Familial Adenomatous Polyposis (FAP)

Literature and regulatory information updated: 4 October 2026.

APC-associated polyposis: classic FAP, attenuated FAP, Gardner syndrome and Turcot syndrome (APC variant), distinguished from MUTYH-associated polyposis (MAP)

0. Initial Reference Table

1. Introduction

Familial adenomatous polyposis is a hereditary colorectal cancer (CRC) predisposition syndrome characterised by hundreds to thousands of colonic and rectal adenomas from the second decade, progressing to carcinoma in virtually all carriers without colectomy [1, 2]. Orphanet defines it as a rare intestinal polyposis syndrome with hundreds to thousands of large-bowel adenomas and as a multisystem disorder with relevant extracolonic manifestations [2]. Heterozygous germline pathogenic variants in the tumour suppressor APC at 5q22.2 cause autosomal dominant disease [1, 3].

Its history encompasses three clinical descriptions followed by molecular discoveries. In 1951, Eldon J. Gardner published the genetic and clinical study of a Utah family with intestinal polyposis predisposing to colorectal carcinoma in the American Journal of Human Genetics [19]. In 1953, Gardner and Richards described osteomatosis and multiple cutaneous/subcutaneous epidermoid cysts and fibromas alongside polyposis in this pedigree, establishing what became Gardner syndrome [20]. In 1959, Jacques Turcot, Després and St. Pierre reported two siblings with colonic polyposis and malignant central nervous system tumours, giving rise to Turcot syndrome [21]. Oxford Desk Reference notes Gardner's description of colonic and extracolonic manifestations and states that sufficiently detailed examination identifies extracolonic manifestations in all individuals with FAP [3].

The molecular phase began with Bodmer and colleagues' linkage localisation of the FAP gene to chromosome 5's long arm in Nature in 1987 [22]. In August 1991, three groups identified and characterised APC at 5q21, now 5q22.2: Kinzler and colleagues and Nishisho and colleagues in Science [23, 24], and Groden and colleagues in Cell [25]. Spigelman and colleagues' 1989 upper-endoscopy series of 102 patients established the five-stage (0–IV) duodenal polyposis classification still guiding upper gastrointestinal surveillance [26]. Hamilton and colleagues (1995) demonstrated two distinct molecular bases for brain tumours with multiple colorectal adenomas: germline APC variants, predominantly associated with medulloblastoma, and mismatch repair (MMR) gene variants, predominantly associated with glioblastoma [27]. In 2002, Al-Tassan and colleagues identified biallelic MYH, now MUTYH, variants in recessive polyposis with somatic G:C→T:A mutations, establishing MAP as a separate entity [28]. GAPPS was described in 2012 [29], and its molecular basis, APC promoter 1B point variants, established in 2016 [30].

Current nomenclature reflects this history. GeneReviews regards Gardner and Turcot syndromes as historical terms rather than separate entities, both representing APC-related FAP phenotypes [1]. Orphanet retains them as clinical subtypes, ORPHA:79665 and ORPHA:99818 [2]. These names describe phenotypes within FAP; Turcot syndrome in its broader sense is genetically heterogeneous, with the MMR-associated form, including constitutional mismatch repair deficiency (CMMRD), addressed in the differential diagnosis [3, 31].

2. Molecular Genetics and Pathophysiology

2.1 APC gene and protein

APC lies at 5q22.2, contains 15 exons and 2843 codons, with an exceptionally large exon 15, and encodes a tumour suppressor [1, 3]. APC and glycogen synthase kinase 3β (GSK3B) form the destruction complex that phosphorylates cytosolic β-catenin, directing ubiquitination and proteasomal degradation [1]. β-Catenin participates in E-cadherin-associated cell adhesion and WNT signalling; APC prevents free β-catenin accumulation, maintains apoptosis and reduces proliferation [1]. APC also accumulates at the kinetochore during mitosis, supports kinetochore–microtubule attachment, chromosome stability and segregation, and regulates cell migration along colonic crypts and cell polarity [1].

2.2 Disease mechanism

Disease results from loss of function. Most pathogenic variants produce a truncated protein unable to bind the destruction complex; free β-catenin accumulates, enters the nucleus, associates with TCF-4 and LEF-1 (T cell factor–lymphoid enhancer factor) and activates targets including MYC and CCND1 oncogenes [1]. Abnormal APC disrupts crypt cell positioning and contributes to CRC chromosomal instability [1]. Each adenoma arises after somatic inactivation of the remaining wild-type allele in crypt cells, the second hit. Because the germline variant is present throughout the body, hundreds to thousands of adenomas arise, including single-crypt microadenomas (monocryptal adenomas), a histological feature of FAP and AFAP also found in MAP [3]. Somatic APC inactivation likewise initiates most sporadic, non-hereditary CRC [1].

2.3 Variant spectrum

FAP variants are almost exclusively null: nonsense, frameshift or splicing variants. An apparent missense variant is a priori unlikely to cause FAP unless it alters messenger RNA processing [3]. Three recurrent changes, 5-base-pair deletions at codons 1061 and 1309 and whole-gene deletion, account for approximately 25–30% of variants; the remainder are predominantly private [3]. The commonest reported germline variant is c.3927_3931delAAAGA (p.Glu1309AspfsTer4) [1]. Deep intronic pseudoexon-generating variants explain some molecularly unresolved families [3]. Fewer than 1% of cases involve cytogenetically visible 5q22 abnormalities, usually contiguous-gene syndromes with dysmorphism and learning difficulties, particularly language delay [1, 3]. Sequencing detects up to 90% of variants and deletion/duplication analysis 8–12%; promoter 1B should be included [1].

2.4 Genotype–phenotype correlations

APC variant position influences polyp burden, CRC risk and extracolonic profile. Inter- and intrafamilial variation is nevertheless common, and surveillance/surgery should follow the patient's phenotype rather than genotype alone [1]. Variants around codons 160–1600 are associated with hundreds of adenomas (classic FAP); codon 1300 or nearby variants with thousands and the highest CRC risk [3]. Without treatment, mean CRC age is 28 with thousands of polyps, 44 with hundreds, and 55 in AFAP [3]. Variants 5′ of codon 160 or 3′ of codon 1600 are associated with AFAP [3]. A multicentre study found variants in one of three regions in 78% of AFAP phenotypes: the 5′ end (codons 1–233), alternatively spliced exon 9 (codons 311–412), or 3′ of codon 1595. However, only 65% of carriers in these regions had ≤100 adenomas; 35% had classic FAP and underwent colectomy at a median age of 18 [1]. Variants 5′ of exon 9 (codons 312–438) are not associated with congenital hypertrophy of the retinal pigment epithelium (CHRPE), except some exon 6 variants, whereas those 3′ of exon 9 usually are [3].

2.5 Low-penetrance variants

Missense p.Ile1307Lys (c.3920T>A) has been associated with an AFAP-like phenotype in Ashkenazi Jews, with approximately 8% population frequency. In average-risk Ashkenazi individuals, adjusted CRC odds ratio was 1.75 (95% CI 1.26–2.45) [3, 33]. p.Glu1317Gln has been inconsistently associated with multiple adenomas in non-Jewish Europeans, potentially through linkage disequilibrium with a 5′ nonsense variant [3].

2.6 Mosaicism and de novo cases

Approximately 15–20%, up to 25%, arise de novo, and approximately 15% of these are mosaic [1, 3]. GeneReviews estimates somatic mosaicism in approximately 20% of simplex cases, potentially missed by leucocyte DNA testing. The same variant in multiple adenomas after negative germline testing is consistent with mosaicism [1, 34]. Documented germline mosaicism includes an asymptomatic 79-year-old woman whose two children had thousands of adenomas [1, 34]. Oxford Desk Reference cautions that a substantial proportion of apparently new cases reflect MAP rather than de novo APC variants [3].

3. Clinical Spectrum and Manifestations by System

3.1 Colon and rectum

Classic FAP adenomas emerge in the second and third decades, with mean polyp diagnosis age 16 (range 7–36); 50% of carriers have polyps by 15 and 95% by 35 [1, 3]. Numbers then rapidly increase to hundreds or thousands [1]. Without colectomy, CRC is almost inevitable: mean diagnosis age is 39 (34–43), with CRC in 7% by 21, 87% by 45 and 93% by 50 [1]. Oxford Desk Reference gives 98% risk by 50; the ESMO Handbook states 100% risk with mean age 39, underpinning prophylactic colectomy [3, 6]. CRC can occur before 20 without colectomy, particularly with codon 1300 or nearby variants [3].

AFAP has fewer adenomas (mean 30), more proximal distribution, frequently flat/non-polypoid morphology, and CRC diagnosis 10–15 years later than classic FAP (50–55), with approximately 70% cumulative risk by 80 [1, 6]. Knudsen's international collaborative study clinically defined AFAP as ≤100 adenomas at age ≥25. Adenomas develop at 35–45 and median diagnosis age is 43 (12–67) [1, 9, 35]. Rectosigmoid sparing occurs particularly in AFAP [3].

3.2 Upper gastrointestinal tract

Duodenal adenomas affect 50–90%, predominantly the second and third portions; periampullary adenomas of the duodenal papilla and ampulla of Vater, sometimes endoscopically subtle, occur in at least 50% and can cause pancreatitis or biliary obstruction [1]. Spigelman's original series found duodenal abnormalities in 100 of 102 patients, dysplasia in 94, and periampullary abnormalities in 87 of 97 biopsied patients [26]. Colonic and upper gastrointestinal polyp numbers show no clear association [1]. As colectomy prevents CRC, duodenal cancer has become a principal cause of death: Oxford Desk Reference estimates overall risk at 3–4%; GeneReviews gives lifetime small-bowel carcinoma risk of 4–12%, predominantly duodenal, with mean age 45–52 (range 17–81); EHTG-ESCP gives 18% lifetime risk (95% CI 8–28%), increasing with age: 3.2% by 40, 7.6% by 60 and 34.0% by 73 [1, 3, 9]. Baseline Spigelman stage predicts lifetime duodenal cancer risk: 33% in IV, 13% in III, 12% in II and 0% in 0–I; stage IV has 30% 10-year risk [9]. Jejunal and ileal carcinomas are rare, with 17 jejunal and 3 ileal cases published by 2010 [1].

Gastric fundic gland polyps occur in approximately half of patients (26–88%), including children, with dysplasia more frequent than in sporadic polyps [1, 9]. Historically rare Western gastric cancer has increased recently (1.3% since 2016 in Western populations); frequency in Japanese and Korean patients is approximately tenfold higher than in the general population [1, 36]. GAPPS fundic gland polyps are confined to the body and fundus (>100 proximal polyps), without significant colonic or duodenal polyposis. Lifetime intestinal-type gastric adenocarcinoma risk is 12–25% according to EHTG-ESCP, or 13–25% according to GeneReviews, with onset ranging from 22 to 75 [1, 9].

3.3 Desmoid tumours

Desmoid-type fibromatosis comprises clonal myofibroblast proliferations that are histologically benign, locally invasive and non-metastatic [1]. They occur in 10–30% of FAP patients, with approximately 10% clinically evident disease in Oxford Desk Reference, at over 800 times population risk. At least 7.5% of desmoid fibromatosis occurs in FAP carriers [1, 3]. Incidence peaks in the second and third decades (80% by 40); approximately 65% are abdominal or abdominal-wall lesions [1]. FAP-associated desmoids predominantly involve central sites (head, neck, trunk, abdominal wall and mesentery), whereas sporadic tumours favour limbs [3]. Independent predictors are variants 3′ of codon 1399, family history (sevenfold risk with an affected first-degree relative), female sex and previous abdominal surgery [1, 37]. Codon 1400 or downstream families may have 30–40% risk [3]. Approximately 5% experience desmoid-related morbidity or mortality, highest for intra-abdominal tumours; alongside duodenal disease, desmoids are a principal cause of premature FAP death [1, 3]. Gardner-associated fibroma is considered a precursor lesion [1]. In some families, childhood desmoids first revealed FAP [3]. Among 147 Brazilian patients operated for FAP during 1990–2021, 26 (17.7%) developed desmoids; 61.5% were women, 84.6% had a family history, and four died from complications [38].

3.4 Non-malignant extraintestinal manifestations

3.5 Malignant extracolonic neoplasms

Papillary thyroid carcinoma has an 80:1 female:male ratio, with over 80% diagnosed at 18–35. Prevalence is 0.4–2.6% in retrospective series and 2.6–11.8% in prospective ultrasound studies [1]. The cribriform-morular variant is typical of FAP but can occur sporadically [1, 6]. Hepatoblastoma occurs predominantly before 3, with highest incidence at 1–4 [1, 9, 40].

3.6 Turcot syndrome (APC variant)

Colorectal adenomatous polyposis with primary CNS tumours is genetically heterogeneous [3]. Hamilton and colleagues identified germline APC variants in 10 of 14 registry families, where medulloblastoma predominated (11 of 14 patients, 79%). Cerebellar medulloblastoma relative risk in FAP was 92-fold higher than population risk (95% CI 29–269) [27]. Absolute CNS tumour risk is approximately 1% [1, 41]. Primary brain tumours are rare and most likely medulloblastomas, although all types occur [3]. APC-associated medulloblastomas belong to the WNT-activated molecular subgroup [32]. Polyposis and brain tumours in the first decade instead suggest CMMRD [3, 31].

3.7 Gardner syndrome

Gardner phenotype denotes FAP with prominent extracolonic manifestations: particularly craniofacial/mandibular osteomas, dental abnormalities, epidermoid cysts, fibromas and desmoid tumours [1, 20]. Oxford Desk Reference's cancer-pattern table lists osteomas/desmoids (Gardner syndrome), CHRPE in 50–80%, papillary thyroid carcinoma in 1–12%, CNS tumours in 1–3% (Turcot syndrome), hepatoblastoma in ~1%, and duodenal cancer in 4–12% [42].

4. Clinical Recognition and Warning Signs

Recognition integrates the pedigree, histopathology reports and examination findings [33]. NCCN guidance cited by GeneReviews suggests APC-associated polyposis with at least 10–20 cumulative colorectal adenomas; family history of multiple adenomas (>10 in one person, or fewer if several relatives are affected, particularly young), a known familial APC variant or extracolonic manifestations; hepatoblastoma; multifocal/bilateral CHRPE; desmoid tumour; or cribriform-morular papillary thyroid carcinoma [1]. Additional clues are early CRC with few or no adenomas, supernumerary teeth, osteomas, odontomas, epidermoid cysts, duodenal adenomas/cancer, fundic gland polyposis, gastric, pancreatic or small-bowel cancer, and medulloblastoma [1].

EHTG-ESCP recommends considering FAP in women under 35 with cribriform-morular papillary thyroid carcinoma; APC testing with multiple unilateral or bilateral CHRPE lesions, followed by early-adult colonoscopy if negative; considering FAP with osteomas, particularly oral/facial; and excluding FAP through at least colonoscopy and APC testing in previously undiagnosed desmoid patients, particularly below 60 or with intra-abdominal/abdominal-wall lesions [9]. Children with hepatoblastoma warrant germline APC assessment [1, 40].

Oxford Desk Reference recommends a three-generation pedigree documenting benign/malignant tumours and histology (>100 adenomas); apparent inheritance; who underwent screening or surgery, when and where; prior polyposis-registry contacts; extracolonic manifestations (upper gastrointestinal disease, sebaceous cysts, desmoids/“fibromatosis”, osteomas, dental/eye history); and learning difficulties [3]. Examine for scalp/trunk sebaceous cysts, seldom volunteered by patients; dental abnormalities, mandibular cysts/osteomas; and head, neck, trunk, abdominal-wall and limb swellings. Abdominal masses require gastroenterology or colorectal surgery referral [3]. Many suspected FAP referrals are excluded after histopathology retrieval [33]. Teach CRC warning symptoms: rectal bleeding, persistent bowel habit change, an abdominal mass and unexplained anaemia [33].

Psychological distress is frequent in FAP; evidence suggests APC carriers understand key concepts better through images than words [3].

5. Diagnosis: Criteria, Tests and Algorithms

5.1 Criteria

An APC-associated polyposis diagnosis requires a heterozygous germline pathogenic or likely pathogenic APC variant; uncertain variants neither establish nor exclude it [1]. Classic clinical diagnosis requires over 100 colorectal adenomas on colonoscopy or colectomy histology; below 100, AFAP or “multiple adenomas” applies [3].

5.2 Molecular testing

Testing may be single-gene APC sequencing plus deletion/duplication analysis, including promoter 1B if initially negative, or a multigene panel [1]. EHTG-ESCP recommends panels for >20 cumulative colorectal adenomas, with a threshold of 10 in selected circumstances such as diagnosis before 60; panels for gastrointestinal cancers before 50; and somatic adenoma testing for APC mosaicism in unexplained polyposis [9]. Panels should include APC, MUTYH, MMR genes (MLH1, MSH2, MSH6, PMS2, MSH3, MLH3), POLE/POLD1 exonuclease domains, NTHL1 and MBD4 [9]. The laboratory needs apparent dominant, potentially recessive or de novo inheritance; familial desmoid predisposition may aid interpretation [3]. If no variant is identified, 5q22 linkage using flanking markers is possible with unequivocal dominant inheritance, histological proof and samples from multiple generations [3]. Chromosome analysis or CGH array is indicated with learning difficulties and/or dysmorphism [3].

5.3 Risk assessment and algorithm

Oxford Desk Reference's framework associates FAP with dominant inheritance presumptively with APC. Without demonstrated dominance, isolated or affected-sibling FAP is probably APC-related but may be MUTYH-related. Dominant AFAP may reflect APC in ~10%, with ~90% unexplained except rare hereditary mixed polyposis syndrome (HMPS); AFAP with >9 adenomas without dominance is more likely MAP (~25%) [3]. Inheritance may emerge only after first-degree relatives undergo colonoscopy or CHRPE examination [3]. Approximately 20–30% of cases/families with <100 adenomas remain molecularly unresolved [3].

5.4 Genetic test limitations and reporting requirements

Coding-region APC sequencing is insufficient alone. Exon or whole-gene deletions/duplications require dosage methods such as MLPA or validated coverage analysis; deep intronic pseudoexon variants require RNA or genome sequencing; promoter 1B variants require that region in panel design; somatic mosaicism may escape leucocyte DNA testing, requiring low-allele-fraction-sensitive methods and, if necessary, two or more adenomas [1, 3, 9, 34]. Negative germline testing does not exclude convincing disease, such as over 100 adenomas, and surveillance remains phenotype-based [1, 9]. Reports should specify the gene, versioned transcript, HGVS nomenclature, zygosity, ACMG/AMP classification with APC expert-panel specifications where applicable, and technical limits. MANE Select APC NM_000038.6 is used by ClinVar; GeneReviews uses NM_000038.5, with identical c./p. numbering for cited coding variants, for example NM_000038.6:c.3927_3931del, p.(Glu1309AspfsTer4), expert-panel pathogenic in ClinVar VCV000000816 [4]. Historical codon labels (1309, 1061) should accompany normalised HGVS notation. GAPPS promoter 1B variants use NM_001127511.3 and have non-uniform ClinVar classifications, including discordant c.-195A>C classifications in May 2026, requiring variant-specific interpretation [4]. ClinVar registers p.Ile1307Lys (c.3920T>A) as a risk factor/association with discordant classifications, rather than a monogenic FAP cause [4, 33]. MUTYH has three numbering systems (section 6.1); reports must state the transcript. Intervention response or partial segregation in a small family cannot make an uncertain variant pathogenic; segregation, RNA or tumour testing remains additional investigation until formal reclassification [1, 9].

6. Differential Diagnosis

6.1 FAP versus MAP

Distinguishing FAP from MAP is central to clinical genetics because polyp burdens overlap [3]. Biallelic MUTYH variants at 1p34.1 cause MAP. This base-excision repair gene removes adenines mispaired with oxidative-damage-derived 8-oxoguanine; deficiency produces somatic G:C→T:A transversions, notably KRAS c.34G>T in 40–100% of MAP adenomas and 60–90% of CRC [3, 8, 28].

Three MUTYH numbering systems coexist: original Y165C/G382D; longest transcript NM_001128425, used by GeneReviews/Oxford Desk Reference and now MANE Plus Clinical NM_001128425.2, with p.Tyr179Cys (c.536A>G) and p.Gly396Asp (c.1187G>A); and ClinVar's MANE Select NM_001048174.2, with c.452A>G, p.(Tyr151Cys) (VCV000005293) and c.1103G>A, p.(Gly368Asp) (VCV000005294), both pathogenic/likely pathogenic [3, 8, 43]. NM_001128425 numbering is retained to match the cited clinical sources, but laboratory reports must state the transcript and cross-report comparisons require explicit conversion. MAP can have upper gastrointestinal tumours and CHRPE; some CRC acquires microsatellite instability through somatic MMR mutations, mimicking Lynch syndrome. Suspected Lynch without an identified MMR variant warrants MUTYH testing [3, 33]. Heterozygous MUTYH carriers in MAP families have approximately twice the CRC risk, comparable to having a first-degree CRC relative, and require no greater surveillance intensity than that group [3].

Exome sequencing shows a moderate MAP CRC mutator phenotype: approximately twice the global mutation rate of microsatellite-stable carcinomas, compared with nearly tenfold for microsatellite-unstable CRC. Excess G:C→T:A transversions preferentially in AGAA/TGAA contexts define mutational signature 36 (SBS36) [8, 44]. GeneReviews lists this signature or somatic KRAS c.34G>T in tumour tissue as MAP suspicion criteria [8]. Most MAP CRC is microsatellite-stable; high instability occurs in a minority (0–18%, mean 4%). MMR immunohistochemistry and microsatellite-instability testing therefore neither establish nor exclude MAP, which requires biallelic germline MUTYH variants [8].

Large population/family studies found only marginally increased CRC risk in heterozygous pathogenic MUTYH carriers; GeneReviews gives twofold, at most threefold population risk for late-onset CRC [8, 45, 46]. In 2332 monoallelic carriers among 9504 relatives of 264 MUTYH-variant CRC cases, cumulative age-70 risk was 7.2% in men (95% CI 4.6–11.3%) and 5.6% in women (95% CI 3.6–8.8%), rising to 12.5% and 10%, respectively, with a variant-negative first-degree relative diagnosed by 50 [46]. A French multicentre prospective study of 62 heterozygous first-degree relatives of MAP patients, assessed by colonoscopy and upper endoscopy with chromoendoscopy, found none with more than five adenomas or any duodenal adenomas [47]. Extracolonic risk is uncertain: a Colon Cancer Family Registry study estimated hazard ratios of 9.3 for gastric, 4.5 hepatobiliary, 2.1 endometrial and 1.4 breast cancer [48], whereas other case-control studies, including a panel cohort of 30,456 breast-cancer women and 12,289 controls, found no breast association [8, 49]. NCCN 2019 guidance reproduced in GeneReviews suggests colonoscopy every 5 years from 40, or 10 years before the relative's diagnosis, only for heterozygotes with a first-degree CRC relative without MAP. No specific recommendation exists with only second-degree history or no family history because evidence is inconclusive [8].

For biallelic MAP, NCCN-based GeneReviews recommendations are colonoscopy/polypectomy every 1–2 years from 25–30 and side-viewing duodenoscopy from 30–35, with 3-month to 4-year intervals by Spigelman stage. Annual physical examination, baseline thyroid ultrasound and dermatology may be considered but lack firm extraintestinal recommendations because data are scarce [8]. Endoscopic polypectomy suffices with a small burden (<20 adenomas, all <1 cm and without advanced histology); size/density exceeding endoscopic control warrants subtotal colectomy or proctocolectomy. Dysplastic or villous duodenal polyps are excised endoscopically [8]. ClinGen rates MAP actionability strong in adults without a paediatric rating, consistent with adult surveillance onset [7].

6.2 Other polyposis and predisposition syndromes

7. Treatments and Risk Management Strategies

7.1 Principles

Management should follow phenotype, involve patients early and occur in specialist centres with experienced surgical teams [3, 9]. Guidance comes from NCCN, the American Society for Gastrointestinal Endoscopy (ASGE) [50], American College of Gastroenterology (ACG), American Society of Colon and Rectal Surgeons (ASCRS) [51], American Society of Clinical Oncology, British Society of Gastroenterology (BSG), European Society of Gastrointestinal Endoscopy (ESGE), European Society for Medical Oncology (ESMO), Desmoid Tumor Working Group and Europe's joint European Hereditary Tumour Group/European Society of Coloproctology (EHTG-ESCP) 2024 revision. This updated the 2008 Mallorca recommendations with 140 recommendations covering FAP, MAP, GAPPS and other rare polyposes [1, 9–14, 52]. The European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) Polyposis Working Group has a position paper for children/adolescents [53]. ClinGen rates APC–FAP actionability definitive in children and strong in adults, reflecting childhood initiation of prognosis-changing colonoscopy and, when undertaken, hepatoblastoma screening [7].

7.2 Colorectal surveillance before surgery

In AFAP, colonoscopy/polypectomy every 1–2 years may postpone or avoid colectomy; approximately one third have a burden manageable by endoscopy alone [1]. Classic-FAP surveillance is unsuitable for AFAP because of later onset, rectosigmoid sparing and variable expressivity [3].

7.3 Prophylactic surgery

Colectomy is the reference treatment preventing FAP CRC [1, 9]. EHTG-ESCP absolute immediate-surgery indications are confirmed/suspected cancer, severe symptoms, severe disease (≥1000 polyps) and adverse histology (high-grade intraepithelial neoplasia, villous adenoma); planned-surgery indications are polyps >10 mm, substantial increase between examinations and sparse disease (100–1000 polyps) [9]. GeneReviews adds inability to adequately survey the colon as a relative indication and allows delay at 10–20 with <6 mm adenomas lacking villous components/high-grade dysplasia to permit physical and emotional maturity [1]. Oxford Desk Reference states most surgeons plan colectomy at 16–20 [3]; its reproduced Cairns table recommends pouch proctocolectomy or colectomy before 30, when cancer risk increases [54]. Among 303 patients operated during 2000–2012 in a multicentre cohort, 38% already had CRC [9].

IPAA does not invariably require a protective ileostomy; ileosigmoid anastomosis may be considered when the rectum can be retained [9]. A single-stage operation is preferred for women at high desmoid risk, with codon 1395–1493 variants or a desmoid family history [1]. Specialist centres achieve the best outcomes [3].

7.4 Postoperative surveillance

After IRA, rectal endoscopy should be no more than 2 years apart, annual in Cairns, removing all >5 mm polyps. Consider secondary proctectomy with uncontrollable polyposis or at least two high-grade dysplastic polyps [9, 54]. Annual pouch endoscopy after IPAA starts 12 months postoperatively and includes the proximal ileum; repeat in 6 months with high-grade dysplasia, while pouch carcinoma requires pouchectomy [9].

7.5 Upper gastrointestinal tract

Upper endoscopy starts at 18–30 (EHTG-ESCP), or 20–25/before colectomy (GeneReviews/NCCN), in all phenotypes, with complete papillary visualisation using a cap-assisted forward-viewing endoscope or side-viewing duodenoscope [1, 9]. Intervals depend on Spigelman stage and papillary appearance [1, 9].

Stages: 0 = 0 points; I = 1–4; II = 5–6; III = 7–8; IV = 9–12 [1, 26]. Generally accepted intervals are 5 years for 0–I, 3 years for II and at least annually for III–IV, with surgical referral in IV [1]. EHTG-ESCP recommends endoscopic removal of non-papillary duodenal lesions >10 mm, removal or surveillance of 5–10 mm lesions, papillary adenoma removal particularly above 10 mm or with high-grade dysplasia/villous components, endoscopic downstaging of IV and attempted III downstaging, annual surveillance even afterwards (up to 50% return to IV within 1 year), and surgery for invasive carcinoma [9]. Surgical options are pancreaticoduodenectomy (Whipple) and pancreas-preserving duodenectomy, with high morbidity requiring high-volume centres [1]. After duodenal surgery, neoduodenal adenomas occur in up to 59.4% [9]. Gastric adenomas >5 mm require en bloc resection; consider gastrectomy with advanced neoplasia [1, 9]. Small-bowel surveillance is not routine but capsule endoscopy is recommended before duodenal surgery [9].

GAPPS lacks guidelines supported by robust evidence [1, 9]. EHTG-ESCP recommends genetic testing with clinical suspicion, individualised upper-endoscopy starting age/intervals considering the youngest familial gastric cancer, colorectal surveillance particularly with familial CRC, and total gastrectomy for high-grade dysplasia or progressive gastric polyposis. Evidence cannot establish a prophylactic gastrectomy age; decisions are individualised and all recommendations have low evidence levels [9]. A review cited by EHTG-ESCP proposes upper endoscopy from 15 for promoter 1B-carrier first-degree relatives, index colonoscopy from 18 repeated every 3 years with adenomas/serrated lesions or age below 40, and prophylactic total gastrectomy from 30–35 or 5 years before the earliest familial gastric cancer [9]. Rapid metastatic adenocarcinoma progression has occurred despite endoscopic surveillance. Despite antral sparing, proximal gastrectomy lacks demonstrated long-term safety; gastric surgery should permit subsequent duodenal assessment because its risk cannot yet be excluded [9]. GeneReviews states uncertainty about prophylactic gastrectomy and, on expert opinion, suggests gastroscopy from 15 with removal of all suspected adenomas, pyloric gland adenomas or dysplastic polyps, random fundic gland polyp biopsies, and gastrectomy for advanced neoplasia [1].

7.6 Extracolonic manifestations

7.7 Desmoid tumour treatment

Current management prioritises active surveillance (watch-and-wait) for stable tumours and active treatment for rapidly growing or life-threatening disease [9, 15]. Church stages are I (asymptomatic, <10 cm, no growth), II (mild symptoms, <10 cm, no growth), III (moderate symptoms, bowel/ureteral obstruction, 10–20 cm or slow growth), and IV (severe symptoms requiring hospitalisation, >20 cm or rapid growth) [9]. Surgery is preferred for well-defined extra-abdominal/abdominal-wall desmoids; avoid mesenteric resection requiring small-bowel sacrifice. Confirmatory biopsy is reserved for diagnostic uncertainty or initiating medical treatment [9]. Systemic options include non-steroidal anti-inflammatory drugs (NSAIDs), anti-oestrogens, low-dose or anthracycline-based cytotoxic chemotherapy, tyrosine kinase inhibitors and γ-secretase inhibitors [1, 15]. Intestinal transplantation has been used in complex desmoids [9].

Varegacestat, formerly AL102, is a once-daily oral γ-secretase inhibitor evaluated in phase 3 RINGSIDE (NCT04871282) for adults with progressive desmoids. Available data are sponsor press releases and a 2026 American Society of Clinical Oncology oral presentation rather than a peer-reviewed article. According to the 15/12/2025 release, 156 patients were randomised to 1.2 mg/day or placebo; the blinded independent-central-review progression-free survival primary endpoint gave HR 0.16 (p<0.0001), and objective response was 56% versus 9%. Common adverse events were diarrhoea 82%, fatigue 44%, rash 43%, nausea 35% and cough 34% [58]. The NDA was submitted in April 2026 and accepted in July 2026 with PDUFA decision target 28/04/2027; the sponsor announced intended EMA submission by late 2026 [18, 59]. It remains investigational without authorisation in any jurisdiction at this review date; 1.2 mg is a trial rather than labelled dose.

7.8 Chemoprevention

No FDA-approved FAP chemopreventive agent exists. Adenoma number/size changes are considered insufficient; FDA requires clinical benefit such as reduced cancer or surgery [1]. EHTG-ESCP finds insufficient evidence for routine colorectal/duodenal polyp chemoprevention and recommends offering it only in trials [9].

Oxford Desk Reference reproduces Vasen and colleagues' 2008 position: NSAID chemoprevention may complement endoscopic surveillance after prophylactic surgery to reduce rectal burden, with selective COX-2 inhibitors restricted to selected patients without cardiovascular risks [3, 52]. Oestrogen-containing contraceptives are associated with 18% relative CRC risk reduction in the general population, and EHTG-ESCP recommends informing carriers [9].

7.9 Comparative regulatory status: United States and European Union

No medicine is specifically authorised for FAP or adenoma prevention. Relevant regulatory indications target desmoids, a major FAP morbidity cause, or use is off-label. Distinguish peer-reviewed DeFi/sorafenib evidence, sponsor topline releases, application acceptance initiating assessment, EMA Committee for Medicinal Products for Human Use (CHMP) opinion before authorisation, and FDA/European Commission authorisation decisions. Marketing authorisation does not guarantee national marketing, reimbursement or access. These depend on INFARMED assessment in Portugal and ANVISA registration in Brazil, with CONITEC assessment for Sistema Único de Saúde (SUS). Consulted sources yielded no Portuguese nirogacestat funding decision or Brazilian registration.

7.10 Pivotal trials and interpretation limits

Indirect comparison cannot rank these drugs. Desmoid trials differ in inclusion (documented progression versus symptomatic/recurrent disease), progression assessment (independent central versus investigator) and FAP proportions. RINGSIDE remains unpublished in a peer-reviewed journal; a lower HR does not establish superiority. Chemoprevention polyp-count reductions are surrogate outcomes, distinct from FDA-required clinical benefits of less cancer or surgery. Individual-change medians such as eRapa phase 2 are not population means or, without placebo, causal effects. Relative reduction must be considered alongside residual absolute rates: approximately one third progressed on eflornithine/sulindac. Negative celecoxib/eflornithine and eflornithine/sulindac trials and celecoxib withdrawals inform Europe's recommendation for trial-only chemoprevention [9].

7.11 Evidence extrapolation and off-label use

Evidence extrapolation differs from off-label use. Nirogacestat trials involved adults with progressive desmoids; US/EU labels cover such adult tumours regardless of aetiology, so adult FAP use is on-label. However, the magnitude of benefit in FAP-related, often intra-abdominal/mesenteric desmoids is extrapolated because it was not precisely estimated in a dedicated subgroup. Paediatric/adolescent use is off-label in both jurisdictions; the US label describes paediatric epiphyseal changes [55]. γ-Secretase inhibitors are discouraged in pregnancy because of embryofetal toxicity, requiring effective contraception [55]. Sorafenib, sulindac, tamoxifen and celecoxib use in desmoids or FAP is always off-label, with doses derived from cited trials/guidelines rather than labels. These distinctions depend on jurisdiction-specific labels and patient age and should be explicit in informed consent.

8. Reproductive Options and Family Counselling

FAP is autosomal dominant, with 50% variant inheritance risk for each child [1]. Approximately 75–80% have an affected parent and up to 25% a de novo variant [1]. Parental testing is recommended in simplex cases. If both parents test negative, consider de novo variation or parental germline/somatic-and-germline mosaicism; siblings retain above-population risk and should be tested [1]. Mosaic parents may be only mildly or minimally affected [1].

Predictive testing should be offered to all first-degree relatives, followed by cascade testing [1, 9]. Since colonoscopy starts at 10–12, molecular testing is usually offered by 10; birth testing may be justified if parents choose hepatoblastoma surveillance. AFAP testing may wait until late adolescence [1]. Oxford Desk Reference recommends early-adolescent testing to begin surveillance around 14 and notes adolescent adjustment after counselling/testing [3]. A solitary adenoma in a young at-risk individual should indicate carrier status [3]. Family-identified patients have longer life expectancy than symptom-diagnosed patients [1]. Testing an at-risk relative without prior index-case testing requires caution: a negative result does not exclude a familial variant [1]. Long-term psychological support should be available, as recommended by ESPGHAN [1, 53].

Prenatal diagnosis and preimplantation genetic testing (PGT-M) are possible with a known familial variant; more FAP couples choose preimplantation than prenatal diagnosis [1, 3]. Fetal variant detection cannot predict onset or severity [1]. Fertility without surgery or after IRA resembles population fertility; it decreases after IPAA, although EHTG-ESCP finds no convincing IPAA–IRA difference. Total IPAA before completing reproductive plans requires discussion [1, 9]. After risk-reducing surgery, women not conceiving within one year should be referred for reproductive medicine; cancer-diagnosed women require fertility-preservation referral [9]. Colectomised women have obstetric risk comparable to other major abdominal surgery and a greater caesarean likelihood. Pregnancy's desmoid effects are poorly characterised; severe duodenal disease was more frequent in multiparous than nulliparous women [1].

MAP siblings have 25% affected and 50% carrier probabilities. An affected person's offspring risk with a Northern European, Australian or US partner is 0.5–1%; offering common-variant partner testing is reasonable, considering consanguinity [3, 8].

ERN GENTURIS, the European Reference Network on Genetic Tumour Risk Syndromes, includes adenomatous polyposis and Lynch syndrome and enables cross-national complex-case discussions [78]. Patient resources include EuropaColon Portugal, a digestive/colorectal cancer organisation without an FAP-specific remit, and the US Desmoid Tumor Research Foundation [79, 80]. Consulted sources identified no dedicated Brazilian FAP organisation; section 9's hospital polyposis registries provide cascade-testing reference points.

9. Special Considerations: Population Diversity and Epidemiology

FAP frequency is relatively constant worldwide, affecting both sexes equally [1]. Orphanet classifies point prevalence as 1–9/100 000, with 4.65/100 000 in Denmark, 3.2 Sweden, 2.63 Finland, 5.3 UK and 2.8 Australia; European estimate 6/100 000 (European Medicines Agency, 2011) [2]. Denmark's fully ascertained registry gives 1:8,500 prevalence and 1.3 new cases/million/year incidence [3, 5]. FAP historically accounted for approximately 0.5% of all CRC, declining with prophylactic colectomy [1]; AFAP is probably underdiagnosed [1]. From MAP heterozygote frequencies of 1–2% in Northern Europe, Australia and the US, approximately 0.8% in gnomAD, estimated biallelic prevalence is 1:20,000 to 1:60,000. MAP accounts for approximately 0.7% of all CRC and 0.5–6% of familial/early-onset CRC cohorts with few adenomas [8].

Founder effects include Ashkenazi p.Ile1307Lys (approximately 8%, moderate risk), Newfoundland c.221-1G>A, and Amish codon 1526 Alu insertion [1, 33]. Upstream GREM1-duplication HMPS is more common in Ashkenazi Jews [33]. FAP gastric cancer risk in Japanese/Korean patients is approximately tenfold population risk [1]. Northern European MAP predominantly involves p.Tyr179Cys and p.Gly396Asp; c.1227_1228dup is common in Spain, Portugal and Tunisia; p.Glu480del in Italy; p.Pro405Leu in the Netherlands; p.Gly286Glu in Japan/Korea; p.Tyr104Ter (c.312C>A) in Pakistan; p.Glu480Ter in British people of Indian origin; and exon 4–16 deletion in Spain, France and Brazil [3, 8].

A Portuguese study of 85 FAP families identified eleven novel variants, predominantly frameshift or premature-stop substitutions, without a described dominant founder effect [81]; national prevalence data were not located. Among 23 Brazilian probands, detection was 87% (14 APC variants, six MAP cases), with 30% novel variants and desmoids in six of eight families with variants upstream of codon 1444, contrary to the classical correlation [82]. A three-decade Brazilian surgical series reported desmoids in 17.7% [38]. Among 176 patients treated in one São Paulo centre during 1982–2023, comparison of 1982–2006 versus 2007–2023 showed earlier diagnosis, more familial-aggregation diagnoses (26.1% to 57.1%), less CRC at surgery (59.7% to 32.1%), lower long-term mortality (19.5% to 9.5%), and more desmoid diagnoses (9.8% to 22.6%) [83]. Portuguese hospital series supplement the 2000 molecular study: a Lisbon familial-risk clinic with 151 families treated 22 patients endoscopically for ≥10 mm duodenal adenomas during 2010–2021, with complications in 6.3% of lesions and no adenocarcinomas [84]. Among 53 Porto patients, 32% had gastric adenomas, isolated or with fundic gland polyps, predominantly distal intestinal-type with intestinal metaplasia, resembling Asian cohorts; authors attributed this to high Portuguese Helicobacter pylori prevalence [85]. Another series treated 17 desmoid patients from 9 families predominantly with NSAIDs/tamoxifen [86]. These are referral-care series, not population prevalence measures. No population prevalence estimates were located for Portugal or Brazil. Consulted literature likewise lacks estimates for Africa, the Middle East, South Asia and most Latin American countries; available cases include Saudi Arabia's first published FAP mutational profile (2025) and Trinidad and Tobago's type 2 Turcot case (2024) [32, 87]. These gaps are acknowledged without extrapolation.

Unequal molecular testing/endoscopy access in low- and middle-income countries constrains early diagnosis. Trinidad and Tobago's case illustrates international collaboration through the SickKids-Caribbean Initiative for tumour molecular classification and cascade testing [32].

10. Illustrative Clinical Case

10.1 APC-associated Turcot syndrome (WNT-activated medulloblastoma)

A 12-year-old Indo-Trinidadian girl presented to emergency care after four days of intermittent vomiting and one reduced-consciousness episode, preceded by five months of headaches, three weeks of fatigue/progressive gait imbalance, and diplopia/bilateral tinnitus in the final week [32]. CT showed a posterior fossa mass with obstructive hydrocephalus, requiring a ventriculoperitoneal shunt [32]. Paediatric oncology identified familial CRC/clinical FAP: the paternal grandfather had CRC at 53, and her father and paternal aunt with multiple colonic polyps underwent prophylactic total colectomy at 37 and 32 [32]. Genetic testing identified pathogenic APC c.3183_3187del (p.Gln1062Ter), a five-base-pair deletion around codon 1061, an Oxford Desk Reference hotspot. Cascade testing confirmed it in her father, brother and paternal aunt [3, 32]. Subtotal resection histology confirmed WHO grade 4 WNT-activated medulloblastoma, stage M0 but high-risk because residual tumour exceeded 1.5 cm². She received craniospinal irradiation (36 Gy in 20 fractions plus posterior-fossa boost 18 Gy, total 54 Gy in 30 fractions), weekly vincristine, and eight 42-day cycles of vincristine, cyclophosphamide and cisplatin (A9961 regimen B), achieving remission after treatment [32]. Axial CT is available at https://pmc.ncbi.nlm.nih.gov/articles/PMC10973883/figure/f1/ and the pedigree at https://pmc.ncbi.nlm.nih.gov/articles/PMC10973883/figure/f2/ [32].

The case illustrates APC-related Turcot, WNT subgroup as a predisposition indicator, the need for colorectal surveillance in the patient and carrier brother from 12 under EHTG-ESCP, and annual neurological examination in carriers [1, 9].

10.2 Gardner phenotype revealed by craniofacial osteomas

A 34-year-old Moroccan woman presented with two years of craniofacial swellings and left orbital discomfort despite normal ophthalmological examination [88]. Craniofacial CT showed over seven osteomas, including a left orbital lesion risking optic nerve compression, ethmoid sinus, middle cranial fossa and mandibular angle lesions; alveolar density changes consistent with hypercementosis; and a frontal soft-tissue mass representing recurrent desmoid [88]. Her brother had been the first diagnosed, with vague abdominal pain, a mandibular osteoma and multiple colonic polyps. Family screening found polyposis in the father, with polyp cellular atypia and hypochromic microcytic anaemia (Hb 11 g/dL), leading to prophylactic colectomy, and in her sister. The patient underwent colonoscopic surveillance, and transnasal endoscopic orbital osteoma excision was proposed [88]. The report does not mention molecular APC testing, a limitation warranting germline index-case and cascade testing under current guidance [9, 88]. CT images are available at https://pmc.ncbi.nlm.nih.gov/articles/PMC11795357/figure/fig0001/ and https://pmc.ncbi.nlm.nih.gov/articles/PMC11795357/figure/fig0002/ [88].

11. Prognosis and Long-Term Follow-up

Polyposis registries, cascade testing and prophylactic colectomy changed FAP natural history: family-identified patients have longer life expectancy than symptom-diagnosed patients [1, 5]. CRC prevention shifted principal mortality causes to duodenal/periampullary cancer and desmoids [1, 3]. Cairns' table gives unsurveyed CRC death risk of 1 in 2 with clinical FAP criteria and 1 in 4 for FAP family members without an identified variant. Rectal cancer risk after IRA is 1 in 15 and deemed negligible after pouch proctocolectomy [54]. Pouch, rectal cuff and anal transition-zone cancer risk is low but non-zero (1.9–3.8%) [9].

Lifelong follow-up includes residual rectum/pouch endoscopy, Spigelman/papilla-based upper endoscopy, thyroid surveillance, annual extracolonic/desmoid examination and optional childhood hepatoblastoma surveillance [1, 9]. Paediatric–adult transition, psychological support, fertility and sexual function are integral [1, 9]. Cairns estimates 1–3 procedures/year per 300,000 residents for these groups, useful for service planning [54]. Care should occur in specialist centres with polyposis-registry access [3, 9].

12. Summary and Final Considerations

FAP is autosomal dominant, caused by germline null APC variants disrupting WNT/β-catenin, with approximately 100% classic-form colorectal adenoma penetrance and nearly 100% CRC risk without colectomy [1, 3]. AFAP, Gardner and APC-related Turcot describe phenotypes within one spectrum, partly modulated by variant position; GAPPS is a promoter 1B allelic entity [1, 2]. Diagnosis combines endoscopic/histological phenotype, pedigree and panels including APC deletion/duplication/promoter 1B and MUTYH, with mosaic testing after negative results [1, 9]. MAP differentiation directly changes dominant/recessive counselling and surveillance [3, 8]. Management comprises colonoscopy from 10–12, prophylactic colectomy with IRA/IPAA chosen by rectal/colonic burden and genotype, Spigelman-based upper gastrointestinal surveillance, thyroid surveillance, and active observation/systemic desmoid treatment including nirogacestat (Ogsiveo®), approved in the US/EU for progressive desmoids [1, 9, 16, 17]. No chemoprevention is approved; ongoing trials use clinical endpoints such as surgery requirement [1, 75]. Varegacestat, another γ-secretase inhibitor, awaits FDA decision (target 28/04/2027) on phase 3 results not yet peer-reviewed, while eRapa is in phase 3 [18, 76]. Gaps remain in epidemiology outside Europe, North America and Japan, hepatoblastoma surveillance value and GAPPS management [1, 9].

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