title: Association of biallelic BRCA2/FANCD1 mutations with spontaneous chromosomal instability and solid tumors of childhood.
abstract: The clinical, cytogenetic, and molecular findings of 2 Fanconi anemia (FA) subtype D1 kindreds, initially identified through a young child with a solid tumor (medullobastoma, Wilms tumor), are described. Each kindred subsequently had a second affected child; one developed Wilms tumor followed by a medulloblastoma, and the other developed T-lineage acute lymphoblastic leukemia. Cytogenetic studies revealed an unusually high spontaneous chromosome aberration rate, contrasting with other FA subtypes. Molecular analysis revealed biallelic BRCA2/FANCD1 mutations. The patients did not exhibit bone marrow failure. Our studies suggest that the D1 subtype represents a severe end of the cytogenetic spectrum within FA, consistent with a critical downstream role of BRCA2 in the FA pathway. Furthermore, this FA subgroup may be preferentially associated with an increased predisposition to solid tumors in early childhood. Recognition of this constellation of findings has significant implications for medical management and genetic counseling of FA families.
authors.affiliation: Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, USA.
authors.forename: Betsy
authors.initials: B
authors.lastname: Hirsch
authors.forename: Akiko
authors.initials: A
authors.lastname: Shimamura
authors.forename: Lisa
authors.initials: L
authors.lastname: Moreau
authors.forename: Shari
authors.initials: S
authors.lastname: Baldinger
authors.forename: Maha
authors.initials: M
authors.lastname: Hag-alshiekh
authors.forename: Bruce
authors.initials: B
authors.lastname: Bostrom
authors.forename: Susan
authors.initials: S
authors.lastname: Sencer
authors.forename: Alan D
authors.initials: AD
authors.lastname: D'Andrea
mesh_terms: D000741:Anemia, Aplastic / Q000235:genetics; D020295:Brain Stem Neoplasms / Q000235:genetics; D002648:Child; D043171:Chromosomal Instability / Q000235:genetics*; D024522:Genes, BRCA2; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics; D008527:Medulloblastoma / Q000235:genetics; D009153:Mutagens; D009369:Neoplasms / Q000235:genetics*; D035781:Siblings; D009396:Wilms Tumor / Q000235:genetics
chemical_list: D009153:Mutagens