Background: Familial Adenomatous Polyposis in an autosomal dominant disease in which the large bowel is carpeted by polyps of various dimensions appearing during the second or third decade of life. Several extracolonic manifestations complete the clinical spectrum of familial Adenomatous Polyposis. If untreated, the disease leads invariably to colorectal cancer. The gene responsible for the disease, adenomatous Polyposis Coli, has been localized at chromosome 5q21. Aims: To describe the clinical features of 156 Familial Adenomatous Polyposis patients (from 41 families) and to analyze possible correlations between genotype and phenotype. Patients and Methods: Familial Adenomatous Polyposis was defined as the presence of 100 or more polyps in the large bowel. In 17 families (41%), the proband was the only affected individual (single cases). Adenomatous Polyposis Coli gene mutations were studied on DNA extracted from peripheral white blood cells and evaluated by polymerase chain reaction single strand conformation polymorphism followed by direct sequencing of samples showing abnormal banding at single strand conformation polymorphism. Results: The large majority of Familial Adenomatous Polyposis patients underwent surgery; colectomy with ileorectal anastomosis was the most frequent approach, however, cancer of the rectal stump developed in 11.6% of patients submitted to colectomy and ileorectal anastomosis. Adenomas were rare in the stomach (8.8%), but their frequency increased in the duodenum (33.8%) and jejunum (55.0%, χ2 for trend 23.7, p < 0.001). Desmoid tumours were diagnosed in 17 patients (10.9% of the total) and in 6 families. Mutations of the Adenomatous Polyposis Coli gene were studied in 20 out of 25 families (80%) and on a total of 75 individuals. The most frequent alterations were 1 to 5 bp deletions leading to stop codons and truncated proteins. Desmoid tumours, presence of duodenal or jejunal adenomas were associated with an ample range of mutations, from codon 215 to codon 1464. In contrast, particularly severe polyposis (mean age at appearance of polyps 11-16 years, and of cancer development 27-32 years) was associated with a 'hot-spot' mutation site at codons 1303-1309. Conclusions: In patients with Familial Adenomatous Polyposis, subtotal colectomy with ileorectal anastomosis is still the treatment of choice. Adenomatous lesions seem to show a 'gradient' distribution from the stomach to the large bowel. Desmoid tumours are relatively common, though their incidence is limited to some of the families. Constitutional mutations can be detected in 80% of the investigated families. Genotype-phenotype correlations showed a hot-spot at codons 1303-1309, frequently associated with severe polyposis.
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