American Journal of Gastroenterology
C ?2006 by Am. Coll. of Gastroenterology
Published by Blackwell Publishing
Familial Adenomatous Polyposis
Polymnia Galiatsatos, M.D., F.R.C.P.(C),1and William D. Foulkes, M.B., Ph.D.2
1Division of Gastroenterology, Department of Medicine, The Sir Mortimer B. Davis Jewish General Hospital,
McGill University, Montreal, Quebec, Canada, and2Program in Cancer Genetics, Departments of Oncology
and Human Genetics, McGill University, Montreal, Quebec, Canada
Familial adenomatous polyposis (FAP) is an autosomal-dominant colorectal cancer syndrome, caused by a
germline mutation in the adenomatous polyposis coli (APC) gene, on chromosome 5q21. It is characterized by
hundreds of adenomatous colorectal polyps, with an almost inevitable progression to colorectal cancer at an
average age of 35 to 40 yr. Associated features include upper gastrointestinal tract polyps, congenital hypertrophy
of the retinal pigment epithelium, desmoid tumors, and other extracolonic malignancies. Gardner syndrome is
more of a historical subdivision of FAP, characterized by osteomas, dental anomalies, epidermal cysts, and soft
tissue tumors. Other specified variants include Turcot syndrome (associated with central nervous system
malignancies) and hereditary desmoid disease. Several genotype–phenotype correlations have been observed.
Attenuated FAP is a phenotypically distinct entity, presenting with fewer than 100 adenomas. Multiple colorectal
adenomas can also be caused by mutations in the human MutY homologue (MYH) gene, in an autosomal
recessive condition referred to as MYH associated polyposis (MAP). Endoscopic screening of FAP probands and
relatives is advocated as early as the ages of 10–12 yr, with the objective of reducing the occurrence of colorectal
cancer. Colectomy remains the optimal prophylactic treatment, while the choice of procedure (subtotal vs
proctocolectomy) is still controversial. Along with identifying better chemopreventive agents, optimizing screening
of extracolonic cancers and applying new radiological and endoscopic technology to the diagnosis and
management of extracolonic features are the major challenges for the future.
(Am J Gastroenterol 2006;101:385–398)
Familial adenomatous polyposis (FAP) is an inherited col-
orectal cancer syndrome characterized by the early onset
of hundreds to thousands of adenomas throughout the large
bowel. Left untreated, there is a nearly 100% progression to
as a heightened risk of various other malignancies. CRC can
programs, and certain medico-surgical interventions.
A literature search was performed from 1980 to August
2005, using the computerized PubMed database, looking
for English publications regarding “familial adenomatous
polyposis,” “attenuated familial adenomatous polyposis,”
and “MYH associated polyposis.” Original articles and case
reports discussing genetics, clinical features, genotype–
phenotype correlations, screening, and prophylaxis were re-
Familial adenomatous polyposis (FAP) is a highly penetrant
autosomal-dominant disorder, caused by a germline muta-
tion in the adenomatous polyposis coli (APC) gene, located
on chromosome 5q21. APC is a tumor suppressor gene, first
localized in 1987, and cloned in 1991 following mutation
bp open reading frame, and consists of 15 transcribed exons
(6–8) (Fig. 1). This gene is expressed in a variety of fetal
and adult tissues, including mammary and colorectal epithe-
step in the development of CRC in FAP. APC’s major func-
tion is that of a scaffolding protein, affecting cell adhesion
and migration. It is part of a protein complex, modulated by
the Wnt signaling pathway, which regulates the phosphory-
lation and degradation of β-catenin (9, 10). β-catenin is an
intracellular protein that binds to the cell adhesion molecule
The phosphorylation of β-catenin attracts ubiquitin ligases,
leading to its destruction at the proteasome (9, 10). When
APC is mutated, β-catenin accumulates in the cytoplasm and
binds to the Tcf family of transcription factors, altering the
expression of various genes affecting the proliferation, dif-
ferentiation, migration, and apoptosis of cells, namely those
encoding cyclin D1, the proto-oncogene c-myc, the metal-
loproteinase matrilysin, as well as ephrins and capsases (9,
10). APC also plays a role in controlling the cell cycle, by
inhibiting the progression of cells from the G0/G1to the S
386 Galiatsatos and Foulkes
Figure 1. APC cDNA (below) and important protein motifs (above). Adapted from Van Es et al. (6), Fearnhead et al. (7), and Foulkes (8).
phase, helping to suppress tumorigenesis (10). Furthermore,
APC stabilizes microtubules, thus promoting chromosomal
aneuploidy leading to cancer (9).
Over 700 different disease-causing APC mutations have
been reported to date, but the most common germline mu-
tation involves the introduction of a premature stop codon,
either by a nonsense mutation (30%), frameshift mutation
(68%), or large deletion (2%), leading to truncation of the
protein product in the C-terminal region (11). Most of these
germline mutations are clustered at the 5?end of exon 15,
otherwise referred to as the mutation cluster region (12). The
1309 (11). Correlations have been observed between sites of
mutations and variations in the phenotype, as will be dis-
cussed later. An updated database of APC gene mutations is
available online at http://www.cancer-genetics.org.
Despite genetic testing, 20–30% of classical FAP patients
ing methods. One possibility is the presence of a nontruncat-
ing missense mutation that could be missed by protein trun-
cation testing (PTT), previously used as a first-line screening
tool. Heinimann et al. found that 12.9% of APC mutation
carriers are missed by standard PTT (13). Using SNP as-
say and direct DNA sequencing, they identified four possibly
in the coding region, A290T within the APC promoter, and
A8822G in the 3?UTR end of the gene (13). However, valida-
tion of these candidate disease-associated mutations was not
performed. Nowadays, PTT has been largely replaced as the
first-line genetic test by other mutation-finding techniques,
particularly DNA sequencing (currently the standard screen-
ing tool in most North American centers), and newer diag-
more sensitive second-line technique, whereby the two APC
alleles can be examined independently. Using this method,
Laken et al. demonstrated significantly reduced expression
in one APC allele 7 of 9 FAP patients with no identified trun-
cating APC mutation (14). The authors concluded that APC
mutations can be identified in >95% of FAP patients when
MAMA is combined with standard genetic testing (14). A
modified version of this technique is now called “conversion
match repair genes that have been difficult to detect by other
means (15). Multiplex ligation-dependent probe amplifica-
tion (MLPA) is yet another test that quantifies all APC exon
copy numbers. It has been useful in identifying a deletion of
the entire APC gene in a patient with classical FAP, as well
as large deletions involving several exons of the gene, often
missed by conventional tests (16).
The APC missense polymorphism I1307K, resulting from
a T-to-A transversion, has also been indirectly linked to col-
orectal adenoma and carcinoma, by rendering the gene sus-
ceptible to somatic mutations. This variant allele has been
identified in 6% of Ashkenazi Jewish controls and 10% of
Ashkenazi CRC patients (17). Apart from a modest increase
in risk of CRC, I1307K has also been linked to a heightened
risk of breast cancer among Ashkenazi Jews (18), although
nazi Jewish families is CRAC1 (colorectal adenoma and car-
cinoma gene), located on chromosome 15q14-q22 (19). This
polyposis syndrome in a large Ashkenazi family, character-
ized by the development of various different colorectal tu-
mors (including juvenile, hyperplastic, adenomatous polyps,
as well as CRC). It is inherited as an autosomal-dominant
the same patient suggests a somatic inactivation of hMLH1
by promoter hypermethylation, rather than a germline muta-
tion (13). Hence, mismatch repair (MMR) gene deficiency is
unlikely to be a cause of APC mutation-negative polyposis.
Recently, biallelic mutations in MYH have been deemed re-
sponsible for up to 7.5% of APC-negative classic FAP (21),
a milder phenotype, as will be discussed later.
The birth frequency of FAP in Northern European popula-
tions is estimated at roughly 1 in 13,000 to 1 in 18,000 live
births (1, 22), and is responsible for less than 1% of all CRC
Familial Adenomatous Polyposis387
of probands with CRC at diagnosis was 42 yr, compared to
34 yr for those without CRC, while asymptomatic relatives
were diagnosed at a median age of 22 yr (22). In the Poly-
posis Registry of Japan, the mean age of diagnosis of FAP
in patients without CRC was 28 yr, compared to 33 yr for
those with early cancer (in situ or submucosal) and 40 yr for
advanced cancer (24). The cumulative risk of CRC exceeded
50% by the age of 42 yr in women, and 44 yr in men (24). In
the Danish and Finnish registries, 66–69% of symptomatic
probands, versus only 2–7% of call-up patients (relatives re-
cruited from pedigrees) had CRC at the time of diagnosis of
FAP (25, 26).
Lower Gastrointestinal Tract Polyps and Cancer
The hallmark of FAP is the development of hundreds of ade-
nomatous polyps in the colon and rectum usually in adoles-
cence, with an almost inevitable progression to CRC by the
age of 35–40 yr, significantly younger than sporadic cancers.
A total of 70–80% of tumors occur on the left side of the
Upper Gastrointestinal Tract Polyps and Cancer
Upper gastrointestinal polyps (gastric and duodenal adeno-
mas) are present in nearly 90% of FAP patients by the age
of 70 yr, with a median age of diagnosis of 38 yr, based on
a prospective study from Nordic and Dutch polyposis reg-
istries (27). Interestingly, 12% of duodenal polyps discov-
ered during the initial upper endoscopies in this study were
microadenomas, diagnosed from random biopsies without
visible lesions (27). Roughly two-thirds of duodenal adeno-
mas occur in the papilla or periampullary region (28). Ad-
vanced duodenal adenomas confer an increased risk of small
bowel cancer, which is the third leading cause of death in
desmoid tumors (10.9%) (29). The cumulative risk of devel-
estimated to be 43% at the age of 60 yr and 50% at the age of
systematic biopsies of the duodenal papilla (30). The mean
age of duodenal cancer diagnosis ranges between 47 and 51
yr according to Dutch and Danish polyposis registries, with
a cumulative risk of 3–4% by the age of 70 yr (31). In the
prospective Nordic study mentioned above, the cumulative
incidence rate was as high as 4.5% at the age of 57 yr (27).
One retrospective study of 180 Swedish FAP patients found
an unusually elevated cumulative risk of periampullary ade-
nocarcinoma of 10% by the age of 60 yr (32). This stresses
the added value of random biopsies even in the absence of
FAP patients are also at an increased risk for fundic gland
26–61% (27, 33–36), compared with a 0.8–1.9% incidence
in the general population (37, 38). FGPs are indeed the most
common type of gastric polyp to occur in FAP patients. In
contrast to sporadic FGPs, FAP-related FGPs are more nu-
merous, tend to occur at a younger age, with more equal
gender distribution (39). Helicobacter pylori and its associ-
against the development of FAP-related FGPs as they do in
sporadic FGPs (40). Although FGPs in the general popula-
tion are typically benign lesions, up to 25% of those in FAP
cinoma associated with diffuse FGP have also been reported
(42–45). In a study of 41 FGPs from 17 FAP patients, 51%
of polyps demonstrated an inactivating somatic APC gene
alteration, whereas there were no such APC gene mutations
in 13 sporadic FGPs used for comparison (46). There was
no significant difference in mutation rate among FGPs with
or without dysplasia (46). These second-hit somatic APC
gene alterations, superimposed on germline APC mutations,
could account for the neoplastic potential of FGPs in FAP,
which appear to be not only clinically, but also pathologi-
cally distinct from sporadic lesions. In fact, sporadic FGPs
have recently been shown to harbor a high frequency of so-
matic mutations in exon 3 of the β-catenin gene, not identi-
fied in FAP-associated FGPs (47), reinforcing the difference
in initial mutational events (despite similarity in the altered
pathways) causing sporadic versus syndromic FGPs.
Congenital Hypertrophy of the Retinal Pigment
Congenital hypertrophy of the retinal pigment epithelium
(CHRPE) refers to the presence of characteristic pigmented
patients with FAP (48–50). These ophthalmic manifestations
are usually present at birth, largely preceding the develop-
ment of intestinal polyposis, and are asymptomatic with no
malignant potential. They are specific to FAP, as opposed to
other hereditary or sporadic colonic cancers (51, 52). The
diagnostic criteria with the highest specificity/sensitivity for
CHRPE include the detection of four small pigmented le-
sions, or two lesions of which one is large (>25% of disc
surface), using bilateral lens fundoscopic examination (53).
The presence of multiple bilateral lesions appears to be a
highly specific marker for FAP (95–100% specificity) (54).
ment and upper gastrointestinal involvement), and correlates
with DNA test positivity in undiagnosed kindred belonging
to FAP families that are CHRPE-positive (48). This makes
ophthalmological examination an attractive noninvasive and
early diagnostic test for at-risk family members, aside from
genetic analysis. CHRPE lesions can also help predict the
mutation site, since they are restricted to a specific mutation
subgroup along the APC gene (55) (see section “genotype–
phenotype correlations” for more details).
388 Galiatsatos and Foulkes
Desmoid tumors are rare, locally invasive fibromatoses that
are a major cause of morbidity, and the second leading cause
of β-catenin (56), or associated with estrogens. The overall
ative risk of ∼850 times that of the general population (58).
The majority of tumors occurs within the abdomen (50%),
usually involving small bowel mesentery, or in the abdomi-
nal wall (48%), with few arising in the trunk or limbs (59).
Most tumors are solitary (58%), although the number of tu-
mors per individual can range from 1 to 10 (59). Although
most abdominal wall tumors are asymptomatic, intraabdom-
inal tumors can cause abdominal pain, or can be complicated
by bowel obstruction or perforation, ureteric obstruction, in-
testinal hemorrhage, even enterocutaneous fistula (59). The
have been linked to trauma, particularly abdominal surgery
such as prophylactic colectomy. In a Canadian retrospective
study, 80% of desmoids developed postcolectomy, after an
average of 4.6 yr (60). Females have twice the odds of devel-
oping desmoids compared to males (57, 61). Family history,
presence of osteomas, and germline mutations after codon
desmoid occurrence (57, 61). To this day, treatment remains
a challenge. Surgical excision carries risks of bleeding and
short bowel syndrome, with recurrence rates as high as 45%
(62). Nonsteroidal antiinflammatories (usually sulindac) and
antiestrogens have been used, but less than a third of the tu-
mors stabilize or regress (59, 62). Results from the use of
Another malignancy associated with FAP is thyroid cancer,
with an estimated incidence of 1–2% (63, 64). The average
age of diagnosis is 25 to 33 yr, with an overwhelming pre-
tological type of thyroid cancer in these patients is papillary
(>75%), with an unusual cribriform pattern (63–67). Most
tumors are multicentric, unilateral (64–66), with one North
American series reporting a strong predilection for the left
with a low metastatic potential and 10-yr mortality (63–65,
of the thyroid gland, there is ongoing debate about the need
for additional radiological screening, due to the rarity and
excellent long-term prognosis of these tumors.
Hepatoblastomas are rapidly progressive embryonal liver tu-
mors, usually affecting children under the age of 2.5 yr, with
have made the link between these lethal tumors and a family
history of FAP (69–74). Indeed, the incidence of hepatoblas-
Table 1. Extracolonic Cancer Risks in FAP
Note. Adapted from Giardiello et al. (78), Jagelman et al. (76), Sturt et al. (57), Lynch
et al. (58), B¨ ulow et al. (27).
∗The Leeds Castle Polyposis Group.
1 in 100,000 in the general population (75). As with sporadic
at risk (72).
Other Extracolonic Malignancies
Although rare, five cases of jejunal and one case of ileal ade-
nocarcinoma were reported by Jagelman et al. among 1,255
patients with FAP (76). Other extraintestinal cancers associ-
ated with FAP include adrenal, pancreatic, and biliary tract
malignancies. Patients from the Johns Hopkins Registry had
a relative risk of pancreatic adenocarcinoma of 4.46 com-
pared to the general population, with an absolute risk of 21.4
cases per 100,000 person-years (77). Table 1 summarizes the
different extracolonic malignancies with their relative and
lifetime risks (27, 57, 58, 76, 78).
SPECIFIED VARIANTS OF FAP
Gardner syndrome is more of a historically coined variant
of FAP rather than a truly distinct subtype of the disease. It
is characterized by the association of gastrointestinal poly-
posis with osteomas, as well as multiple skin and soft tissue
tumors (79–81), including desmoids and thyroid tumors. Al-
though most FAP patients can be found to have at least sub-
tle findings of Gardner syndrome on thorough investigation,
the term is usually used by health professionals to refer to
patients and families where the aforementioned extraintesti-
cur in the mandible, but can also present in the skull and
long bones (82). Benign and painless, they usually precede a
clinical or radiological diagnosis of intestinal polyposis (82).
Epidermal cysts are the most common skin manifestation of
Gardner syndrome, typically occurring at an earlier age and
at multiple sites, including the face, scalp, and extremities
(82). Other cutaneous features of the syndrome include lipo-
mas, fibromas, and leiomyomas. Dental abnormalities, such
as supernumerary and impacted teeth, are seen in 22–30%
Familial Adenomatous Polyposis389
of FAP patients on panoramic radiographs, and constitute yet
another feature of Gardner syndrome (83–85).
conjunction with colorectal polyposis (86). Turcot syndrome
colorectal cancer syndrome (HNPCC), attributable to muta-
tions in mismatch repair genes. In families with germline
APC mutations, the most common CNS tumor is medul-
loblastoma, although anaplastic astrocytomas and ependy-
momas have also been described (87). This contrasts with
HNPCC, where the major associated CNS tumor seems to
be glioblastoma (87). Strict neurological evaluation has been
recommended for FAP families with a member affected by a
CNS tumor, due to evidence of familial clustering (87). No
guidelines exist, however, and there are no studies so far to
determine whether such an intervention could improve sur-
Hereditary Desmoid Disease
In 1996, Eccles et al. proposed the existence of yet another
variant of FAP, termed “hereditary desmoid disease” (HDD).
inherited across three generations, but occurring at sites un-
usual for FAP-related desmoid disease (paraspinal muscles,
who had a palpable rectal mass, and another who had <50
adenomatous polyps documented by colonoscopy (88). Like
FAP, HDD was inherited in an autosomal-dominant fashion,
Figure 2. APC cDNA (below) and extracolonic genotype–phenotype correlations (above). Except for CHRPE (congenital hypertrophy of
the retinal pigment epithelium), most lesions can occur with mutations anywhere along the APC gene, but are more likely in the locations
illustrated. AFAP = attenuated FAP. Adapted from Fearnhead et al. (7), Foulkes (8), Bertario et al. (84), and Cetta et al. (92).
with 100% penetrance. All affected family members were
found to have truncating frameshift mutations at codon 1924
of the APC gene, located in the 3?half of exon 15 (88).
Several genotype–phenotype correlations have been consis-
tently observed (Fig. 2). As regards aggressivity of the dis-
ease, mutations at codon 1309 have been typically associated
with a more severe clinical phenotype. Patients with muta-
tions at this site tend to develop bowel symptoms more than
sites (89), and have significantly more colorectal polyps (ap-
proximately 4,000) at the time of colectomy compared with
matched FAP controls (90). Also, mutations at codon 1309
35 yr) (84).
As regards extracolonic manifestations, mutations from
codons 976 to 1067 are associated with a three- to four-
fold increased risk for developing duodenal adenomas, while
those spanning between codons 543 and 1309 are associated
with a high risk of CHRPE (84). In fact, CHRPE lesions are
tematically present with mutations past this exon (55). Mu-
tations beyond codon 1309 are linked to a six-fold increased
tions concentrated between codons 1445 and 1580 (89, 91).
Patients with papillary thyroid cancer often have mutations
between codons 140 and 1309, the majority of which are
concentrated in the CHRPE-associated area on exon 15 (92).
Mutations beyond codon 1444 are associated with a two-fold
increased risk of osteomas (84, 93).
390 Galiatsatos and Foulkes
Apart from mutation site, variations in phenotype have
also been potentially attributed to environmental factors, as
well as interdependence of first and second hits, consistent
with Knudson’s two-hit hypothesis. Moreover, the discovery
of a modifier locus (Mom1) on chromosome 4 of the mouse
polyposis model (94) has led to the identification of a pos-
sible modifier gene on human chromosome 1p35–36, which
may also be implicated in the clinical heterogeneity of FAP
(95,96). Variations in the N-acetyltransferase loci NAT1 and
NAT2, located on chromosome 8p22, have also been shown
to affect the severity of disease (97). These modifier genes
are not in clinical use at this point in time. In most cases, the
family history is the best guide as to the likely phenotypic
expression of APC mutations.
MULTIPLE COLORECTAL ADENOMA SYNDROMES
Attenuated familial adenomatous polyposis (AFAP) is a phe-
notypically distinct variant of FAP, characterized by the pres-
ence of fewer than 100 adenomas, a more proximal colonic
location of polyps, and delayed age of CRC onset (15 yr later
than patients with classic FAP). The cumulative risk of CRC
occur in the proximal colon (98). Patients often have no fam-
ily history of polyps or CRC, and lack extracolonic features,
AFAP arises from mutations in the extreme proximal
or distal portions of the APC gene, specifically truncating
frameshift mutations at the 3?end of the gene (100–104), and
Also reported as a cause of AFAP are nonsense mutations at
exon 9 (100, 101).
APC Gene Polymorphisms
Only a minority of patients with “multiple colorectal ade-
nomas” (usually defined as the presence of 3–100 colonic
adenomas) harbor an identifiable APC germline mutation,
which has made genetic diagnosis challenging. In a British
study of 164 unrelated patients with multiple colorectal ade-
nomas, only 8.5% carried germline APC variants, with pos-
the missense polymorphism E1317Q, carried by 4.3% of pa-
tients (relative risk 11.17, p < 0.001), while 1.8% of the
the E1317Q variant are so far contradictory and controver-
sial. Frayling et al. found an E1317Q variant to be present in
2 of 134 multiple adenoma patients, 2 of 30 CRC patients,
but in none of 80 controls (106). In another study, the odds
was 2.0, but did not reach statistical significance (p = 0.4)
(107). More recent studies have shown no difference in the
prevalence of this variant between patients with multiple col-
orectal adenomas and controls (108–110). This variant was
also absent in 194 Swedish CRC patients, with sporadic or
familial tumors (111).
MYH Associated Polyposis
More recently, an autosomal recessive type of oligopolypo-
sis has also been recognized, involving the human MutY
homologue (MYH, or more accurately MUTYH) gene, re-
ferred to as MYH associated polyposis (MAP). MYH, lo-
cated on the short arm of chromosome 1, is a base excision
repair gene preventing mutations from products of oxidative
damage, particularly the oxidized guanine lesion 8-oxodG
(112). Biallelic mutations in MYH were first associated with
polyposis after the study of a family with multiple colorec-
tal adenomas/carcinomas, who lacked inherited mutations in
have also been found to be homozygous or compound het-
erozygous carriers of MYH mutations. Y165C and G382D
missense mutations account for the majority (>80%) of
disease-causing alleles in Caucasians, whereas E466X non-
sense mutation has been identified in Indian families, and
Y90X in Pakistani families (114). A mutation in exon 14 of
the MYH gene, 1395delGGA, has also recently been identi-
fied in three Italian patients with colorectal polyposis (115).
In a British study of multiple colorectal adenoma patients,
Other studies have noted similar frequencies of MYH alter-
ations in multiple colorectal adenoma patients, ranging from
23% to 36% (114, 117). No unaffected carrier of biallelic
cohort study to date, including 2,239 CRC cases and 1,845
controls from across Scotland, G382D/G382D homozygotes
and Y165C/G382D compound heterozygotes had a 93-fold
excess risk of CRC (95% CI 42–213) compared to wild-type
individuals, while all G382D/G382D homozygote carriers
had developed CRC by the age of 65 years (119). The impli-
cations of a single MYH-mutated allele remain unclear, but
the risk for CRC is unlikely to be more than 50% increased.
In Sieber’s study of multiple adenoma patients, 6 patients
(3.8%) were heterozygotes for an MYH mutation, and had
3–12 (median of 4) adenomas in the colon, as opposed to
18–100 adenomas in homozygous carriers (116). In a Cana-
dian case-control study comparing 1,238 CRC patients and
1,255 healthy controls, 2.34% of case patients versus 1.67%
of control subjects were heterozygous for either the Y165C
or G382D mutation, suggesting a possible weakly penetrant
autosomal-dominant inheritance pattern of increased CRC
risk associated with monoallelic germline MYH mutations
(120). Carriers of either single mutation had a combined OR
of 1.4 for CRC, although this did not reach statistical signif-
icance (95% CI 0.8–2.5) (120). In the Scottish cohort study
mentioned above, there was a 1.68-fold excess risk of CRC
(95% CI 1.07–2.95) for heterozygote carriers aged >55 yr,
Familial Adenomatous Polyposis391
while the risk for heterozygotes of all ages did not reach sta-
tistical significance (119). Further studies are needed before
more accurate estimates of risk can be quoted.
Screening of patients and family members, with timely treat-
ment of affected individuals, has led to a 55% reduction in
the occurrence of CRC at diagnosis of FAP, and an improve-
ment in cumulative survival for all FAP patients (121, 122).
The American Gastroenterological Association recommends
an annual sigmoidoscopy, beginning at the age of 10–12 yr,
for patients with a genetic diagnosis of FAP, or at-risk fam-
ily members who have not undergone genetic testing (123).
Most authors also recommend front and/or side-viewing en-
doscopies of the stomach, duodenum, and periampullary re-
gion, every 6 months to 4 yr depending on the polyp burden
(27, 35, 36, 124). Some even advocate the systematic use of
0.5% indigo carmine dye, and routine biopsy of the duode-
nal papilla, even in the absence of macroscopic lesions (30).
As far as thyroid cancer is concerned, most would agree that
it is reasonable to include a simple thyroid palpation in the
routine physical exam (63), while others would go as far as
recommending routine thyroid ultrasonography (77). Some
experts recommend screening for hepatoblastomas in chil-
exist. Proposed algorithms for screening probands and unaf-
fected first-degree relatives are presented in Figure 3A and
Colectomy is the recommended treatment to reduce the risk
of colorectal cancer in FAP patients with adenomatosis. In
children and adolescents, surgery can usually be safely post-
scopies, until an appropriate psychological age is reached
where colectomy can be accepted (usually late teens to early
twenties). Surgical options include a subtotal colectomy with
ileorectal anastomosis, a total proctocolectomy with a conti-
nent ileostomy, or a proctocolectomy with ileoanal pouch.
Subtotal colectomy with ileorectal anastomosis (IRA), al-
though simpler and traditionally associated with less periop-
erative complications and better functional results, has be-
come a less attractive option due to an ongoing CRC risk
associated with residual rectal mucosa. The estimated cumu-
lative risk of rectal cancer with this limited procedure is 10%
at the age of 50 yr, reaching up to 29% by the age of 60
yr (126). Meanwhile, others have argued that the risk of dy-
ing from rectal cancer after an IRA is only 2% after a 15-yr
follow-up, making it an acceptable primary treatment option
for FAP patients (127). Laparoscopic colectomy with IRA
has also proven to be a safe and minimally invasive treatment
surveillance of the remaining rectum approximately every 6
months, for recurrent adenomas or cancer (126).
Proctocolectomy with an ileal pouch–anal anastomosis
(IPAA) has emerged as the surgical treatment of choice, al-
lowing for complete resection of vulnerable colorectal mu-
cosa, while preserving transanal defecation. Although IPAA
has been associated with a higher rate of postoperative com-
plications, the functional results of IRA and IPAA appear to
be similar, as far as the frequency of bowel movements and
daytime soiling are concerned (129). Incontinence occurs in
roughly 5.9% of FAP patients with an IPAA, and the average
number of bowel movements is 5–6 per 24-h period (129,
130). Pouch failure can occur in 7.7% of FAP patients over
a 2–10-yr follow-up period, mostly due to ischemia and late-
onset pelvic sepsis (131). Pouchitis occurs in only 11% of
FAP patients, compared to 53.8% in patients with underly-
ing ulcerative colitis (130). Concerns have been raised about
a marked reduction in female fertility following IPAA, as
noted in ulcerative colitis patients (132, 133). Pelvic adhe-
sions, disrupting the normal anatomic relationships between
the fallopian tubes and ovaries, may be the cause. In a recent
study by Olsen et al., the fecundity of women with FAP after
IPAA dropped to 46% compared to the preoperative level (p
= 0.001), while there was no observed change in fecundity
before and after IRA (133). Still, the fertility rate of women
after IPAA was greater for those with FAP compared to ul-
cerative colitis (134).
IPAA patients remain at risk for ileal polyps. The risk of
developing adenomas within the ileal pouch 5, 10, and 15 yr
after proctocolectomy is roughly 7%, 35%, and 75%, respec-
tively (135). Others have estimated an incidence of 53% to
as high as 83%, 10–20 yr postsurgery (136, 137). The risk
patients undergoing a mucosectomy with hand-sewn anasto-
mosis, compared with the simpler, more traditional stapled
anastomosis (138). Although IPAA significantly decreases
the residual risk of rectal cancer that accompanies an IRA,
there have been four cases of invasive adenocarcinoma at
the ileoanal anastomosis (139–142), one case of adenocar-
cinoma within the ileal pouch (143), and two cases of ade-
nocarcinoma within the anal transitional zone (144) reported
in the literature. Continued endoscopic surveillance of the
ileoanal anastomosis is probably warranted, although no for-
mal guidelines exist.
Medical interventions for CRC prevention have also been
proposed, although at this point in time they are not effective
enough to be considered a reasonable alternative to surgery.
Sulindac, a nonsteroidal antiinflammatory drug, has been
proven to cause regression of colorectal adenomas in FAP
patients, by the induction of apoptosis (145). Most studies,
however, have shown incomplete polyp regression, and over
short follow-up periods (≤1 yr) (146–150). Long-term ben-
efits of sulindac therapy for FAP patients having had IRA
are inconsistent, ranging from no difference (151), to a 72%
decrease in baseline polyp number (152). COX-2 inhibitors
392 Galiatsatos and Foulkes
Proband with clinical diagnosis of FAP
No mutation identified
Second-line genetic testing:
MAMA, MLPA. Consider
Refer for appropriately
every 6 months.
or other NSAID to
incidence of rectal
forward + side-viewing upper
endoscopy every 1-3yrs
(depending on polyp burden)
annual thyroid exam by
palpation (consider U/S)
consider periodic abdominal
U/S for pancreatic cancer +
desmoid tumor screening
consider routine alpha-
fetoprotein and liver U/S for
children of proband until age 5.
Offer first-line genetic testing: full DNA
sequencing of APC gene
relatives genetic testing
for known mutation
Mutation identified Mutation not identified
relatives with flexible
sigmoidoscopy as of age
10-12. Consider eye
exam for CHRPE. If
proband has CHRPE,
offer eye exam to first-
degree relatives as
No mutation identified in
proband, or mutation
identified but relative refuses
or has no access to genetic
annually starting at age 10-12,
biennially from 26-35, every
third year from 36-50.
Consider eye exam for CHRPE.
proband as of age 10-12
Unaffected first-degree relative of FAP proband
or mutation identified in
Proband not available for
from age 10-12
colon cancer screening
Refer for appropriately
Total colectomy with
IPAA. Periodic flexible
sigmoidoscopy for pouch
Subtotal colectomy with IRA.
Flexible sigmoidoscopy every 6
months. Consider sulindac or other
NSAID to decrease incidence of rectal
forward + side-viewing upper endoscopy
every 1-3yrs (depending on polyp
annual thyroid exam by palpation
consider periodic abdominal U/S for
pancreatic cancer + desmoid tumor
If no polyps
by age 50,
Offer relative genetic testing
(as in Fig 3a)
Onset of polyps
Follow algorithm as for
families where no mutation is
identified in proband
Figure 3. (A) Algorithm for proband with clinical diagnosis of FAP.∗Extracolonic cancer screening is not yet established for MYH mutation
carriers. (B) Algorithm for first-degree relatives of FAP proband. CHRPE = congenital hypertrophy of the retinal pigment epithelium, IPAA
= ileal pouch-anal anastomosis, IRA = ileorectal anastomosis, MAMA = monoallelic mutation analysis, MLPA = multiplex ligation-
dependant probe amplification, NSAID = nonsteroidal antiinflammatory drug, U/S = ultrasound.
have also been investigated. Celecoxib was proven to signif-
icantly decrease duodenal polyposis after 6 months of high-
dose treatment (400 mg twice daily) (153). Rofecoxib was
also shown to reduce the rate of colorectal polyp formation
in eight patients with FAP (154). Recent reports, however, of
increased cardiovascular and thrombotic events with COX-2
inhibitors in adenoma chemoprevention trials are cause for
concern (155, 156), and make the use of these drugs for this
indication much less appealing.
Although surgical prophylactic measures have favor-
ably changed the natural history of FAP with regards to
CRC risk, management of duodenal adenomatosis remains
a challenge. There are several endoscopic options avail-
able, including snare polypectomy, thermal ablation (using
Familial Adenomatous Polyposis 393
monopolar/bipolar cautery or argon plasma), and laser coag-
ulation. Unfortunately, the multiplicity of lesions, their of-
ten sessile or flat configuration, and the risk of scarring and
stricturing of the ampulla as a result of repeated excisions
and diathermy limit their usefulness. Photodynamic therapy
(PDT) is a method used to induce localized necrosis using an
endoscopic light after the administration of a photosensitiz-
ing agent. There is still very little experience in using PDT to
treat duodenal polyps in FAP, and one pilot study has shown
only limited responses, with reduction in adenoma size but
no complete eradication (157). A more radical approach for
isolated extraductal ampullary lesions involves endoscopic
snare papillectomy with or without pancreatic stent place-
ment. This technique seems to be well tolerated, with an 8–
15% complication rate (including pancreatitis, bleeding, and
perforation); however, adenomas have been shown to recur
The high prevalence of FAP-associated duodenal adeno-
mas, the difficulty in early detection of duodenal cancer, the
for severe or progressive duodenal adenomatosis. However,
the optimal timing and technique remain unclear, and con-
clusive evidence of improved prognosis with early surgical
treatment is still lacking.
Most experts agree that prophylactic surgery should
be considered for Spigelman stage III–IV polyps (villous
changes, severe dysplasia), rapidly growing lesions, peri-
ampullary adenomas in patients over 35–40 yr of age, par-
ticularly if there is a family history of duodenal cancer
duodenotomy with surgical polypectomy, and ampullectomy
mas within 6–36 months (162). There are few follow-up data
on the use of pancreas-sparing duodenectomy, and concern
that cancer may develop in the area of mucosa surrounding
the ampulla that is left behind. PPPDR is the preferred pro-
cedure in most centers. Notwithstanding, there is a reported
morbidity and mortality rate in the range of 40% and 4.5%,
patients due to adhesions and desmoplastic changes related
to previous surgery, notably colectomy.
Genetic counseling is essential in the management of FAP
patients and families, and in most centers constitutes a pre-
requisite for genetic testing. Not only do individuals need
to understand the clinical aspects and implications of FAP,
they must be made aware of the risks, benefits, and limita-
tions of genetic testing in order to make an informed deci-
sion, and be prepared to cope with the eventual results. The
American Society of Clinical Oncology (ASCO) advocates
that genetic testing only be done in the setting of pre- and
posttest counseling, to address the clinical, psychological,
and ethical issues that are raised during the process (164). In
a nationwide study of 177 American patients being tested for
APC gene mutations, only 18.6% received pretest counsel-
ing, while only 16.9% provided informed consent (165). The
authors found that nearly 20% of tests were ordered for indi-
cations considered unconventional, resulting in a low rate of
positive results (2.3%) in this subgroup of individuals (165).
Also, it was estimated that as many a third of patients tested
ity of many physicians interviewed to correctly interpret the
would likely have avoided many of these problems. Ideally,
genetic counseling sessions should be face-to-face, with a
professional who could collect the necessary data to con-
struct a three-generation pedigree, educate the patient and
family as to the medical aspects of the disease, the inher-
itance pattern, and the recommended screening guidelines,
explore the psychosocial aspects of testing, obtain informed
consent, disclose the results and address the risks and man-
agement, as well as be available to answer further questions
and assure follow-up when this is required (166, 167).
FAP is an autosomal-dominant syndrome, most commonly
caused by a truncating mutation in the APC gene at chromo-
colonic adenomas, with an almost inevitable progression to
relations have been observed. An attenuated form of FAP
exists, characterized by the development of <100 colorectal
adenomas, and a delayed CRC onset. MYH-associated poly-
posis is an distinct autosomal recessive condition, caused by
mutations in the MYH gene, which should figure in the dif-
ferential diagnosis of anyone with multiple colorectal ade-
nomas, particularly in the absence of an identifiable APC
all FAP patients and at-risk family members. The optimal
treatment remains prophylactic colectomy, while continued
surveillance of the rectal remnant or ileoanal anastomosis
seems warranted because of ongoing risks of adenomas and
carcinomas within residual mucosa.
Although heightened awareness, endoscopic surveillance,
and the establishment of polyposis registries have success-
fully decreased the incidence and mortality from CRC, the
challenge now lies in determining the optimal screening and
therapeutic modalities for associated extracolonic malignan-
cies that are consequently becoming more prominent. The
emergence of capsule endoscopy raises the question of its
utility in detecting small bowel polyps and cancers in the
394 Galiatsatos and Foulkes
context of FAP, as in other hereditary polyposis syndromes.
tomy with or without thermal ablation are being evaluated as
the aim is to decrease morbidity, and strive for longevity and
an acceptable quality of life for those affected.
Ph.D., Department of Medical Genetics, Room A801, Sir Mortimer
B. Davis Jewish General Hospital, 3755 Cˆ ote Ste-Catherine, Mon-
treal, QC, H3T 1E2, Canada.
Received July 11, 2005; accepted September 12, 2005.
rate. Hum Mutat 1994;3:121–5.
2. Bussey HJR. Familial polyposis coli; family studies,
histopathology, differential diagnosis, and results of treat-
ment. Baltimore: John Hopkins University Press, 1975.
gene for familial adenomatous polyposis on chromosome
5. Nature 1987;328:614–6.
4. Kinzler KW, Nilbert MC, Su LK, et al. Identification
of FAP locus genes from chromosome 5q21. Science
5. Groden J, Thliveris A, Samowitz W, et al. Identification
coli gene. Cell 1991;66:589–600.
6. Van Es JH, Giles RH, Clevers HC. The many faces of the
tumor suppressor gene APC. Exp Cell Res 2001;264:126–
Hum Mol Genet 2001;10:721–33.
8. Foulkes WD. A tale of four syndromes: Familial adeno-
Turcot syndrome. Q J Med 1995;88:853–63.
9. N¨ athke I. APC at a glance. J Cell Sci 2004;117:4873–5.
coli tumor suppressor. J Clin Oncol 2000;18:1967–79.
11. B´ eroud C, Soussi T. APC gene: Database of germline and
somatic mutations in human tumors and cell lines. Nucl
Acids Res 1996;24:121–4.
12. Nagase H, Nakamura Y. Mutation of the APC (adenoma-
tous polyposis coli) gene. Hum Mutat 1993;2:425–34.
13. Heinimann K, Thompson A, Locher A, et al. Nontruncat-
ing APC germ-line mutations and mismatch repair defi-
ciency play a minor role in APC mutation-negative poly-
posis. Cancer Res 2001;61:7616–22.
14. Laken SJ, Papadopoulos N, Petersen GM, et al. Analysis
of masked mutations in familial adenomatous polyposis.
Proc Natl Acad Sci USA 1999;96:2322–6.
15. Casey G, Lindor NM, Papadopoulos N, et al. Conver-
sion analysis for mutation detection in MLH1 and MSH2
in patients with colorectal cancer. J Am Med Assoc
16. Meuller J, Kanter-Smoler G, Nguyen AO, et al. Identifi-
cation of genomic deletions of the APC gene in familial
adenomatous polyposis by two independent quantitative
techniques. Genet Test 2004;8:248–56.
17. Laken S, Petersen G, Gruber S, et al. Familial colorectal
cancer in Ashkenazim due to a hypermutable tract in APC.
Nat Genet 1997;17:79–83.
allele and cancer risk in a community-based study of
Ashkenazi Jews. Nat Genet 1998;20:62–5.
tibility to colorectal adenomas and carcinomas: Evidence
for a new predisposition gene on 15q14-q22. Gastroen-
20. Jaeger EE, Woodford-Richens KL, Lockett M, et al. An
syndrome. Am J Hum Genet 2003;72:1261–7.
21. Sieber OM, Lipton L, Crabtree M, et al. Multiple colorec-
tal adenomas, classic adenomatous polyposis, and germ-
line mutations in MYH. N Engl J Med 2003;348:791–
22. Bjork J, Akerbrant H, Iselius L, et al. Epidemiology of
familial adenomatous polyposis in Sweden: Changes over
time and differences in phenotype between males and fe-
males. Scand J Gastroenterol 1999;34:1230–5.
23. Burt RW, Bishop DT, Lynch HT, et al. Risk and surveil-
lance of individuals with heritable factors for colorectal
cancer. WHO Collaborating Centre for the Prevention of
familial adenomatous polyposis derived from the database
of the Polyposis Registry of Japan. Int J Clin Oncol
25. Bulow S, Bulow C, Nielsen TF, et al. Centralized reg-
istration, prophylactic examination, and treatment results
in improved prognosis in familial adenomatous polyposis.
Results from the Danish Polyposis Register. Scand J Gas-
26. Jarvinen HJ. Epidemiology of familial adenomatous poly-
posis in Finland: Impact of family screening on the
colorectal cancer rate and survival. Gut 1992;33:357–
27. B¨ ulow S, Bj¨ ork J, Christensen IJ, et al. Duodenal ade-
nomatosis in familial adenomatous polyposis. The DAF
Study Group. Gut 2004;53:381–6.
28. Bertoni G, Sassatelli R, Nigrisoli E, et al. High preva-
lence of adenomas and microadenomas of the duodenal
papilla and periampullary region in patients with famil-
ial adenomatous polyposis. Eur J Gastroenterol Hepatol
29. Arvanitis ML, Jagelman DG, Fazio VW, et al. Mortality in
patients with familial adenomatous polyposis. Dis Colon
30. Saurin JC, Gutknecht C, Napoleon B, et al. Surveillance
of duodenal adenomas in familial adenomatous polyposis
reveals high cumulative risk of advanced disease. J Clin
31. Vasen HFA, B¨ ulow S, Myrhøj T, et al. Decision analysis
in the management of duodenal adenomatosis in familial
adenomatous polyposis. Gut 1997;40:716–9.
32. Bj¨ orkJ,˚AkerbrantH,IseliusL,etal.Periampullaryadeno-
mas and adenocarcinomas in familial adenomatous poly-
posis: Cumulative risks and APC gene mutations. Gas-
33. Watanabe H, Enjoji M, Ohsato K. Gastric lesions in
Familial Adenomatous Polyposis395
familial adenomatosis coli: Their incidence and histologic
analysis. Hum Pathol 1978;9:269–83.
34. Iida M, Yao T, Itoh H, et al. Natural history of
fundic gland polyposis in patients with familial ade-
nomatosis coli/Gardner’s syndrome. Gastroenterology
35. Sarre RG, Frost AG, Jagelman DG, et al. Gastric and
duodenal polyps in familial adenomatous polyposis: A
prospective study of the nature and prevalence of upper
gastrointestinal polyps. Gut 1987;28:306–14.
denal polyps in patients with familial adenomatous poly-
posis. Dis Colon Rectum 1992;35:1170–3.
37. Kinoshita Y, Tojo M, Yano T, et al. Incidence of fundic
gland polyps without familial adenomatous polyposis.
Gastrointest Endosc 1993;39:161–3.
38. Marcial MA, Villafana M, Hernandez-Denton J, et al.
tures. Am J Gastroenterol 1993;88:1711–3.
39. Odze RD, Marcial MA, Antonioli D. Gastric fundic gland
polyps: A morphological study including mucin histo-
chemistry, stereometry, and MIB-1 immunohistochem-
istry. Hum Pathol 1996;27:896–903.
40. Nakamura S, Matsumoto T, Kobori Y, et al. Impact of He-
licobacter pylori infection and mucosal atrophy on gastric
lesions in patients with familial adenomatous polyposis.
41. Wu TT, Kornacki S, Rashid A, et al. Dysplasia and dys-
of fundic gland polyps from patients with familial adeno-
matous polyposis. Am J Surg Pathol 1998;22:293–8.
42. Coffey RJ, Knight CD, Van Heerden JA, et al. Gastric ade-
nocarcinoma complicating Gardner’s syndrome in a North
American woman. Gastroenterology 1985;88:1263–6.
43. Goodman AJ, Dundas SA, Scholefield JH, et al. Gastric
carcinoma and familial adenomatous polyposis (FAP). Int
J Colorectal Dis 1988;3:201–3.
44. Zwick A, Munir M, Ryan CK, et al. Gastric adenocarci-
attenuated adenomatous polyposis coli. Gastroenterology
45. Hofg¨ artner WT, Thorp M, Ramus MW, et al. Gastric ade-
nocarcinoma associated with fundic gland polyps in a pa-
tient with attenuated familial adenomatous polyposis. Am
J Gastroenterol 1999;94:2276–81.
46. Abraham SC, Nobukawa B, Giardiello FM, et al. Fundic
gland polyps in familial adenomatous polyposis. Am J
47. Abraham SC, Nobukawa B, Giardiello FM, et al. Spo-
radic fundic gland polyps: Common gastric polyps arising
through activating mutations in the β-catenin gene. Am J
48. Ruhswurm I, Zehetmayer M, Dejaco C, et al. Ophthalmic
and genetic screening in pedigrees with familial adenoma-
tous polyposis. Am J Ophthalmol 1998;125:680–6.
49. Romania A, Zakov ZN, McGannon E, et al. Congenital
hypertrophy of the retinal pigment epithelium in famil-
ial adenomatous polyposis. Ophthalmology 1989;96:879–
50. Traboulsi EI, Krush AJ, Gardner EJ, et al. Prevalence and
importance of pigmented ocular fundus lesions in Gard-
ner’s syndrome. N Engl J Med 1987;316:661–7.
51. Hartvigsen A, Myrhoj T, B¨ ulow S, et al. Ophthalmoscopy
for congenital hypertrophy of the retinal pigment epithe-
lium (CHRPE) in patients with sporadic colorectal carci-
noma. Int J Colorect Dis 1995;10:138–9.
52. Traboulsi EI, Maumenee IH, Krush AJ, et al. Pigmented
cancer. Ophthalmology 1988;95:964–9.
53. Tiret A, Taiel-Sartral M, Tiret E, et al. Diagnostic value of
fundus examination in familial adenomatous polyposis. Br
J Ophthalmol 1998;81:755–8.
54. Morton DG, Gibson J, Macdonald F, et al. Role of con-
genital hypertrophy of the retinal pigment epithelium in
the predicitve diagnosis of familial adenomatous polypo-
sis. Br J Surg 1992;79:689–93.
55. Olschwang S, Tiret A, Laurent-Puig P, et al. Restriction
of ocular fundus lesions to a specific subgroup of APC
mutations in adenomatous polyposis coli patients. Cell
56. Miyoshi Y, Iwao K, Nawa G, et al. Frequent mutations
in the beta-catenin gene in desmoid tumors from pa-
tients without familial adenomatous polyposis. Oncol Res
57. Sturt NJH, Gallagher MC, Bassett P, et al. Evidence for
genetic predisposition to desmoid tumours in familial ade-
tation. Gut 2004;53:1832–6.
familial adenomatous polyposis: Case report and literature
review. Am J Gastroenterol 1996;91:2598–601.
complicating familial adenomatous polyposis. Br J Surg
60. Soravia C, Berk T, McLeod RS, et al. Desmoid disease in
patients with familial adenomatous polyposis. Dis Colon
61. Bertario L, Russo A, Sala P, et al. Genotype and phe-
notype factors as determinants of desmoid tumors in pa-
tients with familial adenomatous polyposis. Int J Cancer
62. Heiskanen I, J¨ arvinen HJ. Occurence of desmoid tumours
Int J Colorect Dis 1996;11:157–62.
63. B¨ ulow C, B¨ ulow S, Leeds Castle Polyposis Group. Is
screening for thyroid carcinoma indicated in familial ade-
nomatous polyposis? Int J Colorectal Dis 1997;12:240–
type of patients with both familial adenomatous polyposis
and thyroid carcinoma. Fam Cancer 2003;2:95–9.
65. Perrier ND, Van Heerden JA, Goellner JR, et al. Thyroid
cancer in patients with familial adenomatous polyposis.
World J Surg 1998;22:738–42.
66. Harach HR, Williams GT, Williams ED. Familial adeno-
matous polyposis associated thyroid carcinoma: A dis-
tinct type of follicular cell neoplasm. Histopathology
67. Cameselle-Teijeiro J, Chan JK. Cribriform-morular vari-
ant of papillary carcinoma: A distinctive variant repre-
senting the sporadic counterpart of familial adenoma-
tous polyposis-associated thyroid carcinoma? Mod Pathol
68. Hartley AL, Birch JM, Kelsey AM, et al. Epidemiological
69. Kingston JE, Herbert A, Draper GJ, et al. Association be-
tween hepatoblastoma and polyposis coli. Arch Dis Child
70. Garber JE, Li FP, Kingston JE, et al. Hepatoblastoma
and familial adenomatous polyposis. J Natl Cancer Inst
71. Bernstein IT, Bulow S, Mauritzen K. Hepatoblastoma in
396 Galiatsatos and Foulkes
two cousins in a family with adenomatous polyposis. Re-
port of two cases. Dis Colon Rectum 1992;35:373–4.
72. Giardiello FM, Petersen GM, Brensinger JD, et al.
Hepatoblastoma and APC gene mutation in familial ade-
nomatous polyposis. Gut 1996;39:867–9.
73. Thomas D, Pritchard J, Davidson R, et al. Familial hep-
atoblastoma and APC gene mutations: Renewed call for
molecular research. Eur J Cancer 2003;39:2200–4.
74. Inukai T, Furuuchi K, Sugita K, et al. Nuclear accumula-
tion of beta-catenin without an additional somatic muta-
tion in coding region of the APC gene in hepatoblastoma
from a familial adenomatous polyposis patient. Oncol Rep
75. Hughes LJ, Michels VV. Risk of hepatoblastoma in
familial adenomatous polyposis. Am J Med Genet
76. Jagelman DG, DeCosse JJ, Bussey HJR. Upper gastroin-
testinal cancer in familial adenomatous polyposis. Lancet
of thyroid and pancreatic carcinoma in familial adenoma-
tous polyposis. Gut 1993;34:1394–6.
78. Giardiello FM, Offerhaus JGA. Phenotype and can-
cer risk of various polyposis syndromes. Eur J Cancer
79. Gardner EJ, Plenk HP. Hereditary pattern for multiple os-
teomas in a family group. Am J Hum Genet 1952;4:31–6.
80. Gardner EJ, Richards RC. Multiple cutaneous and subcu-
taneous lesions occuring simultaneously with hereditary
81. Gardner EJ. Follow-up study of a family group exhibiting
dominant inheritance for a syndrome including intestinal
polyposis, osteomas, fibromas and epidermal cysts. Am J
Hum Genet 1962;14:376–90.
82. Bilkay U, Erdem O, Ozek C, et al. Benign osteoma with
Gardner syndrome: Review of the literature and report of
a case. J Craniofac Surg 2004;15:506–9.
83. Oku T, Takayama T, Sato Y, et al. A case of Gardner syn-
case of genotype-phenotype correlation in dental abnor-
mality. Eur J Gastroenterol Hepatol 2004;16:101–5.
exploration of genotype-phenotype correlations in famil-
ial adenomatous polyposis. J Clin Oncol 2003;21:1698–
stigmas in patients with familial adenomatosis coli. Br J
Oral Maxillofac Surg 1986;24:410–6.
86. Turcot J, Despr´ es J-P, St Pierre F. Malignant tumors of
the central nervous system associated with familial poly-
posis of the colon: Report of two cases. Dis Colon Rectum
of Turcot’s syndrome. N Engl J Med 1995;332:839–47.
88. Eccles DM, Van der Luijt R, Breukel C, et al. Hereditary
of the APC gene. Am J Hum Genet 1996;59:1193–201.
nomatous polyposis? Experience from 680 FAP families.
90. Nugent KP, Phillips RK, Hodgson SV, et al. Phenotypic
expression in familial adenomatous polyposis: Partial pre-
diction by mutation analysis. Gut 1994;35:1622–3.
91. Gebert JF, Dupon C, Kadmon M, et al. Combined molec-
ular and clinical approaches for the identification of fam-
ilies with familial adenomatous polyposis coli. Ann Surg
92. Cetta F, Montalto G, Gori M, et al. Germline mutations
of the APC gene in patients with familial adenomatous
polyposis-associated thyroid carcinoma: Results from a
European Cooperative Study. J Clin Endocrinol Metab
93. Davies DR, Armstrong JG, Thakker N, et al. Severe Gard-
ner syndrome in families with mutations restricted to
a specific region of the APC gene. Am J Hum Genet
94. Dietrich WF, Lander ES, Smith JS, et al. Genetic iden-
tification of Mom-1, a major modifier locus affect-
ing Min-induced intestinal neoplasia in the mouse. Cell
95. Tomlinson IP, Neale K, Talbot IC, et al. A modifying lo-
cus for familial adenomatous polyposis may be present on
chromosome 1p35-p36. J Med Genet 1996;33:268–73.
a modifier gene locus on chromosome 1p35–36 in familial
adenomatous polyposis. Hum Genet 1997;99:653–7.
candidate modifier loci for the severity of colonic familial
adenomatous polyposis, with evidence for the importance
of the N-acetyl transferases. Gut 2004;53:271–6.
98. Burt RW, Leppert MF, Slattery ML, et al. Genetic testing
and phenotype in a large kindred with attenuated familial
adenomatous polyposis. Gastroenterology 2004;127:444–
99. Lynch HT, Smyrk T, McGinn T, et al. Attenuated fa-
milial adenomatous polyposis (AFAP). A phenotypically
and genotypically distinctive variant of FAP. Cancer
100. Lamlum H, Al Tassan N, Jaeger E, et al. Germline APC
evidence for the particular importance of E1317Q. Hum
Mol Genet 2000;9:2215–21.
101. Soravia C, Berk T, Madlensky L, et al. Genotype-
phenotype correlations in attenuated adenomatous poly-
posis coli. Am J Hum Genet 1998;62:1290–301.
adenomatous polyposis due to a mutation in the 3?part of
APC protein. Hum Genet 1996;97:579–84.
103. Van der Luijt RB, Khan PM, Vasen HFA, et al. Germline
mutations in the 3?part of APC exon 15 do not result in
truncated proteins and are associated with attenuated ade-
nomatous polyposis coli. Hum Genet 1996;98:727–34.
104. Brensinger JD, Laken SJ, Luce MC, et al. Variable pheno-
type of familial adenomatous polyposis in pedigrees with
3?mutation in the APC gene. Gut 1998;43:548–52.
105. Spirio L, Olschwang S, Groden J, et al. Alleles of the
APC gene: An attenuated form of familial polyposis. Cell
106. Frayling IM, Beck NE, Ilyas M, et al. The APC variants
but not always with a family history. Proc Natl Acad Sci
107. Fearnhead NS, Wilding JL, Winney B, et al. Multiple rare
ited susceptibility to colorectal adenomas. Proc Natl Acad
Sci USA 2004;101:15992–7.
108. Figer A, Irmin L, Geva R, et al. Genetic analysis of the
APC gene regions involved in attenuated APC phenotype
in Israeli patients with early onset and familial colorectal
cancer. Br J Cancer 2001;85:523–6.
Familial Adenomatous Polyposis397
E1317Q variant of the APC gene in Italian patients with
colorectal adenomas. Genet Test 2002;6:313–7.
110. Hahnloser D, Petersen GM, Rabe K, et al. The APC
111. Evertsson S, Lindblom A, Sun XF. APC I1307K and
E1317Q variants are rare or do not occur in Swedish col-
orectal cancer patients. Eur J Cancer 2001;37:499–502.
112. Slupska MM, Baikalov C, Luther WM, et al. Cloning and
sequencing a human homolog (hMYH) of the Escherichia
coli mutY gene whose function is required for the repair of
oxidative DNA damage. J Bacteriol 1996;178:3885–92.
113. Al-Tassan N, Chmiel NH, Maynard J, et al. Inherited vari-
ants of MYH associated with somatic G:C→A mutations
in colorectal tumors. Nat Genet 2002;30:227–32.
114. Sampson JR, Dolwani S, Jones S, et al. Autosomal re-
cessive colorectal adenomatous polyposis due to inherited
mutations of MYH. Lancet 2003;362:39–41.
115. Gismondi V, Meta M, Bonelli L, et al. Prevalence of
the Y165C, G382D and 1395delGGA germline muta-
tions of the MYH gene in Italian patients with adenoma-
tous polyposis coli and colorectal adenomas. Int J Cancer
adenomas, classic adenomatous polyposis, and germ-line
mutations in MYH. N Engl J Med 2003;348:791–9.
117. Venesio T, Molatore S, Cattaneo F, et al. High fre-
quency of MYH gene mutations in a subset of patients
with familial adenomatous polyposis. Gastroenterology
118. Lipton L, Tomlinson I. The multiple colorectal adenoma
phenotype and MYH, a base excision repair gene. Clin
Gastroenterol Hepatol 2004;2:633–8.
ceptibility to colorectal cancer due to base-excision repair
gene defects. Am J Hum Genet 2005;77:112–9.
120. Croitoru M, Cleary SP, Di Nicola N, et al. Associa-
tion between biallelic and monoallelic germline MYH
mutations and colorectal cancer risk. J Natl Cancer Inst
121. B¨ ulow S. Results of national registration of familial ade-
nomatous polyposis. Gut 2003;52:742–6.
122. HeiskanenI,LuostarinenT,J¨ arvinenHJ.Impactofscreen-
posis. Scand J Gastroenterol 2000;35:1284–7.
123. Winawer S, Fletcher R, Rex D, et al. (U.S. Multisoci-
ety Task Force on Colorectal Cancer). Colorectal can-
cer screening and surveillance: Clinical guidelines and
rationale—Update based on new evidence. Gastroenterol-
124. Morpurgo E, Vitale G, Galandiuk S, et al. Clinical
characteristics of familial adenomatous polyposis and
management of duodenal adenomas. J Gastrointest Surg
125. Giardiello FM, Offerhaus GJA, Krush AJ, et al. The risk
of hepatoblastoma in familial adenomatous polyposis. J
126. Nugent KP, Phillips RK. Rectal cancer risk in older pa-
tients with familial adenomatous polyposis and an ile-
orectal anastomosis: A cause for concern. Br J Surg
127. De Cosse JJ, Bulow S, Neale K, et al. Rectal cancer risk in
patients treated for familial adenomatous polyposis. The
Leeds Castle Polyposis Group. Br J Surg 1992;79:1372–
128. Milsom JW, Ludwig KA, Church JM, et al. Laparoscopic
total abdominal colectomy with ileorectal anastomosis
for familial adenomatous polyposis. Dis Colon Rectum
129. Ambroze WL Jr, Dozois RR, Pemberton JH, et al. Famil-
ial adenomatous polyposis: Results following ileal pouch-
anal anastomosis and ileorectostomy. Dis Colon Rectum
130. Barton JG, Paden MA, Lane M, et al. Comparison of post-
operative outcomes in ulcerative colitis and familial poly-
posis patients after ileoanal pouch operations. Am J Surg
131. K¨ orsgen S, Keighley MRB. Causes of failure and life
expectancy of the ileoanal pouch. Int J Colorect Dis
132. Olsen KO, Joelsson M, Laurberg S, Oresland T. Fertility
after ileal pouch-anal anastomosis in women with ulcera-
tive colitis. Br J Surg 1999;86:493–5.
133. Olsen KO, Juul S, Berndtsson I, et al. Ulcerative colitis:
Female fecundity before diagnosis, during disease, and af-
ter surgery compared with a population sample. Gastroen-
134. Olsen KO, Juul S, B¨ ulow S, et al. Female fecundity before
and after operation for familial adenomatous polyposis. Br
J Surg 2003;90:227–231.
135. Parc YR, Olschwang S, Desaint B, et al. Familial ade-
nomatous polyposis: Prevalence of adenomas in the
ileal pouch after restorative proctocolectomy. Ann Surg
136. Parc Y, Piquard A, Dozois RR, et al. Long-term outcome
coloproctectomy. Ann Surg 2004;239:378–82
137. Iida M, Itoh H, Matsui T, et al. Ileal adenomas in post-
colectomy patients with familial adenomatosis coli/ Gard-
Colon Rectum 1989;32:1034–8.
138. Van Duijvendijk P, Vasen HFA, Bertario L, et al. Cumu-
lative risk of developing polyps or malignancy at the ileal
tous polyposis. J Gastrointest Surg 1999;3:325–30.
carcinoma following colectomy with ileoanal anastomosis
for familial polyposis coli. Report of a case. Dis Colon
proctocolectomy for familial adenomatous polyposis. Am
J Surg Pathol 1996;20:995–9.
141. Vuilleumier H, Halkic N, Ksontini R, et al. Columnar cuff
cancer after restorative proctocolectomy for familial ade-
nomatous polyposis. Gut 2000;47:732–4.
142. Remzi FH, Church JM, Bast J, et al. Mucosectomy vs sta-
pled ileal pouch-anal anastomosis in patients with familial
control. Dis Colon Rectum 2001;44:1590–6.
143. Palkar VM, deSouza LJ, Jagannath P, et al. Adenocarci-
ial polyposis coli. Indian J Cancer 1997;34:16–9.
144. Ooi BS, Remzi FH, Gramlich T, et al. Anal transitional
zone cancer after restorative proctocolectomy and ileoanal
anastomosis in familial adenomatous polyposis. Report of
two cases. Dis Colon Rectum 2003;46:1418–23.
dac on colorectal proliferation and apoptosis in familial
adenomatous polyposis. Gastroenterology 1995;109:994–
146. Waddell WR, Loughry RW. Sulindac for polyposis of the
colon. J Surg Oncol 1983;24:83–7.
147. Waddell WR, Ganser GF, Cerise EJ, et al. Sulindac for
polyposis of the colon. Am J Surg 1989;157:175–9.
398 Galiatsatos and Foulkes
148. Labayle D, Fischer D, Vielh P, et al. Sulindac causes re-
gression of rectal polyps in familial adenomatous polypo-
sis. Gastroenterology 1991;101:635–9.
149. Giardiello FM, Hamilton SR, Krush AJ, et al. Treatment
of colonic and rectal adenomas with sulindac in familial
adenomatous polyposis. N Engl J Med 1993;328:131–6.
150. Giardiello FM, Offerhaus JA, Tersmette AC, et al. Sulin-
dac induced regression of colorectal adenomas in familial
adenomatous polyposis: Evaluation of predictive factors.
ment with sulindac in familial adenomatous polyposis: Is
there an actual efficacy in prevention of rectal cancer? J
Surg Oncol 2000;74:15–20.
A prospective study. Gastroenterology 2002;112:641–5.
153. Phillips RK, Wallace MH, Lynch PM, et al. A randomised,
double blind, placebo controlled study of celecoxib, a se-
lective cyclooxygenase 2 inhibitor, on duodenal polyposis
in familial adenomatous polyposis. Gut 2002;50:857–60.
154. Hallak A, Alon-Baron L, Shamir R, et al. Rofecoxib re-
duces polyp recurrence in familial polyposis. Dig Dis Sci
155. Bresalier RS, Sandler RS, Quan H, et al. Cardiovascular
events associated with rofecoxib in a colorectal adenoma
156. Solomon SD, McMurray JJ, Pfeffer MA, et al. Car-
diovascular risk associated with celecoxib in a clinical
trial for colorectal adenoma prevention. N Engl J Med
157. Mlkvy P, Messmann H, Debinski H, et al. Photodynamic
Eur J Cancer 1995;31A:1160–5.
158. Cheng CL, Sherman S, Fogel EL, et al. Endoscopic snare
test Endosc 2004;60:757–64.
159. Norton ID, Geller A, Petersen BT, et al. Endoscopic
surveillance and ablative therapy for periampullary ade-
nomas. Am J Gastroenterol 2001;96:101–6.
sis in familial adenomatous polyposis coli: A review of the
literature and results from the Heidelberg Polyposis Reg-
ister. Int J Colorectal Dis 2001;16:63–75.
161. De Vos tot Nederveen Cappel WH, J¨ arvinen HJ, Bj¨ ork
J, et al. Worldwide survey among polyposis registries of
surgical management of severe duodenal adenomatosis in
familial adenomatous polyposis. Br J Surg 2003;90:705–
severe duodenal polyposis in familial adenomatous poly-
posis. Br J Surg 1998;85:665–8.
163. Gallagher MC, Shankar A, Groves CJ, et al. Pylorus-
sparing pancreaticoduodenectomy for advanced duode-
nal disease in familial adenomatous polyposis. Br J Surg
164. American Society of Clinical Oncology (ASCO) policy
J Clin Oncol 2003;21:2397–3406.
165. Giardiello FM, Brensinger JD, Petersen GM, et al. The
use and interpretation of commercial APC gene test-
ing for familial adenomatous polyposis. N Engl J Med
166. Trimbath JD, Giardiello FM. Review article: Genetic test-
ing and counselling for hereditary colorectal cancer. Ali-
ment Pharmacol Ther 2002;16:1843–57.
167. Wong N, Lasko D, Rabelo R, et al. Genetic counseling
and interpretation of genetic tests in familial adenomatous
polyposis and hereditary nonpolyposis colorectal cancer.
Dis Colon Rectum 2001;44:271–9.