ORIGINAL ARTICLE: GASTROENTEROLOGY
Evaluation of Guidelines for Management of Familial
Adenomatous Polyposis in a Multicenter Pediatric Cohort
Anne Munck, Lamia Gargouri, yCorinne Alberti, Jerome Viala, zMichel Peuchmaur,
Catherine Lenaerts, jjLaurent Michaud, ôThierry Lamireau, yz§jjô#Jean Francois Mougenot,
Alain Dabadie, yyChantal Maurage, zzAlain Lachaux, §§Michele Scaillon, jjjjJane Languepin,
ôô
Claire Spyckerelle, ##Martine Meyer, and Sylvianne Olschwang
§
ABSTRACT
Objective: To retrospectively assess, in a pediatric multicenter cohort,
guidelines for the management of familial adenomatous polyposis (FAP).
Methods: Ten centers from the French-speaking Pediatric Gastroenterology Hepatology and Nutrition Group provided follow-up data on
patients up to 18 years of age. Clinical records, genetic test results,
endoscopy with histopathology examination, and therapeutic modalities
were reviewed.
Results: A total of 70 children from 47 families were included. When initial
consultation resulted from a surveillance program because of an affected
family member, 12 of 59 children were already symptomatic. Among 11
patients whose initial consultation was based only on symptoms, families
were unaware at the time of a familial FAP history for 7 children, whereas
only 4 cases were sporadic. A panel of 27 different pathogenic adenomatous
polyposis coli (APC) germ-line mutations and large genomic deletions were
identified in 43 families. Extracolonic manifestations were found in half of
the patients. As part of the standard practice for initial screening, the entire
cohort underwent colonoscopy, which revealed adenoma above an intact
rectosigmoid in 8 cases. Prophylactic colectomy was performed in 42 cases;
high-grade dysplastic adenoma and 1 invasive carcinoma were detected in
6 children. For timing of surgery, indications were in accordance with recent
international guidelines.
Conclusions: Defining optimal screening and therapeutic modalities in
pediatric FAP cohorts is a challenge. Specific advice for genetic
screening, endoscopy surveillance, and type of surgery based on recent
guidelines is recommended.
Received September 1, 2010; accepted March 9, 2011.
From the Pediatric Gastroenterology, Nutrition, and Cystic Fibrosis
Department, the yClinical Epidemiology Department, the zPathology
Department, Assistance Publique-Hôpitaux de Paris, Université Paris 7,
Hôpital Robert Debré, Paris, the §CHU Amiens, Amiens, the jjCHRU
Jeanne de Flandres, Lille, the ôCHU Pellegrin, Bordeaux, the #Pediatric
Gastroenterology and Nutrition, Assistance Publique-Hôpitaux de Paris,
Université Paris 5, Hôpital Necker, Paris, the CHU Hopital Sud,
Rennes, the yyCHU Clocheville, Tours, the zzCHU HFME, Lyon,
France, the §§CHU Reine Fabiola, Brussels, Belgium, the jjjjCHU
Dupuytren, Limoges, the ôôHospital Saint Vincent Lille, the ##CHU
Hotel Dieu, Clermont Ferrand, and the Centre de Recherche en
Cancérologie, UMR891 and Institut Paoli-Calmettes, Marseille, France.
Address correspondence and reprint requests to Dr Anne Munck, Pediatric
Gastroenterology, Nutrition, and Cystic Fibrosis Department, University Hospital Robert Debre, AP-HP, 48 bd Serurier 75019 Paris, France
(e-mail: anne.munck@rdb.aphp.fr).
The authors report no conflicts of interest.
Copyright # 2011 by European Society for Pediatric Gastroenterology,
Hepatology, and Nutrition and North American Society for Pediatric
Gastroenterology, Hepatology, and Nutrition
DOI: 10.1097/MPG.0b013e3182198f4d
Key Words: children, colectomy, familial adenomatous polyposis,
mutation analysis
(JPGN 2011;53: 296–302)
F
amilial adenomatous polyposis (FAP) is a highly penetrating
autosomal-dominant colorectal cancer (CRC) syndrome with
significant morbidity and mortality. This rare disease, which occurs
in 1 of 10,000 births (1), is characterized by early onset of numerous
adenomatous colorectal polyps and several extracolonic manifestations. Left untreated, there is nearly 100% progression to CRC by
age 35 to 40 years. Increased risk of malignancy at other sites,
including the brain, thyroid, and liver, has been reported. This
inherited syndrome is caused by a germ-line mutation in the APC
gene, located on chromosome 5q21 (2). Around 15% to 30% of
cases are de novo, with no clinical or genetic evidence of FAP in the
parents (3). More than 800 mutations have been described, with
some genotype–phenotype correlations; however, heterogeneity
exists in the clinical course, even among family members with
the same mutation.
In pediatrics, only small series or case reports (4–12) have
been reported. The aim of the present study was to collect a large
pediatric multicenter cohort with follow-up to 18 years of age.
Clinical presentation, genetic analysis, endoscopy, and histological
reports and outcome were assessed. International recommendations
(13,14) are discussed here because challenges lie in defining both
optimal surveillance and therapeutic modalities.
PATIENTS AND METHODS
Study Centers and Inclusion Criteria
Members of the French-speaking Pediatric Gastroenterology
Hepatology and Nutrition Group were asked to include all of the
patients 18 years or younger regularly studied for FAP, with the
presence of an APC gene mutation (family history or de novo
mutation) or with adenomatous colorectal polyposis and an
unidentified gene mutation. A letter of information was sent by
the referring physician to the selected patient’s parents, who were
free to reject participation by sending back the document with their
signature. The National Committee of Liberty and Information
approved the protocol for anonymous data collection and analysis
(Ref.MCB/AB/no.107.00, 03/03/2004).
Questionnaire
The study centers provided the following items on a standardized questionnaire: age, sex, description of family history, age
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JPGN
Volume 53, Number 3, September 2011
and symptoms at initial consultation, and associated extracolonic
manifestations. Initial and subsequent colonoscopies, esophagogastroduodenoscopies (EGD) with macroscopic findings, and
histopathology data were recorded. Polyps were classified according to their number (none, few, numerous [50 polyps], innumerable or ‘‘carpeted’’), size (<0.5 cm, 0.5–1 cm, >1 cm), and location
(rectosigmoid, left colon, midcolon, right colon, ileum, gastric,
duodenum, and unexplored region). Histopathology results were not
centrally reviewed; pathologists at their own institutions graded
adenoma dysplasia as low, mild to moderate, high, or severe and
invasive carcinoma. Histopathology reports were centrally reviewed
if high-grade dysplasia or invasive carcinoma was reported. Treatment data included, when necessary, age and type of colectomy
(subtotal colectomy with ileorectal anastomosis [IRA], total proctocolectomy or ileal pouch anal anastomosis [IPAA]), postsurgical
complications, follow-up (medication, bowel movements), and, if
the patient died, age and cause of death. All of the patients or legal
representatives signed informed consent for a genetic examination
after an interview with an authorized geneticist. Mutation analysis
was performed at the same center (SO). After genomic DNA
extraction from peripheral blood samples, the entire coding
sequence of the APC gene was screened by sequencing according
to previous reports (15). Search for large genomic rearrangements
was performed using the quantitative multiplex polymerase chain
reaction of short fluorescent fragments technique as developed by
Demange et al (16).
Statistical Analysis
Statistical analysis was carried out using SAS version 9.12
software (SAS Institute, Cary, NC). Qualitative variables were
described as numbers and percentages and quantitative variables
as medians with their quartiles (Q1–Q3). Differences were tested
by Fisher exact test for categorical variables and by Wilcoxon test
for quantitative variables. Time to colectomy was assessed by the
Kaplan-Meier curve.
RESULTS
Between March 2005 and December 2007, a total of
70 patients from 10 centers (9 in France, 1 in Belgium) were
included in the database. No families refused to participate in
the study. There were no duplicates. The oldest patient was born
in 1970 and the youngest in 1995. Table 1 provides characteristics
of the cohort issued from 47 families according to clinical or genetic
evidence of FAP in parents. All of the patients were alive at the time
of chart analysis.
Clinical Presentation
Among the 66 patients with familial FAP (Table 1), 59 had
an initial consultation within the framework of a surveillance
program for families of an affected member and 12 of these
were already symptomatic. The other 7 children had developed
symptoms before FAP diagnosis; families were unaware at that
time of an FAP history. Median age at diagnosis was younger in the
symptomatic group (8.8 years [6.5–10.1]) than in the ‘‘surveillance
asymptomatic’’ group (10.3 years [7.6–12.3]), although this difference was not found to be statistically significant. A small cohort of
4 symptomatic children represented de novo mutation patients seen
at a median age of 11.3 years [8.9–13.4].
In the overall cohort, 23 patients (33%) were symptomatic
at diagnosis, mainly with rectal bleeding (73%), abdominal pain
(36%), anemia (14%), and diarrhea (14%), whereas 1 presented
with costal osteoma.
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Evaluation of Guidelines for Management of FAP
TABLE 1. Familial adenomatous polyposis population characteristics
Variables
Patients, sex (n ¼ 70)
Male
Female
Family history (n ¼ 47)
Positive
Negative
Clinical presentation
Familial FAP
Surveillance program, asymptomatic
Surveillance program, symptomatic
Symptomatic
De novo FAP
Symptomatic
No.
%
34
36
48.5
51.4
43
4
9.5
8.5
66
47
12
7
4
4
94
71
18
10
6
100
FAP ¼ familial adenomatous polyposis.
Colonoscopy and Histology Findings
Median age at initial colonoscopy was similar in familial
FAP and de novo cases, respectively 9.7 (7.6–12.4) and 11.7 (9.1–
13.9) years. A total of 245 procedures were performed before the
patients were 18 years of age, with a median number per patient of
2 (range 1–11), and histopathology reports were available for 85%
of them. The median duration between initial colonoscopy and the
final procedure was 7 (2–10) years (with a total of 494 follow-up
years). Colorectal adenomas were identified in initial colonoscopy
in 80% of the cohort, with this percentage reaching 93% in
subsequent colonoscopy. In all of the patients presenting with rectal
bleeding, polyps were found at initial colonoscopy; thus in our
cohort, rectal bleeding predicted the likelihood of dysplasia. It is
noteworthy that in 8 children, colonic polyps were found above an
intact rectosigmoid, with 2 children presenting rectal bleeding at 8.5
and 9.5 years of age. Polyp sizes were under 0.5 cm in all of the
patients but 5; 4 had a polyp size between 0.5 and 1 cm (2 highgrade dysplastic polyps) and 1 patient had a polyp >1 cm (moderategrade dysplasia). Innumerable polyps were identified in 25 patients.
Histopathology results on preoperative endoscopy and surgical specimens from the 42 patients who underwent prophylactic colectomy
are summarized in Table 2. Exploration above the ileocecal valve
was carried out in 72% of colonoscopies, thus possibly underestimating the extent of ileal polyps. One ileal low-grade dysplastic
polyp was identified before any surgical procedure and remained
stable during the 7-year follow-up. Regular endoscopic surveillance
after both types of surgery found low-grade dysplastic polyps in
the ilea of 2 patients who underwent IPAA (remaining stable after
2- and 3-year follow-up, respectively) and in the recta of 2 patients
with IRA.
Extracolonic Manifestations
A total of 60 extracolonic manifestations were identified in
half of the cohort (Table 3). Desmoid tumors developed in 5 patients
at as early as 1.1 years of age. Follow-up remained uneventful for
all but 1 patient, who developed a mesenteric tumor that led to
compression symptoms and required surgery and conversion to
IPAA 3 years after prophylactic IRA colectomy was performed in
the late 1980 s. Osteomas and epidermoid cysts were also reported;
nevertheless, they may not have been thoroughly noted on the chart
297
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Munck et al
JPGN
TABLE 2. Colon histopathology data on the 42 patients with
PAF who underwent prophylactic colectomy
Pathology
Preoperative endoscopy (n ¼ 42)
Dysplasia
Invasive carcinoma
High-grade
Low to mild to moderate grade
No dysplasia
Surgical specimen (n ¼ 36)
Dysplasia
Invasive carcinoma
High-grade
Low to mild to moderate grade
No dysplasia
Overall (n ¼ 42)
Dysplasia
Invasive carcinoma
High-grade
Low to mild to moderate grade
No.
%
41
0
3
38
0
100
0
7
93
0
37
1
4
31
0
100
2.8
11
86
0
42
1
5
36
100
2.4
12
85.6
Data were not available for 1 patient.
by the gastroenterologist caring for patients with FAP because of
their low morbidity.
Congenital hypertrophy of the retinal pigment epithelium
(CHRPE), a highly specific phenotypic manifestation of the disease
and a predictor of the presence of FAP, was identified in 14 of the
31 documented families.
EGD was performed as part of the evaluation in 54 patients,
with a total of 155 procedures. Fundic (n ¼ 3) and/or antral (n ¼ 4)
gastric adenoma was present in 11%. Duodenal adenomas were
found in 23 patients (43%), with the youngest patient being 6.9 years
old; all of the polyps were stage I Spigelman (17) with remarkable
stability of dysplasia during the follow-up period (median duration
7 years [2–10]). One hepatoblastoma was reported in a 1-year-old
girl. One child had acute lymphoblastic lymphoma at 3 years of age
with complete remission.
Surgery and Follow-Up
Forty-two patients (60%; 18 boys and 24 girls) underwent
prophylactic colectomy. Median ages at surgery were, respectively,
13.5 (10.9–14.7) and 12 years (9.4–14). Figure 1 shows the risk of
colectomy according to age with a median of 14.9 years (95%
confidence interval 13.9–15.7); no significant difference was
observed according to date of birth.
For 25 patients, the decision for surgery relied on innumerable polyps, all with evidence of low- or moderate-grade dysplastic
foci except for 1 with high-grade dysplasia (at 11.6 years); for
11 cases, the decision was based on numerous polyps with a sharp
increase in polyp development in association with rectal bleeding in
6 patients, or else the ‘‘hot-spot’’ 1309 mutation. Finally, indication
relied on high-grade dysplasia on preoperative endoscopy in 2
children (at 13.8 and 15.5 years) and on severity of disease
expression in 4 families (hepatoblastoma [1], glioblastoma in a
sibling [1], father’s recent death [2]).
Surgery was performed on 39 children with a familial history
of FAP (58%) and on all de novo mutation patients. The surgical
procedure consisted of IRA for 14% and IPAA for 86%. The
percentage of patients experiencing complications was similar
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whatever the type of surgery, with discrepancies in their manifestations (Table 4). Locoregional infections, septicemia, postsurgical
abdominal wall desmoid tumors, and soiling after a 6-month delay
occurred only following the IPAA procedure. After IRA, the only
complication was postoperative small bowel obstruction, observed in
3 patients. Long-term medical maintenance therapy to reduce the
average number of bowel movements was required in 39% of patients
with IPAA. None of the children received postoperative chemoprevention with NSAIDs or selective cyclooxygenase-2 inhibitors.
Overall, 6 patients (8.5%), all with a family history of
FAP, presented high-grade dysplasia, with 1 invasive carcinoma at
8.8 years. Diagnosis was made based on endoscopic biopsies in 2
children with polyp size >0.5 cm and in 1 child with innumerable
polyps. For the remaining 3, diagnosis was based on surgical specimens: The indication for prophylactic colectomy was based on rectal
bleeding for 2 patients and innumerable polyps for 1 (Table 5).
None of the patients who underwent IRA developed highgrade adenoma in the rectum during follow-up (median duration
9 years [6–10]). No pouch adenoma was found during regular
follow-up after IPAA. Ileal low-grade dysplastic adenoma occurred
in 2 patients.
Mutation Analysis
Pathogenic germ-line APC alterations and large genomic
deletions were identified in 43 of the 47 families (84%), with
a detection rate, which attained 100% in patients with de novo
mutation. Most alterations (37 of 42) were predicted to lead to
truncated APC proteins, including 20 frameshift mutations caused
by small deletions/insertions, 16 nonsense mutations, and 1 mutation involving a consensus-splicing site. A total of 27 different
mutations and 5 genomic deletions were identified (Table 3).
Attenuated FAP (AAPC) arising from APC gene mutations in
the extreme proximal 50 to codon 168 was present in 1 family.
Mutations between codons 1250 and 1464, usually described for the
classical severe phenotype, involved 16 families with 24 children.
Mutational ‘‘hot-spots,’’ mainly at codons 1309 and 1061, were
present, respectively, in 10 families (15 patients) and 1 family
(2 patients). Mutations at other sites usually involved patients with
classical phenotypes; they characterized 21 families and 25 children.
Large genomic deletions were found in 5 families (7 children); up
until now, only 4 families (11 children) have been found to be
phenotype-positive, genotype-negative. Incomplete gene analysis in
1 family resulted from insufficient biological material.
Genotype–Phenotype Correlations
Genotype–phenotype correlations described in the literature
mainly involved epidemiological data with long-term follow-up of
patients through adulthood. In our pediatric cohort, we may have
missed information on items that developed with increasing age.
In families (Table 6) with codon mutations usually associated
with a classical severe phenotype, 81% underwent colectomy
before 18 years of age. For specific hot-spot mutations at codon
1309, although 60% were clinically symptomatic, with 82% of them
having innumerable colorectal polyps at the time of prophylactic
colectomy, none presented with high-grade polyp dysplasia.
Two patients with the hot-spot mutation at codon 1061, clinically
asymptomatic but with innumerable polyps for 1 of them, refused
surgical treatment at the time of the study at 16 and 17 years of age,
but were followed up by a psychologist. In the remaining patients
with a mutation associated with a classical severe phenotype, 33%
were clinically symptomatic, 66% underwent colectomy, and a
high-grade dysplastic polyp was reported in a 16.2-year-old patient.
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Evaluation of Guidelines for Management of FAP
TABLE 3. Clinical and genetic characteristics of the 49 PAF families
FAP
families
No.
cases
Initial
symptoms
Codon
mutation
Transmission
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
3
2
2
2
1
1
1
1
1
1
1
1
2
1
1
2
2
1
1
1
1
2
2
1
1
5
3
1
1
1
2
1
1
1
1
1
1
1
2
2
1
1
3
1
3
1
1
0
0
0
0
0
0
1
1
1
1
0
1
0
0
1
1
1
0
1
0
0
0
0
0
0
0
1
1
1
0
1
1
0
0
0
1
1
0
1
1
1
1
0
1
1
0
0
1362
936
1061
1065
1538
696
1309
1309
1062
1406
del complete
235
del complete
984
1420
1556
NI
936
1564
del complete
499
158
215
564
136
NI
1309
1370
1370
1309
943
1309
876
1567
216
1309
213
NI
1309
del complete
1396
1309
NI
1309
1309
805
del 8–15
F
M
M
F
M
F
—
F
F
—
F
M
M
F
F
M
M
M
—
M
M
M
M
F
M
M
F
M
F
F
F
F
F
M
F
—
M
F
M
F
F
F
M
F
M
F
M
Extracolonic
manifestations
Surgery/high
grade/carcinoma
D (2), A (2), CHRPE, Ds (2), EC
D (1), A (1), CHRPE
D (2), CHRPE
D, CHRPE
D, EC,
D, CHRPE
D, F, CHRPE
IPAA (2)
IPAA (2)
0
IPAA (2)
IPAA, HG
IPAA
IPAA
IPAA
IPAA, HG
IPAA
0
0
IPAA
IPAA, HG
0
IPAA (1)
IRA (2), IC (1)
0
IRA
IPAA
0
0
IPAA (2), HG (1)
IPAA
0
IPAA (1)
IPAA (3)
0
IRA
IPAA
0
IPAA
0
0
IRA
IPAA
IPAA
0
IRA (1), IPAA(1)
IPAA (1)
0
IPAA
IPAA (2)
IPAA
IPAA (3)
IPAA, HG
0
D, A
D
D, F
EC
D
D, F
Ds
D
CHRPE
CHRPE, EC
CHRPE
D, CHRPE, Ds, EC
H
CHRPE, Ds
D (2), CHRPE
CHRPE, EC
D
D (3)
D
Initial symptoms: presence: 1, absence: 0. Codon mutation: NI ¼ nonidentified. Genetic transmission: F ¼ father; M ¼ mother. Extracolonic manifestations:
A ¼ antral adenoma; CHRPE ¼ congenital hypertrophy of the retinal pigment epithelium; D ¼ duodenal adenoma; Ds ¼ desmoid tumor; EC ¼ epidermal cysts;
F ¼ fundic adenoma; H ¼ hepatoblastoma. Adenoma dysplasia: HG ¼ high-grade dysplasia; IC ¼ invasive carcinoma. Surgery: IPAA ¼ ileal-pouch anal
anastomosis; IRA ¼ ileorectal anastomosis.
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Munck et al
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Volume 53, Number 3, September 2011
TABLE 5. Percentage of colectomy and occurrence of highgrade adenoma dysplasia/invasive carcinoma according with
the genotype
Patients
Total
Familial history
De novo mutation cases
Classical severe genotype
Hot-spot mutation 1309
Classical genotype
Attenuated FAP
Large genomic deletion
Negative genotype
FIGURE 1. Time to colectomy (estimated by the Kaplan-Meier
curve).
Codon mutations located at other sites were usually associated with classical phenotypes; 56% underwent colectomy; and,
surprisingly, 4 high-grade adenomas were identified at 11.6, 12,
13.8, and 16 years of age in asymptomatic children, 2 of whom
presented with innumerable polyps and 2 who had polyps larger
than 0.5 cm. Codon mutations usually associated with AAPC were
found in only 1 family. In patients with large genomic deletions or
from genotype-negative families, rates of colectomy were, respectively, 43% and 33%. Thus, our data confirm important phenotypic
discrepancies in the severity of the disease within each of these
subgroups, even among patients with identical mutations.
Extracolonic manifestations were found in 49% of the
patients. Desmoid tumors were associated with a codon mutation
located at the 30 end of the APC gene in 75%, as previously reported.
CHRPE was identified in families with mutations between codons
311 and 1444, as described in the literature, but 5 families screened
negative even though they had a mutation within this range. The
patient who developed a hepatoblastoma had a mutation in the
proximal half of the APC gene.
DISCUSSION
We describe here the largest series of children ever diagnosed as having FAP. Previous reports mainly involved small
TABLE 4. Short- and long-term complications after prophylactic colectomy
Procedure
No. colectomies (%)
No. patients with complications (%)
Short-term complications (%)
Pelvic abscess
Anastomotic separation
Septicemia
Postoperative bowel obstruction
Anal stenosis
Pelvic hematoma
Pancreatitis postlaparoscopic healing
Long-term complications (%)
Daytime/nighttime soiling
Intrabadominal desmoid tumor
Medicine prescription (%)
IRA
IPAA
6 (14)
3 (50)
3 (50)
0
0
0
3
0
0
0
0
0
0
0
37 (86)
16 (44)
17 (47)
5
3
2
4
1
1
1
3 (8)
1/1
1
14 (39)
IPAA ¼ ileal pouch-anal anastomosis; IRA ¼ ileorectal anastomosis.
300
70
66
4
24
15
25
3
7
11
Colectomy (%)
42
38
4
21
15
14
1
3
3
(60)
(58)
(100)
(81)
(100)
(56)
(33)
(43)
(33)
HG/IC
6
6
0
1
0
4
1
0
0
FAP ¼ familial adenomatous polyposis; HG ¼ high-grade adenoma
dysplasia; IC ¼ invasive carcinoma.
cohorts, and most of them were published before the era of
genotyping (4–8) or were case reports (9–12). The role of molecular testing for at-risk members in childhood in case of mutations
that predispose to early onset of FAP has been emphasized (18–22),
leading to recently published guidelines for the clinical management of FAP.
Several studies recently reviewed by Nieuwenhuis et al (20)
showed that the severity of colonic polyposis partly depends on the
mutation site. Thus, mutations between codons 1250 and 1464 with
the 2 identified hot-spot mutations at codons 1309 and 1061 are
associated with a classical severe phenotype (thousands of polyps).
In those patients, bowel symptoms and neoplastic disease tended to
develop more than 10 years earlier and patients had significantly
more colorectal polyps at the time of colectomy (21). Conversely,
mutations before codon 157, after codon 1595 and in the alternatively spliced region of exon 9, were usually associated with an
attenuated form of FAP (AFAP) (<100 colorectal polyps) and CRC
at a more advanced age (23); in the remainder of the gene, a
classical phenotype (100–1000 polyps) usually has been described.
It should be borne in mind, however, that the site of mutation will not
necessarily predict a certain gene product with a subsequent phenotype. Although general correlations can be established, inconsistencies and contradictions have been extensively reported (13,24), thus
limiting the interpretation of genotype–phenotype relations.
In our cohort, half of the 15 children with a hot-spot codon
mutation located at 1309 had undergone prophylactic colectomy
before age 11 years, earlier than recommended in the literature (3),
thus, perhaps, preventing malignant changes. Four of the 6 patients
with high-grade dysplastic adenoma presented a mutation usually
associated with a classic phenotype (age range 12–16 years) and
colonoscopy overlooked severe dysplasia in 3 cases, pointing first
to the difficulty in endoscopically diagnosing severe lesions when
numerous or innumerable polyps are present, and second, to the lack
of an association between polyp size and the degree of dysplasia,
as previously reported (25,26).
Colectomy remains the optimal prophylactic treatment; however, the timing of surgery has not yet been standardized because
patients and families differ in the severity of disease expression and
the social context (13). It is tempting to delay surgery until children
mature physically and finish school; nonetheless, there is concern
about CRC in teenagers when surgery is deferred. Thus far, the
literature has provided little information on the age distribution at
diagnosis of CRC in FAP patients younger than 20 years because
most cases are diagnosed at a premalignant stage. Before the era of
genotyping, Peck et al (5) reviewed the literature and identified
10 pediatric CRC. Later, Hyer et al (18) found a 3% occurrence of
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Evaluation of Guidelines for Management of FAP
TABLE 6. Patients’ characteristics with high-grade adenoma dysplasia/invasive carcinoma
Symptoms
No
No
No
No
Rectal bleeding
Rectal bleeding
Codon mutation
Preoperative endoscopy
Colectomy, y
Specimen
215
805
1538
984
NI
1406
Innumerable polyps HG
Polyps >0.5 cm HG
Polyps >0.5 cm HG
Innumerable polyps
Numerous polyps
Innumerable polyps
11.5
13.8
16
12
8.8
16.2
HG
HG
—
HG
IC
HG
HG ¼ high-grade adenoma dysplasia; IC ¼ invasive carcinoma; codon mutation: NI ¼ nonidentified; —.
severe dysplasia in a cohort of 13 patients 11 to 16 years of age,
all of whom presented significant gastrointestinal symptoms, in
contrast to our study results (2 rectal bleedings of 6). Surprisingly,
in a small monocentric cohort of 11 teenagers (22) who underwent
prophylactic colectomy at a mean age of 13 3.2 years, a high rate
of severe dysplasia (27%) was reported. Recently, Church et al (8)
surveyed 16 polyposis registries to assess the risk of CRC in
teenagers; the estimated calculated incidence was 1 case per 471
patients with FAP younger than 20 years of age. Fourteen cases
were identified (the youngest was 9 years old), all of them presenting with severe phenotypic polyposis (defined as more than
1000 colonic polyps), whereas 36% were clinically symptomatic.
Vasen et al (13) reported data from several European registries,
which included more than 1000 patients younger than 20 years; they
found a low proportion of patients with FAP with CRC (0–10 years:
0%, 11–15 years: 0.2%, 16–20 years: 1.3%). Prospective studies
comparing early surgical intervention with standard care management in the younger FAP population would help to clarify this issue,
but are ethically impractical. Unfortunately, none of these studies
provided data on gene mutation analysis.
In recent international guidelines (13), prophylactic colectomy
is recommended if there are ‘‘large numbers of adenomas larger than
5 mm including adenoma showing a high degree of dysplasia.’’ We
agree with the authors who stated that the majority of patients with
classical FAP should undergo surgery between 15 and 25 years of age.
Conversely, Barnard (14), in his recent article on pediatric FAP,
suggests a more aggressive attitude: ‘‘Once adenomas are identified,
it is recommended that ileal pouch anal anastomosis or ileal anastomosis be performed’’; however, that statement does not indicate
the patient’s genotypic data, nor is a specific bibliography provided.
The choice between the 2 types of surgical procedure (28)
had been controversial until recent guidelines began to approach a
consensus, (13), suggesting use of the outcome of genetic testing to
guide the choice between IRA and IPAA (20–29). IPAA is now
advisable in patients with a mutation located distal to codon 1444.
Indeed, such patients are at risk of desmoid tumors, and conversion of
IRA to IPAA may be difficult in cases of asymptomatic mesenteric
desmoid tumors or in patients with a severe genotype because they
have an increased risk of developing severe rectal polyposis that
would require secondary protectomy if IRA were performed. In our
cohort, 4 patients (2 with innumerable rectosigmoid polyps, 2 with
desmoid tumors) should have undergone IPAA, but this was in the
late 1980s and they were unable to benefit from genetic testing at
that time. Recently, a meta-analysis on quality of life after those
2 surgical options (27) was in favor of IRA (bowel movement
frequency, reoperation within 30 days); IPAA, which implies
more extensive surgery, including pelvic dissection, has a higher
morbidity rate with possible reduction in fertility (28), although the
latter hypothesis is controversial.
Most patients with FAP develop extracolonic manifestations
over time; at present, a higher proportion of deaths in adulthood
may even be attributed to desmoid or duodenal tumors (30) rather
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than to CRC. Desmoid tumors (31), although benign, can lead to
compression of vital organs. Adenomatous gastroduodenal polyps
are common, with rates approaching 100% over time, and only a
small fraction will develop invasive cancer in adulthood (3%–5%)
(32). Scott et al (33) found duodenal adenomas in childhood at the
same frequency as in our cohort; an association between a germ-line
APC mutation and severity of upper gastrointestinal (GI) polyposis
remains controversial (34) and only future large multicentric studies
will provide confirmation. In accordance with international guidelines, upper GI polyposis surveillance should begin when colonic
adenoma is identified (14) or between the ages of 25 and 30 years
(13), with intervals between screening in stage I Spigelman of
5 years; indeed, prospective studies demonstrated the slow progression of duodenal polyp size, number, and histology (35). In our
study, most patients underwent upper GI, with a median of 3
procedures, pointing to possible overscreening by pediatric teams.
An endoscopic retrograde cholangiopancreatographic side-viewing
endoscopy is recommended to enable detailed inspection of the
papilla for ampullary carcinoma detection; however, in early
Spigelman stages typical of the pediatric population, the use of
a forward-viewing endoscope is considered appropriate (13).
Optimal surveillance protocols for genetic counseling, types of
investigation, and surveillance intervals in patients with FAP and
AFAP have recently been proposed (13,14). Predictive testing for
the mutation should be offered to first-degree relatives in cases of
typical FAP; however, the right age for screening of children at risk
of FAP remains subject to careful consideration (36,37). In fact,
early knowledge of the child’s disease status may have detrimental
effects on the family (37). Thus, some authors advise delaying
the process until the child is old enough to take part in the decision
(18); on the contrary, the prognosis has improved substantially for
families under regular surveillance, because CRC is rare and occurs
mainly in those with de novo mutations.
Guidelines for colonoscopic surveillance (13,14) recommended that family members who carry the mutation should
undergo periodic examination of the rectosigmoid starting in the
early teens. They also recommended starting earlier than 12 years
of age in families in which severe dysplasia or carcinoma was
found at a young age or in families with mutations associated with
a severe phenotype (ie, 1309, 1061). In those guidelines, it was
recommended that flexible sigmoidoscopy be performed, at least
initially; once adenomas have been identified by sigmoidoscopy,
there is an indication for full colonoscopy. Those recommendations
were based on a study by Bussey et al (38) in the late 1970s, which
demonstrated that in adults, the rectum was affected in all cases of
colonic adenoma, thus recommending colonoscopy only after the
appearance of rectosigmoid polyps. In our study, all of the centers
immediately investigated the entire colorectum, in contrast to
previous conclusions in adult studies; among the 8 patients with
initial intact rectosigmoid, 3 would have had an initial colonoscopy
in any case because of a rectal or severe genotype; for the
5 remaining patients, therapeutic intervention would not have been
301
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Munck et al
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different in cases of delayed colonoscopy until detection of rectosigmoid polyps. This is the first retrospective study demonstrating
that we can safely use international adult guidelines for pediatric
cohorts. Performing colonoscopy under general anesthesia in
children may provide less discomfort than rectosigmoidoscopy,
and this should be determined case by case.
Additional recommendations included an interval of 2 years
between normal rectosigmoidoscopy and, if adenoma is detected,
yearly colonoscopy until colectomy is required. In AFAP, a different
protocol is advised because no CRCs have been described in patients
younger than age 30 years; periodic examination should begin at 18 to
20 years of age with a colonoscopy because only a few adenomas
develop, mainly in the right part of the colon (39).
Our data suggest that endoscopic surveillance in children
with FAP should be modified according to recently recommended
international guidelines, although in terms of surgical timing,
indications were in complete agreement with those guidelines.
Taking into account molecular-phenotypic correlations and family
history, it is appropriate to provide specifically tailored advice for
genetic counseling, endoscopic surveillance, and choice between
the 2 types of surgical procedures; moreover, first-line management
by pediatric gastroenterology teams should be determined case by
case. Ideally, such patients should be studied at centers specializing
in rare digestive diseases. Such structures have accumulated a
critical mass of data, enabling the best possible patient care. They
participate in well-established national and international registries
and in networking activities for clinical and basic research.
REFERENCES
1. Bisgaard ML, Fenger K, Bülow S, et al. Familial adenomatous polyposis
(FAP): frequency, penetrance, and mutation rate. Hum Mutat 1994;
3:121–5.
2. Bodmer WF, Bailey CJ, Bodmer J, et al. Localization of the gene for familial adenomatous polyposis on chromosome 5. Nature 1987; 328:614–6.
3. Aretz S, Uhlhaas S, Caspari R, et al. Frequency and parental origin of de
novo APC mutations in familial adenomatous polyposis. Eur J Hum
Genet 2004;12:52–8.
4. Abramson DJ. Multiple polyposis in children: a review and a report of a
case in a 6-year-old child who had associated nephrosis and asthma.
Surgery 1967;61:288–301.
5. Peck DA, Watanabe KS, Trueblood HW. Familial polyposis in children.
Dis Colon Rectum 1972;15:23–9.
6. Bülow S, Holm NV, Søndergaard JO, et al. Mandibular osteomas in
unaffected sibs and children of patients with familial polyposis coli.
Scand J Gastroenterol 1986;21:744–8.
7. Ruttenberg D, Elliot MS, Bolding E. Severe colonic dysplasia in a
child with familial adenomatous polyposis. Int J Colorectal Dis 1991;
6:169–70.
8. Church JM, McGannon E, Burke C, et al. Teenagers with familial
adenomatous polyposis: what is their risk for colorectal cancer? Dis
Colon Rectum 2002;45:887–9.
9. Jerkic S, Rosewich H, Scharf JG, et al. Colorectal cancer in two preteenage siblings with familial adenomatous polyposis. Eur J Pediatr
2005;164:306–15.
10. Presciuttini S, Varesco L, Sala P, et al. Age of onset in familial
adenomatous polyposis: heterogeneity within families and among
APC mutations. Ann Hum Genet 1994;58:331–42.
11. Eccles DM, Bunyan DJ, Needell J, et al. Colon cancer in a 16-year-old
girl. Lancet 1995;345:1643.
12. Distante S, Nasioulas S, Somers GR, et al. Familial adenomatous
polyposis in a 5-year-old child: a clinical, pathological, and molecular
genetic study. J Med Genet 1996;33:157–60.
13. Vasen HF, Möslein G, Alonso A, et al. Guidelines for the clinical
management of familial adenomatous polyposis (FAP). Gut 2008;
57:704–13.
14. Barnard J. Screening and surveillance recommendations for pediatric
gastrointestinal polyposis syndromes. J Pediatr Gastroenterol Nutr
2009;48:S75–8.
302
Volume 53, Number 3, September 2011
15. Groden J, Thliveris A, Samowitz W, et al. Identification and characterization of the familial adenomatous polyposis coli gene. Cell 1991;
66:589–600.
16. Demange L, De Moncuit C, Thomas G, et al. Analyse phénotypique de
154 patients porteurs d’une mutation constitutionnelle du gène NF2.
Rev Neurol 2007;63:1031–8.
17. Spigelman AD, Williams CB, Talbot IC, et al. Upper gastrointestinal
cancer in patients with familial adenomatous polyposis. Lancet
1989;30:783–5.
18. Hyer W, Fell JM. Screening for familial adenomatous polyposis. Arch
Dis Child 2001;84:377–3780.
19. Erdman SH. Pediatric adenomatous polyposis syndromes: an update.
Curr Gastroenterol Rep 2007;9:237–44.
20. Nieuwenhuis MH, Vasen HF. Correlations between mutation site in
APC and phenotype of familial adenomatous polyposis (FAP): a review
of the literature. Crit Rev Oncol Hematol 2007;61:153–61.
21. Friedl W, Caspari R, Sengteller M, et al. Can APC mutation analysis
contribute to therapeutic decisions in familial adenomatous polyposis?
Experience from 680 FAP families. Gut 2001;48:515–21.
22. Vasudevan SA, Patel JC, Wesson DE, et al. Severe dysplasia in children
with familial adenomatous polyposis: rare or simply overlooked?
J Pediatr Surg 2006;41:658–61.
23. Nielsen M, Hes FJ, Nagengast FM, et al. Germline mutations in APC
and MUTYH are responsible for the majority of families with attenuated
familial adenomatous polyposis. Clin Genet 2007;71:427–33.
24. Rozen P, Samuel Z, Shomrat R, et al. Notable intrafamilial phenotypic
variability in a kindred with familial adenomatous polyposis and an
APC mutation in exon 9. Gut 1999;45:829–33.
25. Mills SJ, Chapman PD, Burn J, et al. Endoscopic screening and surgery
for familial adenomatous polyposis: dangerous delays. Br J Surg
1997;84:74–7.
26. Galiatsatos P, Foulkes WD. Familial adenomatous polyposis. Am J
Gastroenterol 2006;101:385–98.
27. Aziz O, Athanasiou T, Fazio VW, et al. Meta-analysis of observational
studies of ileorectal versus ileal pouch-anal anastomosis for familial
adenomatous polyposis. Br J Surg 2006;93:407–17.
28. Kartheuser A, Stangherlin P, Brandt D, et al. Restorative proctocolectomy and ileal pouch-anal anastomosis for familial adenomatous polyposis revisited. Fam Cancer 2006;5:241–60.
29. Bülow C, Vasen H, Järvinen H, et al. Ileorectal anastomosis is appropriate for a subset of patients with familial adenomatous polyposis.
Gastroenterology 2000;119:1454–60.
30. Belchetz LA, Berk T, Bapat BV, et al. Changing causes of mortality
in patients with familial adenomatous polyposis. Dis Colon Rectum
1996;39:384–7.
31. Gurbuz AK, Giardiello FM, Peterson Gm, et al. Desmoid tumours in
familial adenomatous polyposis patients. Gut 1994;35:377–81.
32. Bülow S, Björk J, Christensen IJ, et al. Duodenal adenomatosis in
familial adenomatous polyposis. Gut 2004;53:381–6.
33. Scott RJ, Froggatt NJ, Trembath RC, et al. Familial infiltrative fibromatosis (desmoid tumours) (MIM135290) caused by a recurrent 30 APC
gene mutation. Hum Mol Genet 1996;5:1921–4.
34. Enomoto M, Konishi M, Iwama T, et al. The relationship between
frequencies of extracolonic manifestations and the position of APC
germline mutation in patients with familial adenomatous polyposis.
Jppn J Clin Oncol 2000;30:82–8.
35. 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 Oncol 2004;22:493–8.
36. Durno CA, Gallinger S. Genetic predisposition to colorectal cancer:
new pieces in the pediatric puzzle. J Pediatr Gastroenterol Nutr 2006;
43:5–15.
37. Douma KF, Aaronson NK, Vasen H, et al. Psychosocial issues in genetic
testing for familial adenomatous polyposis: a review of the literature.
Psychooncology 2008;17:737–45.
38. Bussey HJ. Familial Polyposis Coli. Baltimore Johns Hopkins University Press; 1975.
39. Burt RW, Leppert MF, Slattery ML, et al. Genetic testing and phenotype
in a large kindred with attenuated familial adenomatous polyposis.
Gastroenterology 2004;127:444–51.
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