FAMILIAL INFILTRATIVE FIBROMATOSIS (DESMOID TUMORS) (MIM135290) CAUSED BY A RECURRENT 3'-APC GENE MUTATION

Desmoid tumours are generally very rare but occur about 100 times more frequently in the colorectal cancer predisposition syndrome familial adenomatous polyposis (MIM 175100), being represented in about 10% of patients, In addition to desmoid disease occurring in familial adenoma tous polyposis (FAP) there exist familial infiltrative fibromatosis (M IM 135290) kindreds where there is no evidence of FAP, Previously we h ave described a kindred with familial infiltrative fibromatosis (FIF) in which desmoid tumours were associated with nonpolyposis colorectal cancer, FAP is caused by mutations in the APC gene and various genotyp e-phenotype relationships have been defined including reports that col orectal polyposis is less severe with mutations 5' to codon 157 and th at the risk of desmoid tumours is high in FAP patients with APC gene m utations between codons 1444 and 1598, There is relatively little info rmation on the phenotype of APC gene mutations 3' to codon 1598; howev er, one large family has been reported with a mutation at codon 1987 w hich presents with a highly variable phenotype which includes desmoid disease, We screened our original FIF kindred and three further famili es with a similar phenotype for mutations in the APC gene. A 4 bp fram eshift deletion in codon 1962 was identified in the original FIF kindr ed and two further apparently unrelated families. Haplotype analysis s uggests a common origin for the APC mutation in all three families, Af fected individuals had no evidence of congenital hypertrophy of the re tinal pigment epithelium, Colorectal polyposis was variable, and most affected patients had either none or a few late onset polyps, These fi ndings demonstrate (i) that FAP and FIF are allelic, and (ii) that APC gene mutations which truncate the APC protein distal to the beta-cate nin binding domain are associated with desmoid tumours, absent CHRPE a nd variable but attenuated polyposis expression.