Fanconi anaemia (FA) is an autosomal recessive inherited disorder characterized by progressive aplastic anaemia, multiple congenital abnormalities and predisposition to malignancies, including leukaemia and solid tumours.1-5

The developmental abnormalities include radial aplasia, hyperpigmentation of the skin, growth retardation, micropthalmia and malformation of the kidneys (Table 14.1).6,7

The disorder generally presents as aplastic anaemia between the ages of 5 and 10 years, but the diagnosis may be made much earlier if characteristic developmental abnormalities are present, or if there is a family history. However, the diagnosis may also be made much later, some cases having presented as young adults with acute myeloid leukaemia (AML).8 The variability in the clinical phenotype of FA is independent of geographical and racial background, and is evident even among siblings with consanguineous parents.3,9 This suggests that embryonic development can be affected at different stages, without precise targeting of a particular organ system.10-12 FA is a rare disease with an incidence of 1 in 200 000-400 000 live births,10,13 and the heterozygote frequency is estimated to be 1 in 200. However, it is more common in some populations, with carrier frequencies of about 1 in 90 reported in South African Afrikaners and Ashkenazi Jews.14,15 The disorder is genetically heterogeneous, with eight complementation groups (A, B, C, D1, D2, E, F and G) having been described

During a period of almost 40 years from the first case report in 1927,16 FA was diagnosed by the concurrence of aplastic anaemia with physical abnormalities (see details in Table 14.1). In 1964, increased chromosomal breakage was observed in lymphoblasts and fibroblasts derived from FA patients,17,18 and later it was discovered that cells

from FA patients were hypersensitive to DNA interstrand cross-linking agents (ICLs).19-22 This discovery provided the basis for sensitive and specific laboratory tests for FA, using DNA ICLs, such as diepoxybutane (DEB) and mitomycin C (MMC), to induce chromosome breakage.23,24 In view of the highly variable clinical presentation of FA, this test, in conjunction with the assessment of haematological and physical abnormalities and family history, is important in confirming the diagnosis of FA. Assessment of the chromosome breakage test result may be complicated by the presence of two cell populations, one sensitive and one resistant to the cross-linker. At least some of these cases arise as a result of somatic mosaicism (see later section on genotype/phenotype correlations). The cloning of seven genes mutated in FA has recently led to the development of two additional diagnostic procedures. One of these takes advantage of the observation that the FANCD2 protein is monoubiquitinated in normal but not in FA cells. Primary lymphocytes are analysed for FANCD2 monoubiquination by immunoblotting. The absence of the monoubiquitinated FANCD2 isoform has been found to correlate with the diagnosis of FA by DEB testing.25 Subtyping of the complementation groups can now be achieved by transfection of retroviral vectors containing the cDNA of the various FA genes into primary T cells from FA patients, which are then tested for correction of ICL hypersensitivity.26