Sarah Reid

ilms tumour (WT) is an embryonal tumour of the kidney that occurs in 1 in 10 000 children. Familial clusters are rare and account for only 1-3% of cases. ] anconi anaemia (FA, MIM 227650) is a rare autosomal recessive condition affecting ,1 in 300 000 children. FA is characterised by variable congenital abnormalities, short stature, bone marrow failure, hypersensitivity to DNA crosslinking agents, and a predisposition to haematological malignancies such as acute myeloid leukaemia in childhood. A is heterogeneous and consists of at least 11 complementation groups, A, B, C, D1, D2, E, F, G, I, J, and L. 6-8 Eight FA genes have been cloned and at least six FA proteins, FANCA, FANCC, FANCE, FANCF, FANCG, and FANCL, form a nuclear complex required for monoubiquitination of FANCD2. This modification promotes translocation of FANCD2 to DNA repair foci that also contain BRCA1, BRCA2, and RAD51. 9 In 2002, Howlett and colleagues reported biallelic BRCA2 mutations in individuals with Fanconi anaemia D1 (FA-D1). Subsequently, additional FA-D1 and unclassified FA cases were examined and cases with BRCA2 mutations and WT and/or brain tumours were reported.

Neuroblastoma (NB) is an embryonal tumor originating from neural crest cells and is one of the most common solid tumors of childhood. Recently, constitutional mutations in PHOX2B have been shown to confer an increased risk of NB. To date, mutations predisposing to neural crest tumors have been reported in 20 individuals from 16 families. These families included additional clinical features such as Hirschsprung (HSCR) disease or congenital central hypoventilation syndrome, either in the index case or relatives. The contribution of PHOX2B mutations to NB cases without additional features is unclear. To address this we sequenced PHOX2B in constitutional DNA from 86 individuals with non-syndromic NB (4 cases had a family history of NB). We identified two mutations, 600delC, a frameshift mutation in an individual with isolated, unifocal NB and G197D, a missense mutation that was present in a family with multiple individuals with NB but no evidence of autonomic dysfunction. These data demonstrate that PHOX2B mutations are a rare cause of non-syndromic NB. The mutations we identified are outside the domains typically mutated in PHOX2B syndromes. This provides further evidence that the underlying PHOX2B mutational mechanism influences tumor risk and suggests that the position of missense mutations may influence the resulting phenotype.