ABSTRACT
Fanconi anemia (FA) is an autosomal recessive genetic condition that was first described by the Swiss pediatrician Guido Fanconi in 1927 (1). FA is caused by homozygous or by compound heterozygous mutations in a number of genes that maintain genomic stability and thus are important for normal aging. The phenotypic features of FA consist of a combination of developmental and somatic abnormalities, including alterations that are reminiscent of premature aging. Developmental defects dominate the clinical phenotype in 70% of patients with FA (2,3). Truly progeroid features are less conspicuous in FA than in the classic progeroid syndromes, and decline of bone marrow function is a much more progressive and devastating event in FA than in normal aging. This may be the reason why Martin and Oshima (4) did not include FA in their tabulation of human genetic instability syndromes with progeroid manifestations. Features such as radial ray defects, pigmentary changes, urogenital malformations, and short stature clearly belong to the category of developmental defects, whereas endocrinopathies, myelodysplastic syndrome, increased incidence, and early onset of squamous cell carcinomas may reflect premature aging. As in normal aging, endocrine abnormalities occur in more
than 80% of patients with FA, including hyperinsulinemia, growth hormone insufficiency, and hypothyroidism (5). Less than 50% of patients survive to adulthood, and reproduction is severely impaired due to spermatogenic failure in males and a low pregnancy rate in females (6). The key feature that justifies the inclusion of FA in a discussion of “premature aging syndromes” is genetic instability that is correlated in these patients with a sharply increased risk of neoplasia. There is a 15,000-fold increased risk for acute myelogenous leukemia, but squamous cell carcinomas of the female genital tract and of the oral cavity (in both male and female patients) are typical cancers of advanced age that occur 30-40 years earlier in patients with FA (7).
