CONGENITAL HYPERTROPHY OF THE RETINAL-PIGMENT EPITHELIUM IN FAMILIAL ADENOMATOUS POLYPOSIS - NOVEL CRITERIA OF ASSESSMENT AND CORRELATIONS WITH CONSTITUTIONAL ADENOMATOUS POLYPOSIS-COLI GENE-MUTATIONS

BACKGROUND. Congenital hypertrophy of the retinal pigment epithelium ( CHRPE) is the most common extracolonic manifestation of familial adeno matous polyposis (FAP) and is an early clinical marker of the disease. It seems to be correlated with the position of constitutional mutatio ns of the adenomatous polyposis coli (APC) gene. METHODS. The authors investigated the expression of CHRPE and its correlation with the posi tion of the APC gene in FAP patients and in ''at risk'' relatives from 31 FAP kindreds. To obtain comparable data on CHRPE expression, the a uthors developed a novel scoring system based on morphologic and dimen sional criteria. RESULTS. A positive CHRPE score was obtained in 29 of 39 EAP patients (74%) and in 16 of 53 relatives who showed no clinica l evidence of FAP (30%). Colonoscopy revealed polyps in 20 of the 47 r elatives who could be examined. The cumulative sensitivity and specifi city of CHRPE were 72.88% and 96.29%, respectively. APC gene mutations were characterized in 34 subjects from 17 kindreds. In 28 of the subj ects, mutations were detected in exon 15, between codons 876 and 1324. Mutations were found in exon 9 in 6 subjects. In 3 of the 6 subjects, they were found at the site where both forms of alternative splicing of the exon occur (codon 437]. In the other 3 subjects (another kindre d), mutations were found in the portion of exon 9 in which alternative splicing occurs (codon 367). Only 1 of the 6 subjects (16.6%) with mu tations in exon 9 had a positive CHRPE score, compared with 28 of 28 s ubjects (100%) with mutations in exon 15. None of the 3 subjects with mutations in codon 437 had a positive CHRPE score, The CHRPE scores of exon 15 mutation carriers varied markedly both within and among kindr eds, irrespective of the mutation site. CONCLUSIONS. The results of th is study indicate that the site of APC gene mutation influences CHRPE expression but is not the only factor responsible for the presence and level of retinal lesions in FAP patients. (C) 1996 American Cancer So ciety.