PHYSICAL AND LABORATORY CHARACTERISTICS OF HETEROZYGOTE CARRIERS OF THE FANCONI APLASIA GENE

Fanconi anaemia (FA) is a recessively inherited disorder associated with a typical physical appearance and a spectrum of clinical and laboratory characteristics. Parental heterozygotes of FA patients are superficially normal in appearance and lack overt laboratory abnormalities. Furthermore, they are indistinguishable from normal subjects on chromosome analysis. In order to determine if any of the clinical or laboratory abnormalities seen in FA patients were detectable to a lesser degree in heterozygotes, we carried out detailed skeletal measurement and laboratory investigation on 16 obligate FA heterozygotes and compared the results with 40 normal control subjects. Skeletal proportions in FA heterozygotes showed significant differences from normal subjects in the ratio of the height to the inter-acromial distance (p<0.001), and in having significantly shorter forearms (p<0.05). Apart from two patients with presumed iron deficiency, haemoglobin levels were normal, but three patients showed neutropenia (<1.5 x 109/l). Foetal haemoglobin measurements were significantly higher (p<0.01) and natural killer cell subsets lower (p<0.05) in heterozygotes. Significantly reduced mitogenic responses to phytohaemagglutinin and interleukin-2 of peripheral blood lymphocytes in heterozygotes was also demonstrated. These results suggest that heterozygotes show minor physical and haematological abnormalities consistent with partial expression of the Fanconi gene in the heterozygote.