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a Institute of
Human Genetics, University of Bonn, Germany, b Department of Medicine I,
University of Bonn, Germany, c Department of Surgery,
University of Heidelberg, Germany, d Department
of Human Genetics, University of Ulm, Germany, e Department of Surgery, University of
Düsseldorf, Germany
Correspondence to: Dr W Friedl, Institute of Human Genetics, University of Bonn, Wilhelmstrasse 31, D-53111 Bonn, Germany. friedlw{at}meb.uni-bonn.de
Accepted for publication 14 November 2000
BACKGROUND AND AIMS
In
familial adenomatous polyposis (FAP), correlations between site of
mutation in the adenomatous polyposis coli
(APC) gene and severity of colonic polyposis
or extracolonic manifestations are well known. While mutation analysis
is important for predictive diagnosis in persons at risk, its relevance
for clinical management of individual patients is open to question.
METHODSWe examined
680 unrelated FAP families for germline mutations in the
APC gene. Clinical information was obtained
from 1256 patients.
RESULTSAPC
mutations were detected in 48% (327/680) of families. Age at diagnosis
of FAP based on bowel symptoms and age at diagnosis of colorectal
cancer in untreated patients were used as indicators of the severity of
the natural course of the disease. A germline mutation was detected in
230 of 404 patients who were diagnosed after onset of bowel symptoms
(rectal bleeding, abdominal pain, diarrhoea). When these patients were
grouped according to the different sites of mutations, mean values for
age at onset of disease differed significantly: patients carrying
APC mutations at codon 1309 showed a disease
onset 10 years earlier (mean age 20 years) compared with patients with
mutations between codons 168 and 1580 (except codon 1309) (mean age 30 years), whereas patients with mutations at the 5' end of codon 168 or
the 3' end of codon 1580 were diagnosed at a mean age of 52 years.
Within each group of patients however large phenotypic variation was observed, even among patients with identical germline mutations. A
higher incidence of desmoids was found in patients with mutations between codons 1445 and 1580 compared with mutations at other sites,
while no correlation between site of mutation and presence of duodenal
adenomas was observed.
CONCLUSIONSAs age at
manifestation and course of the disease may be rather variable, even in
carriers of identical germline mutations, therapeutic decisions should
be based on colonoscopic findings in individual patients rather than on
the site of mutation. However, in patients with mutations within codons
1445-1580, it may be advisable to postpone elective colectomy because
desmoids may arise through surgical intervention.
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