Clinical Features of Fanconi Anaemia

Abstract

Fanconi anaemia is an autosomal recessive disorder in which patients develop bone marrow failure and aplastic anaemia but this can occur at widely differing ages from the first year to age 12 years or more. This means that often the diagnosis is made before the onset of any haematological abnormality is apparent. Many, but not all, FA patients have quite severe congenital abnormalities and so the unusual sensitivity of FA peripheral blood lymphocytes to DNA crosslinking agents has been an important part of the diagnosis in FA. FA patients, however, may have neither bone marrow failure nor congenital abnormalities, when a diagnosis of FA is suspected and this has led to occasional confusion with Nijmegen Breakage syndrome where there is also unusual sensitivity to DNA crosslinking agents. In contrast cells from FA patients, with some rare exceptions, do not show an increased sensitivity to ionising radiation. The absence of particular FANC proteins can result in a more severe phenotype; for example the predisposition to both the presence of congenital abnormalities with early diagnosis in patients with FANCD2 mutations and very early onset of myeloid or lymphoid leukaemia as well as carcinomas in the case of patients with FANCD1 mutations. The pathogenesis of bone marrow failure and congenital abnormalities is not understood in the context of the loss of particular FANC proteins. In addition, the number of genes identified is fairly large and their exact roles in the FA pathways have not yet been fully worked out. Although the cellular targets for these different FA proteins and the FA pathway have not yet been elucidated there appears to be a role for the FA proteins in homology directed repair of DNA double strand breaks.