THE NEED FOR MORE ACCURATE AND TIMELY DIAGNOSIS IN FANCONI-ANEMIA - AREPORT FROM THE INTERNATIONAL-FANCONI-ANEMIA-REGISTRY

Objective. The objective of this study was to address the need for ear ly diagnosis of Fanconi anemia (FA), an autosomal recessive chromosoma l instability syndrome characterized by a unique cellular hypersensiti vity to DNA cross-linking agents, such as diepoxybutane, and by a high risk of malignancies. Methods. We analyzed data from 370 FA patients enrolled in the American Registry of the International FA Registry. Of these individuals, 220 had congenital malformations; the rest were as certained based on hematologic abnormalities only or on clinical evalu ation and screening following the diagnosis of an affected family memb er. The probands noted to have congenital malformations at the time of diagnosis were classified into two groups on the basis of their clini cal presentation: (1) patients manifesting both congenital malformatio ns and hematologic abnormalities (159 individuals); (2) patients manif esting congenital malformations only (61 individuals). Results. The me an age of diagnosis was 6.6 years and 1.1 years for Groups 1 and 2, re spectively. Thus, the majority of FA patients with congenital malforma tions were not diagnosed until after the onset of hematologic abnormal ities. We also report central nervous system, gastrointestinal, and sk eletal malformations which previously have not been included as part o f the FA phenotype. Our review of the patients enrolled in the Interna tional FA Registry indicates that the FA phenotype is more variable th an recognized previously. Conclusions. Testing for sensitivity to diep oxybutane to rule out a diagnosis of FA needs to be applied more widel y in patients with congenital malformations. All siblings of affected probands also should have testing, because a lack of concordance of ph enotype in affected siblings makes clinical diagnosis unreliable even within sibships. A more timely diagnosis of FA in the preanemic phase is needed to implement appropriate therapy and to enable parents to ma ke informed reproductive decisions.