Guidelines on Management of Hereditary Polyposis Syndromes in Pediatric Patients: Agreement, Disagreement and Where It Matters

Abstract

Hereditary polyposis syndromes are rare but potentially devastating conditions which require multidisciplinary care from an early age. Societal guidelines, which ideally combine expert opinions and medical evidence, serve as the framework for disease diagnosis, surveillance and treatment. However, there is a significant underrepresentation of pediatric gastroenterology input in guideline formulation, and additionally, recommendations can vary significantly between societies, which can have a moderate-to-high clinical impact on patient care. This paper aims to summarize key differences in management based on societal guidelines and identify some of the factors which may contribute to divergence in care in hereditary polyposis syndromes in pediatric patients. The authors review the literature underlying the divergence in recommendations and attempt to reconcile these differences with a closer consideration of the pediatric population, considering the available evidence. This review highlights the need to harmonize recommendations across subspecialties and professional societies and sheds light on the significant underrepresentation of pediatric gastroenterology input in guideline formulation. Given the poor-quality evidence underlying many societal guidelines and the lack of pediatric gastroenterology representation in guideline formulation in these rare syndromes, there is a need for collaborative, multicenter, registry-based studies to refine and improve care standards.

1. Introduction

Polyposis syndromes are defined by clinical characteristics including the polyp type and burden and the presence of extraintestinal manifestations; these syndromes confer an increased life-long risk of malignancy. A genetic mutation may confirm the clinical diagnosis. Although the most common polyposis syndromes are inherited in an autosomal dominant pattern, incomplete penetrance and de novo mutations are common in up to 40–50% of patients, making the absence of a family history relatively common.

Societal guidelines are the mainstay for the diagnosis and management of a variety of disorders. However, there may be different recommendations among societies in part due to the background of their authors. Limited experience with rare diseases often leads to heavy reliance on guidelines for clinical management; hence, a high level of agreement amongst guidelines is ideal. Patients with chronic, rare diseases often transition between different providers at various institutions, which can result in further discontinuity and heterogeneity in care.

We conducted a literature review of management guidelines for the three most common pediatric polyposis syndromes: juvenile polyposis syndrome (JPS), Peutz–Jeghers syndrome (PJS) and familial adenomatous polyposis syndrome (FAP). The aim of this review was to (1) identify key areas of discordance and concordance among existing societal guidelines for management and surveillance, (2) investigate the evidence behind differing recommendations, if available, (3) provide recommendations with the consideration of the pediatric patient, if able, and (4) identify knowledge gaps to inform further research in the care of pediatric patients with hereditary polyposis syndromes.

2. Methods

A comprehensive literature search limited to the English language was performed on electronic databases (Medline, CINAHL, EMBASE) in March 2023. The following MeSH subject headings and search terms were used: “hereditary polyposis syndrome”, ”juvenile polyposis syndrome”, “Peutz-Jeghers syndrome”, and “familial adenomatous polyposis syndrome” combined with “practice guideline”, “position paper”, and “consensus statement”. The search was limited to articles published between 2010 and 2023. Duplicate articles were removed. Full-text articles were then reviewed for inclusion and exclusion criteria. The inclusion criteria were as follows: (1) a medical guideline or position paper published by a major society with (2) recommendations on all 3 syndromes, (3) published between 2010 and March 2023 (4) and published in the English language. Surgical guidelines were excluded for review. The reasoning for the exclusion of surgical guidelines was to narrow our focus to the diagnosis and management of inherited polyposis syndromes. Publications that met the inclusion/exclusion criteria were discussed in a face-to-face discussion. Of these, only 7 were found to include recommendations on management in pediatric-age patients. A review of additional publications substantiating key points of discordance in guideline recommendations, as well as the literature published after the initial literature search, was discussed ad hoc (Figure 1).

Societal guidelines were categorized by the major professional society. Extracted data from each guideline were divided into the following specific management domains: genetic testing, gastrointestinal/endoscopic screening and surveillance recommendations and extraintestinal screening and surveillance recommendations. Recommendations were individually tabulated, and the results were collated to identify areas of discordance (

Table 1. Areas of discordance among guidelines.

Polyposis Syndrome	Management Domain
JPS	Initial timing of upper GI tract screening
PJS	Timing of genetic screening
	Frequency of small bowel surveillance
	Ideal size of polyp for removal in elective polypectomy
FAP	Number of adenomas to trigger genetic screening
	Ideal method for initial lower endoscopic evaluation
	Recommendations on routine screening for hepatoblastoma

), which were then reviewed in detail by the authors. Full-text articles of guidelines that appeared to be relevant were independently reviewed and discussed by the authors to assess them for inclusion. Points of discrepancy were discussed by the authors as a group as well as the reasoning for possible discrepancies and future directions. We summarize the specific areas of discordance for each of the three polyposis syndromes in Table 1, followed by the rationale for key recommendations and the supporting literature. For each of these management domains, we discuss the evidence in support of these nuanced differences in recommendations and offer our own recommendations, when able, following the careful consideration and discussion of the current supporting evidence. To highlight the slight, although potentially clinically impactful, differences in recommendations, we follow each discussion with a table summarizing the differences in the guidelines. It is worth noting that several societies do not provide recommendations in some of these domains, often citing a lack of sufficient literature.

3. Results

We reviewed clinical practice guidelines for major gastrointestinal, genetics and oncology societies. After the inclusion and exclusion criteria were applied, the following societal guidelines were included in our final analysis:

• The American Association for Cancer Research (AACR) [1];
• The American College of Gastroenterology (ACG) [2];
• The European Society of Gastrointestinal Endoscopy (ESGE) [3];
• The European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) [4,5,6];
• The National Comprehensive Cancer Network (NCCN) [7].

It is worth noting that agreement regarding most aspects of the reviewed guidelines exists and our focus was to identify and analyze areas of discordance. The key discrepancies noted were in the realms of genetic screening and intestinal and extraintestinal screening.

We observed that the release of guideline publications was infrequent and often with little to no pediatric gastroenterology representation across all the guidelines aside from the ESPGHAN. The authorship among the remaining guidelines comprised adult oncologists, colorectal surgeons and genetics counselors. Furthermore, recommendations were based heavily on adult studies with limited pediatric data.

3.1. Juvenile Polyposis Syndrome

Timing of Initial Upper Endoscopic Evaluation

Evidence Behind Differing Recommendations

JPS is caused by a germline mutation in SMAD4 or BMPR1A in 40–60% of patients, with 25% presenting with a de novo mutation and the remainder with negative genetic testing [8]. JPS has variable penetrance and heterogeneity in disease presentation with a need for further genotype–phenotype correlations.

Patients with a pathogenic SMAD4 mutation are also more likely to have significant gastric polyposis and an increased risk of gastric cancer, anemia and hereditary hemorrhagic telangiectasia (HHT) in contrast to BMPR1A carriers [6,8,9]. Despite the known increased risk of gastric cancer with SMAD4 mutations, there are variable recommendations regarding the initiation of upper endoscopic surveillance (a range of 12 to 25 years of age,

Table 2. Discrepancies in recommendations on timing of initial upper endoscopic evaluation.

Society	AACR	ACG	ESGE	ESPGHAN	NCCN
Recommendations	EGD at age 15, then every 1–2 years	EGD at 12 years; annually if polyps, every 2–3 years if no polyp identified	EGD at 18 years in individuals with SMAD4 mutation, 25 years with BMPR1A mutation	Not required in childhood or teenage years, unless there is unexplained anemia or upper GI symptoms	EGD at 15 years, annually if polyps, every 2–3 years if no polyps identified

), with only the ESGE guidelines delineating recommendations based on this known genotype–phenotype correlation. As such, further genotype–phenotype correlations are needed for the two separate entities of juvenile polyposis (the positive and negative disease-causing variants), which may require different surveillance and management strategies.

3.2. Peutz–Jeghers Syndrome

3.2.1. Genetic Screening of At-Risk Individuals

Evidence Behind Differing Recommendations

The early presentation of polyp-related complications in PJS is common with a median age of the first episode of intussusception between 10 and 15 years of age and 15–30% of patients requiring surgery before the age of 10 years [6,10]. The rationale for the timing of genetic testing is to identify individuals at risk; however, there is significant variation in the age at the first screening (

Table 3. Discrepancies in recommendations on genetic screening for Peutz–Jeghers.

Society	AACR	ACG	ESGE	ESPGHAN	NCCN
Recommendations	No recommendations	Individuals with perioral or buccal pigmentation and/or 2 or more histologically characteristic gastrointestinal polyps should undergo genetic screening	No recommendations	Predictive genetic testing at 3 years in asymptomatic at-risk child, earlier if symptomatic	No recommendations

). Of all the guidelines, only the ACG and ESPGHAN make recommendations regarding genetic screening. Given intussusception and obstruction can be an initial presentation of PJS as early as 14–16 months of age, a recommendation to test at an age of 3 may still fail to identify this subgroup of at-risk patients [11,12].

Lastly, the practical significance of the ACG’s divergence in recommendations for screening individuals with perioral or buccal pigmentation and/or characteristic gastrointestinal polyps is unclear as [12,13] even with a high index of suspicion, mucosal freckling is absent in more than 10% of patients with PJS [1] and may be harder to detect in dark-skinned individuals, leading to a delay in diagnosis.

3.2.2. Small Intestinal Surveillance

Evidence Behind Differing Recommendations

The role of small bowel surveillance in children with PJS, achieved with a combination of upper endoscopic evaluation and video capsule endoscopy (VCE), is to identify and remove polyps at risk of intussusception and obstruction. For clarity, we divided small bowel surveillance into the categories of gastroduodenal and small intestinal surveillance.

There are several points of variation in small bowel surveillance recommendations from the age of screening initiation to the frequency (

Table 4. Discrepancies in recommendations on small intestinal surveillance.

Society	AACR	ACG	ESGE	ESPGHAN	NCCN
Age for gastroduodenal surveillance	EGD at 8 and 18 years	EGD at 8 and 18 years	EGD at 8 and 18 years	EGD at 8 years	EGD in late teen years
Frequency of gastroduodenal surveillance	Every 3 years if polyps present. If no polyps, repeat at 18 years	Every 3 years if polyps present. If no polyps present, repeat at 18 and then every 3 years or earlier, if symptoms occur	Every 1–3 years if polyps present. If no polyps present, repeat at 18 and then every 1–3 years	Every 3 years	Every 2–3 years
Age for small bowel surveillance	VCE at 8 years	VCE at 8 and 18 years	MRI or VCE at 8 years	VCE at 8 years	CTE, MRE or VCE at 8–10 years
Frequency of small intestinal surveillance	Every 2–3 years	Every 3 years if polyps present. If no polyps present, repeat at 18 and then every 3 years or earlier, if symptoms occur	Every 1–3 years based on phenotype	Every 3 years	Follow up based on findings. If no polyps present, repeat at 18 years and then every 2–3 years

). Some guidelines recommend less frequent surveillance in the absence of polyps. The discrepancy in recommendations is likely due to the lack of robust literature on the risk of polyp development and progression to obstruction in individuals with PJS who have negative endoscopic screening at 8 years of age.

Given the ambiguity in polyp progression and the relatively high risk of obstruction by age 18, a more conservative approach with more frequent small bowel surveillance utilizing the same modality may have greater potential to reduce polyp-related morbidity [6,10,13,14]. Further studies are needed regarding the development of small intestinal polyps following a negative initial EGD.

3.2.3. Recommended Size of Polyp for Removal During Elective Polypectomy

Evidence Behind Differing Recommendations

As mentioned previously, the role of a polypectomy in patients with PJS is to decrease polyp-related morbidity and mortality associated with intussusception and obstruction. As noted in

Table 5. Discrepancies in recommendations on ideal size for elective polypectomy.

Society	AACR	ACG	ESGE	ESPGHAN	NCCN
Small bowel polyps	No recommendations	No recommendations	>15–20 mm (or smaller if symptomatic)	>15–20 mm (or smaller if symptomatic)	>10 mm or smaller if symptomatic
Gastroduodenal and colonic polyps	No recommendations	>5–10 mm	No recommendations	No recommendations	>3 mm

, divergence in recommendations exists in two realms, the size and location of the polyp at the time of an elective polypectomy, with only the ESGE and ESPGHAN making recommendations for the size of small intestinal polyps to remove. The discordance in guidelines regarding the timing of an elective polypectomy is understandable given the multiple, poorly defined factors that could influence polyp-related morbidity in a pediatric patient.

Critical considerations regarding the timing of a polypectomy include the growth rate of polyps, the risk of obstruction and the risk from the polypectomy. Two factors to consider related to the polyp itself include the size and interval growth rate. Although there are no pediatric studies to date investigating the growth rate of PJS polyps, one adult study noted that the number of small bowel polyps > 10 mm and colorectal polyps and gastric polyps over 5 mm in size as well as a negative family history were independent predictors of the growth rate of small bowel polyps [15]. In a separate study evaluating the attributes of 37 intussusception-causing polyps in a small cohort of patients, a median size of 35 mm was reported, with a range of 15–60 mm. Of these, three lesions were <20 mm in diameter [13].

Given the little that is known about the interval polyp growth rate, a separate practice, termed the “clean sweep strategy,” has evolved, which involves the bulk removal of small, asymptomatic polyps. In support of this strategy, several adult and pediatric studies have suggested that small intestinal surveillance with the polypectomy of symptomatic and asymptomatic small intestinal polyps <1 cm is feasible and decreases the likelihood of intussusception and surgery, although it should be noted that the screening intervals were variable [16,17,18,19]. However, these lower thresholds for a polypectomy make it difficult to discern the ideal size for polyp removal, particularly for asymptomatic patients.

Lastly, although serious endoscopic complications are uncommon, it is unclear if children are at a higher risk of procedural complications than adults due to their smaller body habitus. One study of 63 pediatric patients who underwent a total of 766 procedures noted two perforations with the excision of larger lesions (a 6 cm colonic polyp and 2 cm duodenal polyp) [14], although this may have been subject to the endoscopist’s comfort and technique with a polypectomy.

The polyp size and number clearly relate to the risk of intussusception; however, non-polyp factors including the mutation status, patient age and size, localization of the polyps and the related risks of a polypectomy should be considered. Given the ambiguity in polyp progression coupled with a high risk of obstruction, a more conservative approach with more frequent small bowel surveillance regardless of initial endoscopic findings should be considered. This in fact underscores the need for pediatric gastroenterologist involvement in the development of guidelines as well as the need for further studies to determine the ideal size for removing small bowel polyps in pediatric patients and to understand their progression, especially in those with negative screening at 8 years of age.

3.3. Familial Adenomatous Polyposis Syndrome

3.3.1. Recommendations for Genetic Testing in Individuals Not at Risk for FAP

Evidence Behind Differing Recommendations

There is some consensus for the predictive genetic testing of at-risk individuals with recommendations ranging from 10 to 14 years of age [2,4,7]. However, there is a less clear consensus regarding the threshold for the genetic testing of individuals who are not deemed at risk for FAP (i.e., those without a prior family history or the presence of extraintestinal manifestations), as demonstrated in

Table 6. Discrepancies in recommendations on number of adenomas to trigger genetic screening.

Society	AACR	ACG	ESGE	ESPGHAN	NCCN
Recommendations	No recommendations	Personal history of >10 cumulative colorectal adenomas, family history of an adenomatous polyposis syndrome or a personal history of adenomas with a FAP-type extracolonic manifestation	No recommendations	Identification of 1 adenoma	Personal history of ≥20 cumulative adenomas or multifocal/bilateral CHRPE Can consider testing if a personal history of any of the following: - Between 10 and 19 cumulative adenomas a - Desmoid tumor - Hepatoblastoma - Cribiform-morular variant of papillary thyroid cancer - Unilateral CHRPE or meets criteria for serrated polyposis syndrome with at least some adenomas

^a The age of onset, family history, personal history of colorectal cancer and/or the presence of other features may influence whether genetic testing is offered in these situations.

. The divergence in guideline recommendations for FAP is largely centered around the number of adenomas that should prompt the genetic testing of standard-risk individuals. Recommendations for genetic testing range from the identification of one lifetime adenoma (ESPGHAN recommendations) to twenty cumulative adenomas (NCCN recommendations). The NCCN guidelines do note that consideration for genetic testing can occur in standard-risk individuals with 10–19 cumulative adenomas depending on the age of onset and personal history but without the clear delineation of the appropriate number of adenomas as they relate to the patient age.

As an increasing age is a known risk factor for the development of colonic adenomas, this divergence in recommendations may be a function of explicitly stated age parameters (i.e., the ESPGHAN criteria assuming a pediatric age range while a non-pediatric age range is assumed by the ACG and NCCN guidelines). However, our literature review did not yield any evidence relating the number of adenomas by the age category to the likelihood of FAP. As such, until further evidence is able to reconcile the number of adenomas needed for the diagnosis of FAP in children, a more conservative approach towards genetic testing upon the identification of one adenoma in the pediatric patient should be considered.

3.3.2. Ideal Method for Initial Lower Endoscopic Evaluation

Evidence Behind Differing Recommendations

All the guidelines apart from the ESGE and ESPGHAN make recommendations that a flexible sigmoidoscopy may be an adequate initial screening method for FAP given predominant rectal involvement in these patients (

Table 7. Discrepancies in recommendations on initial lower endoscopic evaluation.

Society	AACR	ACG	ESGE	ESPGHAN	NCCN
Recommendations	Flexible sigmoidoscopy or colonoscopy starting at 10–15 years and annually until surgery	Flexible sigmoidoscopy a or colonoscopy at puberty and then annually [4,7,20]	Colonoscopy at 12–14 years and then every 1–2 years	Colonoscopy at 12–14 years and then every 1–3 years	Flexible sigmoidoscopy or colonoscopy (preferred) at 10–15 years and then annually

^a A flexible sigmoidoscopy is reasonable until an adenomatous polyp is found, after which a full colonoscopy should be performed.

). The NCCN guidelines state that either method is adequate but colonoscopic evaluation is preferred. One important point of divergence in the recommendations is the ACG’s recommendation to transition from a sigmoidoscopy to a colonoscopy for subsequent evaluations if adenomas are identified on initial evaluation [2].

Although there is a tendency towards the development of polyps in the distal colon, adenomatous polyps can generally also be distributed evenly throughout the colon [2]. Given that proximal colonic polyps have been reported in children without rectosigmoid involvement, the weight of the evidence favors a colonoscopy as the preferred method for initial lower endoscopic assessment, although further studies to support the need for a full colonoscopy in children as an initial screening method are needed.

3.3.3. Hepatoblastoma Screening in Patients with Known FAP

Evidence Behind Differing Recommendations:

The association between hepatoblastoma and FAP has been well documented, with patients with FAP having a 750 to 7500 times higher risk of developing hepatoblastoma than the general population [20]. Additionally, in a study of patients with presumably sporadic hepatoblastomas based on a negative family history of FAP and/or parents with negative colonoscopies, germline APC mutations were detected in up to 10% of patients [20].

However, there is still insufficient evidence to support hepatoblastoma screening in individuals with known FAP or advise genetic screening for FAP in those with sporadic hepatoblastoma [21]. This aligns with the current ESPGHAN recommendations, which emphasize counseling over screening given the increased relative risk and exceptionally low absolute risk of hepatoblastoma in patients with FAP [4]. Despite this, the AACR and ACG guidelines recommend routine biannual screening for hepatoblastoma in patients with FAP with no specific recommendations from the ESGE (

Table 8. Discrepancies in recommendations on routine hepatoblastoma screening.

Society	AACR	ACG	ESGE	ESPGHAN	NCCN
Recommendations	Abdominal US and serum AFP starting in early infancy and every 4–6 months until 7 years	Abdominal US and serum AFP biannually until 7 years	No recommendations	Routine screening not recommended	High- level evidence to support routine screening is lacking but may consider liver palpation, abdominal US and serum AFP every 3–6 months until 5 years

), likely due to the endoscopic focus of their guidelines. Interestingly, the NCCN’s recommendations to consider routine hepatoblastoma screening conflict with their recommendations to complete genetic testing by 10–12 years, when colon screening is initiated [7].

As screening for hepatoblastoma would imply a need for genetic testing at an earlier age and exposure to repeat procedures, imaging and lab draws without clear evidence of a benefit, further studies evaluating the effect of early genetic testing on the hepatoblastoma morbidity and mortality in patients with FAP is needed.

4. Conclusions

Discrepancies in societal guidelines may have a greater clinical impact for relatively uncommon conditions such as pediatric polyposis syndromes. The most significant differences in societal recommendations for polyposis management have a moderate or potentially high clinical impact. Our observations underscore the need to harmonize recommendations across subspecialist societies to optimize the attention to and care for patients with a life-long condition that carries a heavy burden of disease.

An important observation in our review was the common thread of the use of poor-quality evidence in formulating the published guidelines and the need for further study and investigation to answer the questions posed. This paper emphasizes the need for collaborative efforts and prospective, multicenter and registry-based studies to refine the quality of guidelines. The guidelines with the weakest level of evidence should serve as a premise for future studies that should be supported and prioritized for publication in societal journals.

Lastly, apart from the ESPGHAN guidelines, the lack of pediatric gastroenterology input in societal guidelines for diseases of pediatric onset was especially concerning. The published guidelines from preeminent societies include a vast wealth of expertise from different specialist groups intimately familiar with the disease process who may or may not have had exposure to pediatric-age-range patients. We feel that professional societies must engage with rare disease-specific consortia and support efforts to create management guidelines for these patient groups.

In summary, pediatric polyposis syndromes are rare but potentially devastating life-long conditions that carry the burden of gastrointestinal complications and cancer predisposition within and outside the GI tract. Given the nuanced, although potentially clinically significant, differences in recommendations, as well as the lack of guideline recommendations in several management domains due to a lack of sufficient evidence, it is clear that a greater effort is needed to harmonize guideline recommendations across subspecialties, with consideration for pediatric gastroenterology input in future societal guidelines. This will be pivotal in minimizing fragmentation in care as many will inevitably transition through different providers of diverse backgrounds and subspecialties. With the closer consideration of the pediatric patient, certain management domains may benefit from a more conservative management approach. However, further study and investigation are needed to answer all the questions posed, and prospective registry-based collaboration is vital to fill in the gaps of care for our pediatric patients with polyposis syndromes.