Background: Familial adenomatous polyposis (FAP) is a dominantly inherited disorder characterized by the presence of more than 100 adenomatous polyps in the colon and rectum starting in the second decade of life. FAP is associated with extra colonic manifestations, including desmoid tumors.
Methods: A 2-year-old girl presented with a rapidly enlarging tumor of the forehead and a family history of FAP. The tumor was cultured for cytogenetic studies. A DNA linkage study using flanking and intragenic polymorphisms of the adenomatous polyposis coli (APC) gene was performed to identify the allele loss in the tumor. Germline mutation identification was by single strand conformation polymorphism analysis of exon 15 of the APC gene, with subsequent double stranded sequencing of fragments with conformational changes. A mutation-induced loss of a restriction site was used to confirm allele loss in the tumor.
Results: Microscopically, the tumor had desmoid features. Cytogenetic analysis of the tumor demonstrated loss of chromosome region 5(q21q22). A truncating adenomatous polyposis coli (APC) gene mutation was identified in the leukocyte DNA from the child and her affected father. Linked DNA markers suggested that the tumor had lost the maternal, wild-type allele. A mutation-induced restriction endonuclease site alteration demonstrated hemizygosity of the mutant sequence in the tumor DNA.
Conclusions: These findings are compatible with the presence of a "second hit" inactivation of the APC gene and implicate this gene in the pathogenesis of desmoid tumors.