Hematologic abnormalities in Fanconi anemia: an International Fanconi Anemia Registry study.

We analyzed data from 388 subjects with Fanconi anemia reported to the International Fanconi Anemia Registry (IFAR). Of those, 332 developed hematologic abnormalities at a median age of 7 years (range, birth to 31 years). Actuarial risk of developing hematopoietic abnormalities was 98% (95% confidence interval, 93% to 99%) by 40 years of age. Common hematologic abnormalities were thrombocytopenia and pancytopenia. These were often associated with decreased bone marrow (BM) cellularity (75% of cases studied). Clonal cytogenetic abnormalities developed in 23 of 68 persons with BM failure who had adequate studies. Actuarial risk of clonal cytogenetic abnormalities during BM failure was 67% (47% to 87%) by 30 years of age. Fifty-nine subjects developed myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML). Actuarial risk of MDS or AML was 52% (37% to 67%) by 40 years of age. Risk was higher in persons with than in those without a prior clonal cytogenetic abnormality (3% [0% to 9%] v 35% [0% to 79%]; P = .006). One hundred twenty persons died of hematologic causes including BM failure, MDS or AML and treatment related complications. Actuarial risk of death from hematologic causes was 81% (67% to 90%) by 40 years of age.

The need for more accurate and timely diagnosis in Fanconi anemia: a report from the International Fanconi Anemia Registry.

OBJECTIVE: The objective of this study was to address the need for early diagnosis of Fanconi anemia (FA), an autosomal recessive chromosomal instability syndrome characterized by a unique cellular hypersensitivity 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 ascertained based on hematologic abnormalities only or on clinical evaluation and screening following the diagnosis of an affected family member. The probands noted to have congenital malformations at the time of diagnosis were classified into two groups on the basis of their clinical presentation: (1) patients manifesting both congenital malformations and hematologic abnormalities (159 individuals); (2) patients manifesting congenital malformations only (61 individuals). RESULTS: The mean age of diagnosis was 6.6 years and 1.1 years for Groups 1 and 2, respectively. Thus, the majority of FA patients with congenital malformations were not diagnosed until after the onset of hematologic abnormalities. We also report central nervous system, gastrointestinal, and skeletal malformations which previously have not been included as part of the FA phenotype. Our review of the patients enrolled in the International FA Registry indicates that the FA phenotype is more variable than recognized previously. CONCLUSIONS: Testing for sensitivity to diepoxybutane to rule out a diagnosis of FA needs to be applied more widely in patients with congenital malformations. All siblings of affected probands also should have testing, because a lack of concordance of phenotype 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 make informed reproductive decisions.

Fanconi anemia: a model for genetic causes of abnormal brain development.

Fanconi anemia is an autosomal recessive disease resulting in bone-marrow failure, phenotypical abnormalities and predisposition to malignancy. The authors reviewed 257 clinical and neuropathology results from the International Fanconi Anemia Registry at The Rockefeller University. Two patients had hydrocephalus and ventriculoperitoneal shunts. Of 15 neuropathology reports, 10 found CNS abnormalities, with the most common--ventriculomegaly--seen in six, two of whom required shunts. Aqueductal stenosis, agenesis of the corpus callosum and septum pellucidum, and holoprosencephaly were found. The authors conclude that neurological derangements are probably more common in Fanconi anemia than previously recognised. Fanconi anemia cells in culture are highly sensitive to oxidative stress and alkylating agents; Fanconi anemia may provide a model for a genetic disorder potentially predisposing to environmental insults.

Fanconi's anaemia and pregnancy.

We have identified six new cases of Fanconi's anaemia (FA) who had pregnancies, and reviewed 11 others from the literature. At least 110 FA females have reached 16 years of age or more, of whom 15% became pregnant. There were a total of 26 pregnancies, resulting in 19 births and 18 surviving children. Anaemia and/or thrombocytopenia worsened during pregnancy in 10 patients, but five subsequently improved: seven had no haematological problems. Seven of the FA patients who had pregnancies died subsequently from cancer, and two from thrombocytopenic bleeding 3 and 20 years later. There were no peripartum deaths. Pregnancy in FA is clearly possible, with increased risks that are manageable from both the haematological and the obstetric aspects.

Fanconi anemia: evidence for linkage heterogeneity on chromosome 20q.

Fanconi anemia is a rare autosomal recessive disorder in which affected individuals are predisposed to acute myelogenous leukemia and other malignancies. We report the results of a genetic linkage study involving 34 families enrolled in the International Fanconi Anemia Registry. A significant lod score was obtained between D20S20, an anonymous DNA segment from chromosome 20q, and Fanconi anemia (Zmax 3.04, theta max = 0.12). However, six other anonymous DNA segments from chromosome 20q, including D20S19, which is highly polymorphic and tightly linked to D20S20, showed no or only weak evidence for linkage to Fanconi anemia. An admixture test revealed significant evidence for linkage heterogeneity (chi 2 = 6.10, P = 0.01) at the D20S19 locus. Lod scores suggestive of linkage between Fanconi anemia and this locus were obtained with two of the largest kindreds studied (lods = 2.6 and 2.1, at theta = 0.001). Thus, our data support the provisional assignment of a Fanconi anemia gene to chromosome 20q.