Serrated Polyposis Syndrome

Colorectal polyposis defined by endoscopic–histological criteria (World Health Organization, 2019), with increased colorectal cancer risk in patients and first-degree relatives; predominantly non-Mendelian aetiology, with a rare subgroup associated with germline loss-of-function variants in RNF43.

Literature and regulatory information updated: 6 October 2026.

0. Initial Reference Table

1. Introduction

Serrated polyposis syndrome occupies a distinctive position among colorectal cancer predisposition syndromes. Unlike familial adenomatous polyposis, MUTYH-associated polyposis or hamartomatous polyposis syndromes, which are defined by identifying a pathogenic germline variant, SPS continues to be diagnosed exclusively by clinical criteria combining the number, size, location and histology of serrated polyps. This phenotypic definition has practical consequences: diagnosis depends on colonoscopy quality, cumulative recording of resected lesions and histopathological interpretation, and genetic testing has a limited role, mainly to exclude other syndromes [6, 7].

The history of the entity begins with the description of “metaplastic polyposis”. In 1980, Williams, Arthur, Bussey and Morson, from St Mark's Hospital, published a study of 554 colorectal metaplastic polyps in Histopathology. Most lesions were small and sessile, but 16.1% measured more than 0.5 cm and 0.9% more than 1 cm; larger polyps could be pedunculated and show a tubulovillous or villous pattern, with structural similarities to adenomas. The authors also described seven patients with multiple metaplastic polyps who had at some point been diagnosed with adenomatous polyposis; six were men, the mean age at presentation was 37.4 years and large polyps were common. The article emphasised the need for histological confirmation in all cases of intestinal polyposis and discussed the possibility that “metaplastic polyposis” constituted a distinct entity [19]. The Oxford Desk Reference records the terminological evolution, noting that serrated polyposis syndrome, incorporating metaplastic polyposis, came to be recognised as an entity [2].

For years, hyperplastic polyposis was considered non-premalignant. In 1996, Torlakovic and Snover reassessed six patients with presumed hyperplastic polyposis and four with associated carcinoma and found that the polyps more closely resembled serrated adenomas than classical hyperplastic polyps, with large size, marked architectural distortion, atypical nuclei, focal nuclear crowding and rare mitoses in the upper zone; the authors proposed the name “serrated adenomatous polyposis”, distinguished from true hyperplastic polyposis by its possible association with adenocarcinoma [20]. The 2017 BSG position statement summarises this shift: the syndrome was originally described to avoid misclassification as familial adenomatous polyposis and was not thought to confer CRC risk, a perception challenged from 1996 onwards by case series with cancer [16].

The 2010 World Health Organization (WHO) criteria required at least five serrated polyps proximal to the sigmoid colon, two measuring more than 10 mm (criterion I), any number of serrated polyps proximal to the sigmoid in an individual with a first-degree relative with SPS (criterion II), or more than 20 serrated polyps of any size throughout the colon (criterion III) [16, 17]. In 2019, the 5th edition of the WHO classification of digestive system tumours, published in July that year, reformulated the criteria into two types, moved the anatomical boundary from the sigmoid to the rectum and removed former criterion II [6, 21]. According to the BSG, this criterion made false-positive diagnosis likely, as the prevalence of serrated lesions in Western populations may reach 39%, most being sporadic [6]. The 2026 USMSTF consensus adds that the lack of evidence for a genetic basis contributed to removing this criterion and that the new emphasis on sigmoid lesions reflects the observation that approximately half of CRCs in SPS occur in the rectosigmoid [7].

The search for a genetic cause reached a milestone in 2014, when Gala and colleagues sequenced the exomes of 20 unrelated individuals with multiple sessile serrated adenomas, selected using inclusion criteria adapted from the 2010 WHO criteria (without a polyp size requirement and accepting a family history of CRC in place of a family history of SPS), of whom 16 met the WHO criteria, and identified nonsense variants in RNF43 in two, with an odds ratio of 460 (95% confidence interval [CI] 23.1–16,384) compared with 4,300 controls [22]. This was followed by the description of a germline nonsense variant cosegregating with severe SPS in an Australian sibship [23] and identification of a germline RNF43 variant with autosomal dominant cosegregation in one of four families, with a somatic second hit in all polyps and the cancer examined [24]. Subsequent systematic studies showed, however, that these variants are rare in SPS and that penetrance is lower than suggested by the founding families [9, 25, 26].

SPS is now recognised as the most common colorectal polyposis syndrome, more common than all other gastrointestinal polyposis syndromes combined, and is simultaneously underdiagnosed [7]. This article integrates the Oxford Desk Reference, GeneReviews chapters addressing SPS as a differential diagnosis, ESGE, BSG and ACG guidelines, the USMSTF consensus published in September 2026 and the genetic and cohort studies underpinning the recommendations.

2. Molecular Genetics and Pathophysiology

2.1. Serrated lesions and the serrated pathway of carcinogenesis

Serrated lesions of the colon and rectum are characterised histologically by a saw-toothed appearance of the crypt epithelium. For decades, all lesions with this morphology were termed hyperplastic polyps and considered to lack malignant potential; subsequent morphological and molecular characterisation distinguished subtypes with different risks of transformation [16]. The BSG proposes the nomenclature hyperplastic polyp (HP), sessile serrated lesion (SSL), SSL with dysplasia, traditional serrated adenoma (TSA) or mixed polyp, using WHO criteria to define SSLs; the term SSL replaced the earlier terms “sessile serrated adenoma/polyp” [16, 27]. Distribution differs by subtype: HPs and TSAs are usually located in the left colon, whereas SSLs predominate in the proximal colon [16].

The sessile serrated pathway usually begins with a BRAF mutation or, less frequently, a KRAS mutation, and progresses through methylation of tumour suppressor genes, the CpG island methylator phenotype (CIMP, CpG island methylator phenotype). Depending on the genes epigenetically silenced, the resulting tumours may have microsatellite stability or microsatellite instability (MSI) through MLH1 promoter methylation. CIMP-positive tumours account for approximately one-third of all CRCs, and alternatives to the conventional adenoma–carcinoma sequence account for 15–30% of CRCs, with overrepresentation among interval cancers [16]. Gala and colleagues, citing earlier studies, report that sessile serrated adenomas are found in 2% of average-risk individuals undergoing their first screening colonoscopy and that serrated lesions may account for approximately 20–35% of colon cancers, a higher estimate than that of the BSG [22]. There is a progressive increase in BRAF-mutant CIMP-positive tumours from the rectum to the caecum, of unknown cause. A mean interval of 15 years between SSL without cytological dysplasia and cancer has been suggested, but the risk and rate of progression are undefined [16]. The TSA pathway is less well understood: it includes KRAS or BRAF mutations with variable CIMP, does not appear to progress through methylation of mismatch repair (MMR, mismatch repair) genes, and high epithelial GREM1 expression has been described, suggesting that these lesions are the sporadic counterpart of polyps in hereditary mixed polyposis [16].

In SPS, cancers do not follow a single pathway. At a Dutch centre, 35 patients with SPS had 43 CRCs: 21 (48.8%) had BRAF p.V600E (historical notation, = NM_004333.6:c.1799T>A p.(Val600Glu), somatic variant), 10 of these lacked MLH1 expression and 17 (81%) were in the proximal colon; the remaining 22 (51.1%) were BRAF wild type and MLH1 proficient, 17 (77.3%) were in the distal colon and 36.4% had a pathogenic KRAS or NRAS mutation. The authors concluded that the ratio between serrated-pathway and adenoma–carcinoma-pathway cancers in SPS averages 50:50 [28]. In an earlier series cited by the ACG, 18 of 39 CRCs in patients with SPS (46%) had BRAF V600E, 2 of 40 (5%) had KRAS mutations and 17 of 45 (38%) had immunohistochemical loss of MLH1 and PMS2 [17]. The 2026 North American consensus interprets this heterogeneity as indicating that SPS is a marker of CRC risk through both pathways, justifying removal of both significant serrated lesions and all conventional adenomas during colonoscopy [7].

2.2. Genetic architecture: a syndrome without a common causal gene

The BSG considers SPS very likely to comprise a phenotypically and genetically heterogeneous group of diseases, that the increased risk in first-degree relatives does not follow a classical Mendelian pattern, that no single causal gene has been identified and that some forms may be polygenic; diagnosis should therefore be phenotype-based [6]. The USMSTF adds that the older age at diagnosis and lack of a family history of CRC in most patients favour SPS generally not being a genetic syndrome [7].

Germline panel studies confirm the low yield. In the St Mark's Hospital (London) series, 258 of 573 patients with SPS underwent genetic testing; no pathogenic variant was detected among the 119 undergoing targeted testing, and among the 139 undergoing multigene panel testing (R211, 16 genes), 4 actionable pathogenic variants (2.9%) were found: three in Lynch syndrome genes (two in PMS2, one in MSH2) and one in RNF43 [29]. In Oxford, 73 of 173 patients tested had 15 germline variants (20.5%), of which 7 (9.6%) were pathogenic: MUTYH (n = 2, heterozygosity), SMAD4 (n = 1), CHEK2 (n = 2), POLD1 (n = 1) and RNF43 (n = 1) [30]. In a Dutch study, no pathogenic germline RNF43 variant was detected in 26 patients with SPS whose exons were all Sanger sequenced [25]. A Portuguese study from the Instituto Português de Oncologia in Lisbon, involving 60 patients, identified pathogenic or likely pathogenic variants in 6 (ATM, FANCM, MITF, RAD50, RAD51C and RNF43), all in patients with lesions in the proximal colon or throughout the colon, and proposed a role for DNA interstrand crosslink repair genes as a hypothesis requiring validation [31].

2.3. RNF43

RNF43 is located at 17q22 and encodes a transmembrane RING-type E3 ubiquitin ligase of 784 amino acids that degrades Frizzled Wnt receptors and thus acts as a negative regulator of Wnt signalling; the protein has transmembrane, protease-associated, ectodomain, cytoplasmic RING (approximately codons 272–313) and C-terminal regions [1, 9]. RNF43 mutations only activate the Wnt pathway when sufficient extracellular Wnt ligands are present, distinguishing their mechanism from that of APC mutations [9]. The MANE Select reference transcript is NM_017763.6 (protein NP_060233.3) [8].

On 30 December 2022, ClinGen's Hereditary Cancer Gene Curation Expert Panel classified the relationship between RNF43 and sessile serrated polyposis cancer syndrome (MONDO:0014919) as definitive, with autosomal dominant inheritance [4]. Orphanet lists RNF43 as a gene with causal germline mutations, validated by the publication by Taupin and colleagues [1, 23]. In OMIM, entry #617108 (created in September 2016, updated in September 2017 and last edited in July 2024) uses the # sign because there is evidence that SSPCS is caused by heterozygous RNF43 variants (612482; 17q22), with autosomal dominant inheritance and mapping key 3 (molecular basis known), and is based on the two initial observations: the nonsense variants R113X of Gala and colleagues and R132X of Taupin and colleagues (OMIM alleles 612482.0001 and 612482.0002) [5]. This designation describes the RNF43-associated subgroup; it should not be read as proof that SPS is a monogenic disease in most patients, which the panel studies in section 2.2 contradict. The entry retains the terminology and criteria of WHO 2010 (“sessile serrated adenoma”, hyperplastic polyposis, at least five polyps proximal to the sigmoid with two or more measuring over 10 mm, and the first-degree-relative criterion, removed in 2019) and reproduces, from the introduction of Gala and colleagues, figures from early series: lifetime CRC risk “up to 54%”, a 32% risk of multiple serrated polyps and fivefold CRC risk in first-degree relatives, and increased pancreatic cancer risk [5, 22]. These elements have historical value and do not replace the 2019 criteria or the current risk estimates discussed in sections 3 and 8.

Functional evidence comes mainly from selected families. In the family reported by Yan and colleagues, the germline variant cosegregated with the phenotype and all serrated polyps (16), adenomas (5) and the cancer (1) examined showed inactivation of the second allele through loss of heterozygosity or somatic mutation, with a concurrent BRAF mutation in 62.5% of serrated polyps; in organoids, RNF43 inactivation reduced dependence on R-spondin 1 [24]. In the six-generation British Ox7 family, RNF43 c.471del carriers had more than 10 polyps; a second hit was demonstrated in 5 of 7 polyps analysed, most with a somatic BRAF or KRAS mutation, all microsatellite stable and all four tested CIMP-negative [9].

Somatic RNF43 mutations are common in colorectal tumours of the serrated pathway. Yan and colleagues found somatic mutations in 34% of sporadic sessile and traditional serrated adenomas and in no HPs (p = 0.013), and in 85% of CRCs with MSI and MLH1 methylation versus 33.3% of CRCs with MSI without methylation [24]. Somatic hotspots (codons 659 and 117, within short repeats) occur in lesions with MSI, including serrated polyps and adenomas in patients with Lynch syndrome [9, 25]. A somatic RNF43 mutation in a tumour sequencing report is a tumour event and does not in itself indicate germline predisposition [9].

The study by Palles and colleagues (2026), involving 49,823 CRC and/or polyp cases from the CORGI study, the 100,000 Genomes project and UK Biobank and 165,250 controls, changed the clinical interpretation of RNF43. There were 23 cases and 47 controls carrying loss-of-function variants; cases frequently had neither multiple polyps nor a relevant family history, and the familial polyposis phenotype was present only in the Ox7 family. The association with CRC or polyps was not significant (OR 1.615; 95% CI 0.927–2.815), but the association with CRC was (OR 2.696; 95% CI 1.269–5.727; p = 0.010). Restricting analysis to variants up to codon 330 increased the OR for CRC to 6.240 (95% CI 2.079–18.731); C-terminal variants (after codon 330) were not associated with risk (OR 1.459; 95% CI 0.283–4.763). Two female p.(Arg330Ter) carriers had CRCs that developed without RNF43 inactivation (“molecular phenocopies”), and the same variant was found in six controls (five from UK Biobank and one from 100,000 Genomes). The authors concluded that RNF43 is a moderate-risk CRC predisposition gene, comparable to PMS2 when variants are N-terminal, with very limited or absent effects of C-terminal variants [9]. A Danish series of four families with likely pathogenic variants (one multiexon deletion and two nonsense variants) showed that three families had no history of CRC or serrated polyps and that colonoscopy in the probands, some at advanced ages, revealed neither serrated polyps nor CRC [26].

Table 2.1. Germline RNF43 variants described in the sources consulted (NM_017763.6; NP_060233.3)

Nucleotide and protein HGVS descriptions were validated in VariantValidator against the MANE Select transcript, and classifications were obtained by direct consultation of ClinVar [8, 32]. The GeneReviews chapter on MUTYH-associated polyposis gives a CRC risk of “≤54%” for RNF43-associated SPS, without a primary source identified in the table; this figure, derived from selected families, is incompatible with the population estimate of Palles and colleagues and should not be used in counselling [9, 33]. The same number has circulated in the literature since the series of Hyman and colleagues (2004): 13 patients with hyperplastic polyposis (more than 20 hyperplastic polyps throughout the colon and/or one hyperplastic polyp measuring at least 1 cm in the right colon), followed prospectively by a single university surgeon, of whom 7 (54%) had CRC during the study, 4 at diagnosis and 3 despite frequent colonoscopic surveillance [34]. Gala and colleagues cited this work as a CRC risk of “up to 54% over a lifetime” in the syndrome overall, and OMIM repeats it; this is an observed proportion in a small selected series unrelated to RNF43, rather than a lifetime risk [5, 22].

2.4. Other genes and factors investigated

Besides RNF43, the study by Gala and colleagues identified variants in genes regulating oncogene-induced senescence (ATM, PIF1, TELO2, XAF1 and RBL1) in 5 of 20 patients, compared with 424 of 4,300 control exomes (25% versus 9.87%; OR 3.0; 95% CI 0.9–8.9; p = 0.04), with no gene affected in more than one patient; in the analysis of genes with loci from cancer genome-wide association studies, the ULK4 variant R862X (rs199884004) occurred in 2 of 20 patients and in 45 of 4,300 controls (OR 10.5; 95% CI 1.1–45.8; p = 0.02). Of the 19 patients with a genotyped sessile serrated adenoma, 18 had BRAF V600E in the lesion. The authors note that the controls' polyp history was unknown and was assumed negative [22]. Exome sequencing of 39 patients from 16 Spanish families with SPS aggregation proposed 14 candidate genes (ANXA10, ASXL1, CFTR, DOT1L, HIC1, INO80, KLF3, MCM3AP, MCM8, PDLIM2, POLD1, TP53BP1, WNK2 and WRN) [35]. Subsequent functional studies, with replication in 211 independent patients, supported WNK2 variants (effect on the MAPK pathway) [36] and missense variants in HIC1 DNA-binding domains (increased DNA damage and altered binding to the SIRT1 promoter in cellular models) [37]. In 2026, the same group described DOT1L missense variants (NM_032482.3:c.3307G>A p.(Val1103Met), in two siblings with SPS and their mother with CRC; and c.3475G>C p.(Asp1159His)) with altered H3K79 methylation dynamics and cell-cycle progression in cell lines, and a frequency of rare DOT1L variants of approximately 1% (4/411) [38]. In Japan, a panel in 11 patients identified a pathogenic germline BUB1 variant in a 47-year-old woman who had never smoked, with more than 50 serrated polyps and transverse colon cancer [39]. These genes remain research candidates, without established gene–disease validity or diagnostic use.

2.5. Environmental factors

The association with smoking is consistent. In an Australian case–control study, 47% of patients with SPS were current smokers, compared with 17% of colonoscopy controls and 12% of population controls (OR 8.3 and 12.7, respectively) [40]. The ACG notes that, in a series of patients with multiple serrated polyps, 58% (51/88) were current or former smokers and that smoking is speculated to intensify phenotypic expression without being its cause [17]. The USMSTF reports a strong association with smoking, more pronounced in type 2, but emphasises that many patients have never smoked and that there is no evidence that cessation alters the course of disease [7]. Paradoxically, in a Dutch and British cohort of 434 patients, smoking history was inversely associated with CRC (OR 0.36; 95% CI 0.23–0.56), which the authors attributed to possible differences in pathogenesis [41]. In a Washington, D.C. healthcare system, SPS was more common in overweight or obese patients and less common in current or former smokers, findings that the authors themselves classified as inconclusive [42]. A Japanese study from 2026 described histological intestinal spirochaetosis in 18.8% (12/64) of patients with SPS versus 1.6% (6/382) of controls (OR 14.5; 95% CI 5.2–40.2), a new association whose relevance requires confirmation [43].

3. Clinical Spectrum and Manifestations by System

3.1. Colorectal phenotype

SPS is a disease of the large bowel. In the vast majority of patients, the polyps establishing the diagnosis are HPs and SSLs; TSAs are uncommon, partly because pathologists may classify them as tubulovillous adenomas, and distinguishing SSLs from HPs is subject to interobserver variability. For this reason, both count towards diagnosis, and HPs measuring 10 mm or more may be managed as SSLs [7]. Polyp burden varies: in the multicentre Spanish cohort of 296 patients, a median of 26 serrated polyps (interquartile range 18.2–40.7) and 3 adenomas (1–6) were detected per patient [44]. Synchronous conventional adenomas are common: in two descriptive series cited by the ACG, most index cases had pancolonic distribution (89–96%), adenomas (78–80%), CRC (31–42%) and a mean age at diagnosis of 48 years [17].

The USMSTF describes an approximately equal sex distribution, with a female predominance in some series, and a mean age at presentation close to 60 years [7]. Series differ according to patient source: in the St Mark's Hospital polyposis registry, median age at diagnosis was 42 years and 52.7% were women [29]; in a regional Australian gastroenterology practice, mean age was 67.15 years and 62.75% were women [45]. In the London registry, 52.3% of patients were diagnosed following colonoscopy for symptoms (rectal bleeding, altered bowel habit or abdominal pain), 15.9% through the national screening programme, 15.5% in the context of CRC, 7.8% because of a family history of CRC and 3.5% because of a family history of SPS [29].

3.2. Colorectal cancer

The meta-analysis by Muller and colleagues (36 studies, 2,788 patients) estimated an overall CRC risk of 19.9% (95% CI 15.3–24.5%), 14.7% (11.4–18.8%) at SPS diagnosis and 2.8% (1.8–4.4%) during surveillance, corresponding to 7 cases per 1,000 person-years; 7.0% (4.6–11.7%) of patients had CRC before SPS diagnosis. No differences by WHO subtype were found in subgroup analysis [12]. Most CRCs are therefore diagnosed before or at the index colonoscopy [7].

Table 3.1. CRC prevalence in SPS cohorts

Factors associated with CRC were identified in two large European cohorts. In the Spanish cohort, more than two SSLs proximal to the splenic flexure and at least one proximal SSL with high-grade dysplasia were independent risk factors (incremental OR 2; 95% CI 1.22–3.24); patients without these factors had a 55% risk reduction (OR 0.45; 95% CI 0.24–0.86) [44]. In the Dutch and British cohort, at least one serrated polyp with dysplasia (OR 2.07), at least one advanced adenoma (OR 2.30) and simultaneous fulfilment of WHO 2010 criteria I and III (OR 1.60) were associated with CRC, whereas smoking history showed an inverse association (OR 0.36) [41]. The USMSTF summarises that risk is greater in type 1 and combined types 1 and 2 than in type 2 alone, and that SSLs with dysplasia and concomitant advanced conventional adenomas are risk markers [7].

Cancer location in SPS differs from that of sporadic serrated-pathway CRC. Whereas in the sporadic pathway its importance increases from the rectum towards the right colon, approximately half of CRCs in SPS occur in the rectosigmoid [7]. The Dutch series of 43 CRCs showed that BRAF V600E tumours were predominantly proximal (81%) and BRAF wild-type tumours predominantly distal (77.3%) [28]. Patients with multiple serrated polyps approaching but not meeting WHO criteria also have increased risk: in a Spanish study, CRC prevalence was similar in 53 patients with SPS and 145 patients with more than 10 polyps, more than half serrated, who did not meet the criteria (OR 1.35; 95% CI 0.64–2.82) [48].

3.3. Appendix and other sites

Patients with SPS undergoing right hemicolectomy have a high prevalence of appendiceal serrated lesions, generally not visible endoscopically; the incidence of appendiceal cancer in SPS is low and there is no consensus justifying prophylactic appendicectomy [7]. Upper gastrointestinal or small-bowel polyposis has not been described in SPS, and no study has confirmed an association with extracolonic carcinomas [16]. Win and colleagues observed increased pancreatic cancer risk in first-degree relatives (six cases; standardised incidence ratio [SIR] 3.64; 95% CI 1.70–9.21), with no cases in the patients themselves [49]; this finding was not confirmed in a series of 115 patients or in a study of 105 patients and 341 relatives, which found no increased risk of extracolonic malignancies [17]. In Utah, comparison with normal-colonoscopy controls showed no increased risk of other common cancers in patients with SPS and their relatives [50]. In RNF43 variant carriers, Palles and colleagues leave open a hypothetical risk of extracolonic cancers, because the gene is a somatic driver in pancreatic, endometrial, oesophageal, prostate, gastric and gallbladder neoplasms [9].

3.4. SPS and inflammatory bowel disease

The BSG described patients with longstanding inflammatory bowel disease with numerous hyperplastic/serrated polyps resembling those of SPS, but molecular data suggest that the serrated pathway differs from the inflammation–cancer pathway and did not allow recommendations to be formulated [16]. The cohorts underpinning the risks in this article generally excluded patients with inflammatory bowel disease [7, 27, 41].

4. Clinical Recognition and Warning Signs

SPS is recognised at colonoscopy, rather than during consultation. The main warning sign is detection of multiple serrated polyps, particularly proximal or measuring 10 mm or more, and the first diagnostic step is systematic recording of the number, size and location of every resected serrated polyp, maintained until diagnosis is established or excluded [7]. As the criteria are cumulative, diagnosis may require summing lesions across several colonoscopies, sometimes performed at different institutions [6, 42].

Underdiagnosis is documented. At a North American tertiary centre, only 12 of 212 referred patients (5.7%) had an SPS diagnosis before referral; 39 of 187 diagnosed at the centre already had sufficient documented resected lesions to meet the criteria, without having been diagnosed [51]. In a Washington, D.C. healthcare system, among more than 40,000 patients undergoing colonoscopy from 2014 to 2024, 54 met WHO 2019 criteria, but only 24 (44.4%) had the diagnosis recorded in their medical records [42]. The BSG cites a study of 927 consecutive patients in which up to 1.8% of those with a serrated lesion at the first colonoscopy eventually met the criteria when cumulative pathology was considered [6].

Table 4.1. Situations that should prompt consideration of SPS

When present, the patient's clinical presentation is that of CRC or lower gastrointestinal bleeding. The Oxford Desk Reference recommends informing at-risk individuals about the most significant CRC symptoms — rectal bleeding, persistent alteration in bowel habit (usually looser or more frequent stools), abdominal mass and unexplained anaemia — and referring anyone attending consultation with symptoms for gastroenterological assessment, remembering that people very concerned about their family history may be symptomatic [2].

Serrated lesions are more difficult to detect than adenomas. Tandem colonoscopy studies show that approximately 30% of serrated lesions are missed by conventional colonoscopy [11], and lower detection of SSLs and proximal serrated polyps is associated with higher post-colonoscopy CRC rates, independently of the adenoma detection rate [7]. For polyps in general, the Oxford Desk Reference states that colonoscopy misses approximately 6%, particularly those smaller than 1 cm [52].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Clinical criteria

SPS diagnosis is exclusively phenotypic. The BSG recommends diagnosis according to WHO 2019 criteria (moderate evidence, strong recommendation, 95% agreement) and summing the number of serrated polyps from all colonoscopies when applying these criteria (moderate evidence, strong recommendation, 94% agreement) [6]. The USMSTF likewise recommends WHO 2019 criteria (strong recommendation, Oxford level 5), justifying the strength of the recommendation by their widespread acceptance in practice and research, rather than the quality of supporting evidence [7].

Table 5.1. WHO criteria for SPS: 2010 and 2019

The change in criteria had limited impact on individual classification: at a North American centre, 5.5% of 163 patients diagnosed using the 2010 criteria did not meet the 2019 criteria, and 10.3% of 116 diagnosed using the 2019 criteria did not meet the 2010 criteria [53]. Abandoning criterion II does not imply an absence of risk: in a retrospective cohort of 224 first-degree relatives, the 36 (16%) meeting former criterion II had increased risk of advanced neoplasia at baseline (adjusted OR 9.30; 95% CI 3.7–23.3) and during surveillance (hazard ratio 8.94; 95% CI 2.15–37.1), findings the authors request be interpreted cautiously [54].

5.2. Diagnostic colonoscopy and quality

Colonoscopy is the reference test for detecting serrated lesions; faecal occult blood or faecal immunochemical testing, alone or with stool DNA, computed tomographic colonography, flexible sigmoidoscopy and colon capsule perform less well (strong BSG recommendation, moderate evidence) [16]. The 2020 BSG guideline adds that colon capsule and magnetic resonance colonography have no demonstrated efficacy in this population and that, if complete colonoscopy remains impossible even after expert referral, quality-assured low-dose computed tomographic colonography is the preferred alternative [6].

Table 5.2. Endoscopic quality and technique in SPS

Histopathology forms part of the criterion. Distinguishing SSLs from HPs shows interobserver variability and TSAs may be classified as tubulovillous adenomas; the USMSTF therefore allows HPs and SSLs to be counted together and HPs ≥10 mm to be managed as SSLs [7]. The Oxford Desk Reference recommends histological review by a pathologist with a specialist interest when diagnosis depends on it [2].

5.3. Genetic testing: divergent indications

Societies differ on who should undergo germline testing, reflecting their interpretation of the low diagnostic yield.

Table 5.3. Indications for germline genetic testing in SPS

The data supporting these positions consistently show low yield. In the Oxford series, 9.6% of tested patients had a pathogenic variant, but only 60% (9/15) of germline variant carriers would have been tested under BSG criteria [30]. In the London series, multigene panel yield was 2.9%, and three of the four diagnoses were coexisting Lynch syndrome; the authors consider identification of concurrent diagnoses the main benefit of testing [29]. For RNF43, Palles and colleagues consider inclusion in panels for people with multiple polyps or familial CRC reasonable, recognising that this misses many carriers with an ordinary CRC phenotype [9]. The GeneReviews chapter on MUTYH-associated polyposis, based on the 2019 NCCN guidelines, includes SPS among findings suggesting that diagnosis and also lists a combination of 20 or more adenomas, HPs and SSLs, excluding rectal and sigmoid HPs [33]. The current NCCN guideline version was not directly consulted.

5.4. Test limitations and report content

A negative germline panel neither excludes nor confirms SPS, because diagnosis is phenotypic; its role is to identify or exclude another syndrome with its own implications. A positive RNF43 result likewise does not in itself establish an SPS diagnosis or predict a polyposis phenotype, as many carriers have neither multiple polyps nor CRC [9, 26]. The panel used in the Danish series detected single-nucleotide variants in coding regions and 20–50 flanking intronic base pairs, and copy-number variants using specific algorithms; one family had a multiexon deletion that would not have been detected by sequencing without copy-number analysis [26]. The Danish authors themselves emphasise that they applied non-gene-specific ACMG criteria, which assume Mendelian inheritance [26]. The five truncating RNF43 variants located in ClinVar had conflicting classifications in 2026 (table 2.1) [32]. In patients with multiple adenomas and no identified germline variant, the GeneReviews chapter on APC-associated polyposis recommends considering undetected somatic APC mosaicism [55].

For these reasons, the germline report should identify the gene, versioned transcript (for RNF43, MANE Select NM_017763.6), nucleotide and protein HGVS descriptions, zygosity and variant classification, and specify covered regions and whether copy-number analysis was performed [8, 26]. Conflicting ClinVar classifications and variant-position-dependent penetrance require each RNF43 result to be discussed in a genetics consultation [9, 32].

5.5. Tumour tests

CRCs diagnosed in patients with SPS should follow the universal MMR deficiency testing strategy because Lynch syndrome may coexist with SPS [29]. The Oxford Desk Reference recalls that MMR deficiency occurs in approximately 15% of colon cancers (less than 5% due to Lynch syndrome and approximately 10% due to biallelic MLH1 methylation), that BRAF mutations, particularly p.V600E, occur in approximately 15% of CRCs but are rare in Lynch syndrome tumours, and that the 2017 NICE guidelines recommend MSI testing or immunohistochemistry in all CRCs [2]. In SPS, some CRCs show MLH1 loss with BRAF V600E, a pattern typical of the sporadic serrated pathway [28]; interpretation follows the Lynch syndrome tumour screening algorithm.

5.6. Practical algorithm

1. At colonoscopy showing multiple serrated polyps, record the number, size (1–5, 6–9, ≥10 mm) and location of each lesion and add those from previous examinations [6, 7].
2. Confirm histology and apply WHO 2019 criteria (type 1 or type 2) [6, 7].
3. Look for features suggesting another syndrome: numerous conventional adenomas, hamartomatous polyps, mixed-histology polyps, young age, several affected family members, dysplasia, extracolonic manifestations or MMR-deficient CRC. If present, refer to genetics and propose a germline panel according to the applicable guideline [6, 7].
4. Begin the endoscopic clearing phase (section 7) and subsequently surveillance.
5. Inform the patient about first-degree relatives' risk and organise their screening (section 8).

6. Differential Diagnosis

The differential diagnosis of SPS operates on two levels. Clinically, it is distinguished from sporadic serrated lesions, which are very common in the population: in European screening cohorts, serrated polyp detection ranged from 15.1% to 27.2% and SSL detection from 2.2% to 4.8% [10]. Genetically, several monogenic syndromes may present with serrated polyps and some meet WHO criteria. The 2017 BSG statement lists MUTYH, BMPR1A, SMAD4, PTEN, GREM1 and RNF43 among genes associated with an SPS phenotype, and reports a series of 65 patients meeting criteria I or III systematically investigated for these genes without significant abnormalities [16]. Lynch syndrome and familial adenomatous and MUTYH-associated polyposis are part of the differential diagnosis; only distinguishing features are presented here.

Table 6.1. Differential diagnosis

In hereditary mixed polyposis, the Oxford Desk Reference describes how the duplication upstream of GREM1 causes increased and ectopic expression of this BMP antagonist in colorectal mucosa and that affected individuals may have polyps containing more than one mixed histological type [2, 58]. In Lynch syndrome, the same book notes reasons to suspect that some CRCs originate in the serrated polyp pathway [57]. When interpreting a patient with serrated polyps and adenomas, the USMSTF recalls that more than 10 cumulative conventional adenomas or more than 2 hamartomatous polyps is itself an indication for germline testing [7].

7. Treatments and Risk Management Strategies

7.1. Principles

There is no pharmacological or gene-targeted treatment; management is endoscopic and, when necessary, surgical, directed at the polyp phenotype rather than genotype [6, 7]. The USMSTF recommends endoscopic management as the preferred strategy over surgery in patients without concomitant CRC (strong recommendation, Oxford level 3) and suggests referring patients whose polyp burden appears endoscopically uncontrollable to an endoscopist experienced in advanced endoscopic resection before surgery (weak recommendation, level 5) [7]. The ESGE advocates follow-up in dedicated units with experienced endoscopists to avoid unnecessary surgery [11], and the 2017 BSG statement suggests referring all patients to clinical genetics or a polyposis registry, facilitating surveillance recall and identification of relatives [16].

7.2. Clearing phase

Treatment begins with the clearing phase (clearing phase). The USMSTF recommends repeating colonoscopy at 3–6-month intervals until all visible target lesions are removed (strong recommendation, level 3); the phase ends with a colonoscopy at which all visualised lesions ≥5 mm are resected. Target lesions usually comprise all conventional adenomas, all lesions proximal to the sigmoid and all rectosigmoid serrated polyps ≥5 mm or ≥3 mm; as up to half of CRCs in SPS arise in the rectosigmoid, at least all lesions ≥5 mm in this region should be removed [7]. The ESGE recommends endoscopic removal of all polyps ≥5 mm and all polyps of any size optically suspicious for dysplasia, before and after entering surveillance (strong recommendation, low evidence, 100% agreement) [11]. In the prospective Dutch and Spanish protocol, HPs measuring 1–4 mm could be left in situ, colonoscopies were rescheduled within 6 months until complete clearance, and the examination was repeated if the caecum was not reached or the Boston bowel preparation score was below 6 [27].

Clearance requires time and expertise. In series cited by the USMSTF, each clearing-phase colonoscopy included an average of 10 to 16 resections, and 5 to 7 in the surveillance phase; in one study, 5% of patients required more than 100 resections during clearance [7]. The ESGE notes that endoscopic clearance is achieved in most patients and that, in experienced hands, endoscopic mucosal resection of large serrated lesions is safe and has a lower recurrence rate than that of adenomas [11].

7.3. Resection technique

The USMSTF recommends removing SSLs and HPs in patients with SPS using cold snare, with or without submucosal injection for larger lesions, except when endoscopically evident dysplastic areas are present (strong recommendation, level 3). Cold resection has fewer complications than electrocautery resection and does not require clip closure; electrocautery resection of visibly dysplastic areas is recommended by the ESGE, although without supporting evidence, and bulky SSLs may justify electrocautery to facilitate resection [7]. A randomised trial cited by the USMSTF showed that clip closure did not reduce bleeding after resection of large serrated polyps [7].

Following piecemeal mucosal resection of a serrated lesion ≥20 mm, the BSG suggests scar reassessment 2–6 months later (weak recommendation, low evidence); for lesions measuring 10–20 mm resected piecemeal, the decision is left to the endoscopist. In an Australian series cited by the BSG, recurrence at 12 months after piecemeal mucosal resection of SSLs ≥20 mm was 7%, compared with 20% for adenomas [16].

Long-term surveillance safety was demonstrated at a Dutch centre: in 142 patients, 447 surveillance colonoscopies and 1,308 polypectomies, one post-polypectomy bleed, one post-polypectomy syndrome and no perforations were recorded (0.45% adverse events per colonoscopy) [61]. For general context, the Oxford Desk Reference cites, for diagnostic colonoscopies, bleeding in 30 per 10,000 examinations, perforation in 10 per 10,000 and death in 1 per 10,000; after polypectomy, perforation in 22 per 10,000, bleeding in 89 per 10,000 and mortality of 3.9 per 10,000, with complications more frequent in older people and patients with comorbidities [52]. These figures derive from older series not specific to SPS.

7.4. Surveillance phase and intervals

Table 7.1. Colonoscopic surveillance intervals after clearance, by document

For the ESGE, an advanced polyp is a (tubulo)villous adenoma, an adenoma with high-grade dysplasia or ≥10 mm, a TSA, a serrated lesion with dysplasia or a serrated lesion ≥10 mm; a clinically relevant non-advanced polyp is any adenoma or serrated polyp not meeting these criteria, except HPs <5 mm, which may be left in situ [11]. The USMSTF emphasises that the interval figure is not a strict evidence-based recommendation but a framework allowing a colonoscopist with a high detection rate to extend intervals in selected patients; concomitant advanced conventional adenomas generally justify surveillance at 1 year or less, and no evidence supports intervals longer than 3 years [7]. Recommendations assume complete colonoscopy to the caecum, adequate preparation and an endoscopist with demonstrated detection performance [7].

Evidence supporting these intervals is observational, with one exception. The international prospective cohort of Bleijenberg and colleagues followed 271 patients for a median of 3.6 years using a personalised 1- or 2-year protocol: 5-year cumulative CRC incidence was 1.3% (95% CI 0–3.2%) and advanced neoplasia incidence 44% (95% CI 37–52%), lower in 2010 type III (26%) than type I (53%) or combined I and III (59%). Advanced neoplasia following a 2-year recommendation was 15.6%, versus 24.4% following a 1-year recommendation (OR 0.57; p = 0.08) [27]. In follow-up exceeding 10 years at a specialist centre (142 patients, median 47 months after clearance), one CRC occurred during surveillance (5-year incidence 1.0%; 95% CI 0–2.9%), and polyp recurrence showed neither an upward nor downward trend across up to 9 rounds, leading the authors to advise against reducing surveillance intensity after several rounds [61]. Surveillance CRC incidence in series of more than 60 patients ranged from 0% to 7% at 5 years, with lower figures in recent series [7].

The only randomised trial of intervals was published in 2026. At six Spanish hospitals, 131 patients meeting WHO 2019 criteria, without advanced neoplasia and with fewer than five relevant polyps at the preceding colonoscopy, were randomised to colonoscopy at 2 years (n = 72) or 3 years (n = 59). Advanced neoplasia was 6.9% (5/72) versus 13.6% (8/59) (p = 0.208), with a risk difference of +6.7% (95% CI −4.1 to 17.5%) whose upper limit exceeded the prespecified non-inferiority margin of +10%; there were no CRCs. Time since diagnosis ≤3 years was associated with advanced neoplasia (OR 4.4; 95% CI 1.56–14.71). The authors concluded that non-inferiority of the 3-year interval was not demonstrated and that the results do not currently support this extension [21]. This finding is relevant to the weak USMSTF recommendation to consider 3-year intervals, published a few months later.

7.5. Surgery

Surgery is indicated when CRC is diagnosed alongside SPS and when polyp burden cannot be controlled endoscopically by experienced endoscopists [7]. The ACG also includes high-grade dysplasia in a serrated polyp that cannot be completely removed and considers colectomy with ileorectal anastomosis a reasonable option, given the risk of metachronous neoplasia (conditional recommendation, low evidence) [17]. The BSG suggests considering surgery for lesions not endoscopically resectable because of size, location or number, aiming to remove all lesions not treatable endoscopically, through segmental colectomy, total colectomy with ileorectal anastomosis or proctocolectomy (with or without an ileoanal pouch), depending on lesion burden and distribution (weak recommendations, very low evidence) [16]. In an Amsterdam series cited by the BSG, 26 of 78 patients underwent surgery at presentation for cancer, extensive polyposis or high-risk or unresectable polyps, but after colonic clearance only 3 of 41 required surgery during 5 years of intensive surveillance, with no cancers [16].

Surgery for benign polyps has clinical costs: in a national study cited by the USMSTF, postoperative morbidity was 13% and mortality 0.3–0.4% [7]. Following (sub)total colectomy, a prospective study of 48 patients (mean age 61 years) recorded no CRC during a median 4.7 years of follow-up; 5-year cumulative advanced neoplasia incidence was 13%, detected mainly at the first endoscopy after surgery, without a difference between ileorectal and ileosigmoid anastomosis [62]. The authors suggest extending intervals after the first postoperative surveillance, but this proposal was not incorporated as a recommendation in the guidelines consulted. There is no consensus for prophylactic appendicectomy [7].

7.6. Drugs, chemoprevention and regulatory status

No medicine is authorised for SPS. In the European Medicines Agency (EMA) lists of centrally evaluated medicines and orphan designations, consulted on 7 October 2026, there is no product or designation for SPS; polyposis products and designations relate exclusively to familial adenomatous polyposis [14]. The ClinicalTrials.gov search identified no pharmacological trials in SPS [15]. The Food and Drug Administration (FDA) orphan designation database could not be consulted (automated security check), so absence of North American designations was not confirmed in that source; none of the North American guidelines consulted mentions an approved or recommended drug for SPS [7, 17].

Table 7.2. Comparative regulatory status

The Oxford Desk Reference mentions evidence that aspirin and other non-steroidal anti-inflammatory drugs reduce CRC risk and the recommendation to use high-dose aspirin in Lynch syndrome only within trials; these data do not concern SPS [2].

7.7. Lifestyle and other measures

The BSG recommends strongly encouraging people with increased familial CRC risk not to smoke, to maintain a normal body mass index, moderate red and processed meat consumption and exercise regularly (low evidence; recommendation strength is presented as weak in the executive summary and moderate in the main text) [6]. In SPS, the USMSTF considers smoking cessation advisable and diagnosis an additional opportunity to promote it, without evidence that it alters the disease course or CRC risk [7]. The Oxford Desk Reference states there is no evidence of benefit from commercial dietary supplements [2].

Upper gastrointestinal surveillance or extracolonic cancer screening is not indicated in patients with SPS in whom other genetic causes have been excluded (BSG, weak recommendation, very low evidence; ACG, conditional recommendation, very low evidence) [16, 17].

7.8. Trials and prospective studies

Table 7.3. Prospective studies and trials in SPS

These studies have limitations affecting interpretation. The Spanish trial had post hoc power of 33.8%, attributed by the authors to high attrition in the 3-year arm, was limited to one surveillance round and included more patients meeting 2019 criterion II than earlier cohorts; absence of a statistically significant difference does not demonstrate equivalence [21]. The prospective cohort was not randomised: patients assigned a 2-year interval had, by definition, a lower polyp burden, and the lower advanced neoplasia incidence in this group reflects that selection [27]. Surveillance CRC incidences derive mainly from academic centres with high-detection endoscopists and should not be extrapolated to lower-quality settings [6, 7]. No study directly compared intervals using CRC mortality outcomes.

7.9. Developments in the last 12 months

8. Reproductive Options and Family Counselling

8.1. What is transmitted: empirical risk rather than a genotype

In most families, counselling is based on empirical risk because no germline variant is identifiable. The BSG summarises that CRC risk in first-degree relatives is three- to fivefold that of the population, that 1.3–7.7% of index cases have a first-degree relative meeting WHO 2010 criteria I or III and that another 14.3–24.4% of relatives meet former criterion II; in published series, mean or median age of CRC in relatives ranged from 55 to 62 years, with the youngest case at 25 and CRC very rare before 40 [6].

Table 8.1. Cancer risk in relatives of patients with SPS

The USMSTF classifies evidence supporting intensified screening of relatives as mixed: three studies show increased CRC risk, but two small screening-colonoscopy studies had divergent findings for neoplasia yield and SPS prevalence [7]. Some estimates were obtained before 2019 and include, among “affected” relatives, individuals meeting only now-abandoned criterion II.

8.2. Screening relatives

Table 8.2. Colonoscopic screening of first-degree relatives

The BSG extends the same approach to first-degree relatives of patients with multiple serrated polyps (10 or more polyps overall, 50% serrated) who do not meet 2019 criteria [6]. Second-degree relatives have a slight risk increase (SIR 1.38), with no data on colonoscopy yield in this group [6, 49]. The Oxford Desk Reference recommends that the person attending consultation inform the genetics service of new family diagnoses, as these may change risk assessment, and advises considering one-off colonoscopies at younger ages in intermediate-risk families to identify relatives with polyps that alter the risk category [2].

8.3. Families with a germline RNF43 variant

When a pathogenic RNF43 variant is identified, inheritance follows the autosomal dominant model and predictive testing of relatives becomes technically possible [2, 4]. Counselling must, however, incorporate incomplete and variant-position-dependent penetrance: carriers without polyps or CRC, CRC in carriers without polyposis and CRC developing independently of the variant (molecular phenocopies) have been described [9, 26]. Palles and colleagues propose a pragmatic approach, with regular colonoscopy individualised according to variant position, polyp formation and evolution [9]; the Danish series emphasises the complexity of counselling families without polyposis [26]. In families without an identified variant, predictive testing is inapplicable and relatives' screening follows table 8.2.

8.4. Reproductive options

The sources consulted do not describe prenatal diagnosis or preimplantation genetic testing in SPS. In most families, absence of an identifiable causal variant makes these techniques inapplicable; in families with an RNF43 variant, discussion should consider the moderate and variable penetrance described above [9, 26]. Reproductive counselling therefore primarily provides information about empirical risk and colonoscopic screening of offspring in adulthood.

9. Special Considerations: Population Diversity and Epidemiology

9.1. Frequency

Frequency estimates depend on the population studied, screening method and whether counting occurs at one colonoscopy or throughout follow-up. These are not general-population prevalence estimates, but proportions in colonoscopy cohorts.

Table 9.1. Frequency of SPS by setting

The 2015 ACG guideline states that prevalence had been estimated at 1:100,000 based on the study of 50,148 participants, but the same text describes 28 cases (0.06%), corresponding to approximately 1:1,800, as in the BSG table; the 1:100,000 estimate corresponds to the order of magnitude historically cited before screening studies [16, 17]. The regional Australian series comes from a single practice and does not represent the population [45]. SPS is considered the most common colorectal polyposis syndrome and more common than all other gastrointestinal polyposis syndromes combined [7].

9.2. Sex, age and ancestry

Sex distribution is approximately equal, with female predominance in some series [7, 45]. Mean age at presentation is around 60 years in hospital series, but lower in family or tertiary referral registries, such as the median of 42 years in the London registry, where 5.8% of patients were aged 30 or younger [7, 29]. In the London registry, 62.0% of patients were White, 7.8% Asian, 2.7% Black and 1.2% Hispanic, and the authors relate this predominance to studies describing higher prevalence in White people [29]; in a Washington, D.C. healthcare system, SPS was also more common in White patients [42]. These data derive from referred populations and may reflect differences in access to colonoscopy.

9.3. Regional data

In Europe, the main cohorts come from the Netherlands, Spain and the United Kingdom [27, 29, 41, 44]. In the United States, data come from tertiary centres, a Washington, D.C. healthcare system and the Utah population database [42, 50, 51]. The international relatives' cohort of Win and colleagues included index cases from Australia (33), New Zealand (41), Canada (6) and the USA (20) [49].

In Portugal, a series published in 2004 described 14 symptomatic patients with hyperplastic polyposis: 86% had fewer than 100 polyps, 79% also had serrated polyps and classical adenomas, 43% had CRC at diagnosis and 50% had a family history of CRC or polyps; colonoscopy in 17 first-degree relatives revealed polyps in 59% [47]. In 2024, the Instituto Português de Oncologia in Lisbon studied 60 patients using an extended germline panel, finding pathogenic variants in 10% (6/60), including one in RNF43 [31]. In Japan, a multicentre study of 11 patients identified a BUB1 variant [39] and a study of 64 patients described the association with intestinal spirochaetosis [43]. No data on Brazil were found in the sources consulted, which does not demonstrate their absence.

No founder RNF43 variants were described in the sources consulted. The APC variant p.(Ile1307Lys) and the duplication upstream of GREM1, more frequent in people of Ashkenazi Jewish ancestry, are differential diagnoses with metaplastic or mixed polyps rather than causes of SPS [2].

9.4. European network and patient organisations

SPS belongs to thematic group 2 (“Lynch and polyposis”) of the European Reference Network on Genetic Tumour Risk Syndromes (ERN GENTURIS), in the “Other polyposis syndromes” subgroup, alongside hereditary mixed polyposis and gastric adenocarcinoma and proximal polyposis of the stomach. The network lists Lynch and polyposis patient organisations in Belgium, Finland, France, Germany, Italy and the Netherlands, without an SPS-specific organisation [18]. The Oxford Desk Reference lists Bowel Cancer UK, Macmillan Cancer Support and the International Society for Gastrointestinal Hereditary Tumours (InSiGHT) as resources [2]. The 2017 BSG statement recommends registering patients in polyposis units, facilitating surveillance recall, identification of relatives and research [16].

10. Illustrative Clinical Case

10.1. Sibship with severe SPS and RNF43 variant c.394C>T p.(Arg132Ter) (Taupin et al., 2015)

Taupin and colleagues, from Canberra (Australia), published a family with severe SPS in Human Genome Variation in 2015 [23]. The proband, a 23-year-old man who did not smoke, underwent emergency right hemicolectomy for obstructing CRC; multiple synchronous polyps were palpated during surgery. The tumour was staged as T4N0, had developed from a serrated polyp in the setting of more than 50 large serrated polyps throughout the colon, was microsatellite stable, showed normal MMR protein immunohistochemistry and had no KRAS mutations at codons 12 and 13 in the tested panel. Germline MUTYH sequencing was normal. A sister underwent screening colonoscopy at age 27, revealing more than 20 large serrated polyps; as the colon could not be cleared endoscopically, she underwent elective subtotal colectomy, and the specimen contained more than 60 polyps. A third sibling (II.1 in the pedigree), aged 21, had a single rectal adenoma, and colonoscopy one year later was normal. The mother had died aged 50 with pancreatic cancer before the study; there was no paternal history of polyposis or CRC [23].

Exome sequencing of four family members (median depth 99×) identified 49 variants compatible with autosomal dominant inheritance, including a single novel nonsense variant in RNF43, present in both affected siblings and confirmed by Sanger sequencing. The variant lies in exon 2, in a conserved region encoding the extracellular domain, and was predicted to cause nonsense-mediated messenger RNA decay. The authors did not investigate allelic expression or a second hit in neoplastic tissue [23]. Figure 1 of the original article, consulted for this description, shows the pedigree, exome variant summary, Sanger electropherograms (with the variant in both affected siblings and without it in the father and unaffected sibling), conservation of the residue across species and the variant's position within the gene structure (figure 1) [23]. In current nomenclature, validated in VariantValidator, the variant termed R132X in the original article and OMIM corresponds to NM_017763.6:c.394C>T p.(Arg132Ter) [5, 8, 26].

10.2. Interpretation of the case in light of current evidence

The case illustrates the severe phenotype of families that led to the association between RNF43 and SPS: CRC at a very young age, a polyp burden preventing endoscopic clearance in one sister and cosegregation of the variant with the phenotype. The management described — cancer surgery and subtotal colectomy when endoscopic clearance failed — corresponds to surgical indications in current guidelines [7, 16, 17].

The genetic interpretation has changed since 2015. The same c.394C>T variant was identified in the study by Palles and colleagues in a woman with sigmoid carcinoma in her eighth decade, without polyps at presentation (a single polyp in her ninth decade) or a family history, in a population context where RNF43 variants confer moderate CRC risk [9]. In October 2026, the variant had conflicting ClinVar classifications [32]. A family with such severe expression may therefore reflect a combination of the variant with other factors promoting polyp formation, as Palles and colleagues propose [9]. For relatives, the result justifies predictive testing and colonoscopy in carriers, but screening of non-carriers should not be stopped without considering the family's empirical risk, since serrated polyps also occurred in non-carriers in the Ox7 family [9]. The maternal pancreatic cancer recalls the association described by Win and colleagues in relatives of patients with SPS, which was not confirmed in other studies and does not justify pancreatic surveillance in the guidelines [16, 17, 49].

11. Prognosis and Long-Term Follow-up

11.1. Prognosis

CRC risk is concentrated before and at SPS diagnosis (14.7% at diagnosis and 7.0% beforehand, in the meta-analysis by Muller and colleagues). After clearance and under regular surveillance at experienced centres, CRC incidence was 1.3% at 5 years in the international prospective cohort, 1.0% at 5 years in the Dutch cohort with over 10 years of follow-up and 1.9 per 1,000 person-years in the Dutch and British cohort; the meta-analysis, including older series, estimated 2.8% during surveillance [12, 27, 41, 61]. These findings do not equate to untreated natural history: early series, with less structured surveillance, described a 7% risk at 5 years [46], and the USMSTF notes that surveillance incidence has declined in more recent series [7].

Advanced neoplasia recurs: 44% cumulative incidence at 5 years in the prospective cohort, higher in 2010 type I (53%) and combined I and III (59%) than type III (26%) [27], and polyp burden remained approximately stable across up to 9 surveillance rounds, meaning SPS requires indefinite surveillance [61]. In the Spanish randomised trial, the first 3 years after diagnosis were associated with greater advanced neoplasia risk [21]. After (sub)total colectomy, no CRC occurred over a median 4.7 years of follow-up, and advanced neoplasia at 5 years was 13% [62].

The prognosis of CRC diagnosed in a patient with SPS was not specifically described in the sources consulted; stage and tumour biology (including MMR and BRAF status) follow usual oncological assessment [28].

11.2. Follow-up plan

Table 11.1. Follow-up plan by group

Upper gastrointestinal endoscopy, small-bowel investigation or extracolonic cancer screening is not indicated because of SPS, provided other syndromes have been excluded [16, 17].

12. Summary and Final Considerations

Serrated polyposis syndrome is the most common colorectal polyposis syndrome and is defined by WHO clinical criteria revised in 2019: at least five serrated lesions proximal to the rectum, all measuring 5 mm or more and two measuring 10 mm or more (type 1), or more than 20 serrated lesions throughout the large bowel, five proximal to the rectum (type 2), with cumulative counting across several colonoscopies [6, 7]. It is found in 0.4–0.8% of people in European screening programmes when follow-up colonoscopies are considered, and frequently goes unrecognised because diagnosis depends on systematic recording of each lesion and endoscopic detection quality [10, 42, 51].

SPS genetics is non-Mendelian in most cases. RNF43 has definitive gene–disease validity in ClinGen, but germline variants account for a small minority of cases and confer moderate CRC risk in the population (OR 2.7), concentrated in N-terminal variants [4, 9, 29]. Germline panels have low yield and mainly identify other syndromes, including coexisting Lynch syndrome; indications differ between the USMSTF, which limits testing to patients with other suggestive features, and the BSG, which proposes it below age 50, with several affected relatives or dysplasia [6, 7]. HIC1, WNK2, DOT1L and BUB1 are research candidate genes [36–39].

CRC risk is approximately 15% at diagnosis and low during surveillance at experienced centres; approximately half of cancers occur in the rectosigmoid and result in similar proportions from the serrated and adenoma–carcinoma pathways [7, 12, 28]. Management centres on endoscopic clearance with cold resection, followed by surveillance every 1–2 years adjusted to findings; extension to 3 years is a weak USMSTF suggestion that the only randomised trial failed to support [7, 11, 21]. Surgery is reserved for cancer and uncontrollable polyp burden [7, 16]. No drugs are authorised or in trials [14, 15].

First-degree relatives have approximately fivefold CRC risk and should begin colonoscopy at age 40–45, or earlier according to the ages of family diagnoses, repeated every 5 years if normal [6, 7, 11, 13, 49]. Referral to a genetics clinic or polyposis registry, within the ERN GENTURIS framework in Europe, organises surveillance for the patient and family [16, 18].

13. References

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