Pigmented ocular fundus lesions and APC mutations in familial adenomatous polyposis

Background Familial adenomatous polyposis (FAP) results from a germline mutation in the adenomatous polypsis coli (APC) gene on chromosome 5q2I. The extracolonic manifestations of FAP include pigmented ocular fundus lesions (POFLs), cutaneous cysts, osteomas, occult radio-opaque jaw lesions, odontomas, desmoids, and extracolonic cancers. POFLs are present at birth in about 80% of patients with FAP and are excellent clinical congenital markers for the disease. We studied the distribution of POFLs by number and APC mutation in families of the Johns Hopkins Polyposis Registry. Materials and methods Of the 51 families with FAP, 42 (82%) had an identifiable APC mutation. We correlated the presence/absence and distribution by number of POFLS with the type and location of the mutation in the APC gene in 21 families where an ocular examination had been performed in at least one affected member, and where a systematic search for mutations in the APC gene had been undertaken. Families were considered POFL-positive if the average number of lesions per patient was three or more, or if at least one family member had three or more lesions. Results Fifteen of the 21 families (71.4%) were POFL-positive. Mutations of the APC gene were detected in Ig of the 21 families. Of these, 12 (80%) were POFL-positive. Families with mutations at codons 215 (exon 5) and 302 (exon 8) were POFL-negative. Families with mutations at codons 541, 625, 1055, 1059, 1061, 1230, 1309, 1465, and 1546 (exons 12-15) were POFL-positive. One patient with a mutation at codon 2621 (exon 15) had no POFLs. Conclusions Mutations in exons 1-8 and the distal portion of exon 15 of the APC gene are associated with a POFL-negative phenotype, while those in exons 10 to the proximal portion of exon 15 are generally associated with a POFL-positive phenotype.