Biallelic PMS2 mutations and a distinctive childhood cancer syndrome

Abstract

Biallelic mutations in PMS2, a gene usually associated in heterozygous form with hereditary nonpolyposis colorectal cancer (HNPCC), results in a recently described childhood cancer syndrome. The tumor spectrum encompasses atypical brain cancers, hematologic malignancies, and colonic polyposis and cancer. Cutaneous stigmata resembling café-au-lait macules with more diffuse margins are frequently seen. Onset is as young as 2 years. The risk of second malignancy is high. Evidence exists for surveillance for bowel cancer, but surveillance for the wider tumor spectrum is of uncertain benefit. We report a consanguineous Australian-Lebanese family with multiple affected individuals shown to be homozygous for a PMS2 exon 7 deletion. We also review published cases of biallelic mutations in HNPCC-related genes. Early recognition of this familial cancer syndrome is critical, and should prompt investigation for familial HNPCC mutations.