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 fami-

Development of primary early-onset colorectal cancers due to biallelic mutations of the FANCD1/BRCA2 gene

“…12,18 Table 1 gives a review of the 30 patients from 24 families with biallelic BRCA2 mutations and whose phenotype had previously been described in details family. 12,[19][20][21][22][23][24][25][26][27][28] Among these patients, the females and males were equally affected and the mean age of FA diagnosis was 1.9 years (range, 0.1-5.2 years). Most of the patients were diagnosed as FA because of their typical physical features (68%).…”

Agenesis of the corpus callosum and gray matter heterotopia in three patients with constitutional mismatch repair deficiency syndrome

“…Apart from the lack of awareness for this rare cancer predisposition syndrome among pediatric hematologists-oncologists, other factors that may play a role in delayed diagnosis include the lack of clearly disease-specific clinical features and the overlap with other cancer predisposing syndromes, including NF1, 1 familial adenomatous polyposis 9 and to some extent also with Fanconi anemia. [40][41][42] In view of the wide tumor spectrum, it has been suggested that CMMR-D should be considered in the differential diagnosis in all pediatric patients with malignancies (except clearly NF1-associated tumors), who show one or more of the following features: (1) CALMs and/or other signs of NF1 and/or hypo-pigmented skin lesions; (2) consanguineous parents; (3) family history of LS-associated tumors; (4) second malignancy; and (5) sibling with childhood cancer. We suggest including ACC with or without gray matter heterotopia as an additional feature.…”

Fanconi anaemia genes and susceptibility to cancer

“…However, an assessment of the location of BRCA2 mutations in FA-D1 patients in comparison with BRCA2 carriers does not support a bias towards carboxy-terminal mutations in FA-D1 (Reid et al, 2005). Also, the nature of the mutations in many of the reported FA-D1 cases would predict early truncation of the BRCA2 protein expressed from both alleles, and its absence has been confirmed in some cases by Western blot analysis (Hirsch et al, 2004).…”