'Fanconi's anaemia'.