Clinical Guidelines for Diagnosis and Management of Peutz-Jeghers Syndrome in Children and Adults.

BACKGROUND: Peutz-Jeghers syndrome (PJS) is a rare disease characterized by the presence of hamartomatous polyposis throughout the gastrointestinal tract, except for the esophagus, along with characteristic mucocutaneous pigmentation. It is caused by germline pathogenic variants of the STK11 gene, which exhibit an autosomal dominant mode of inheritance. Some patients with PJS develop gastrointestinal lesions in childhood and require continuous medical care until adulthood and sometimes have serious complications that significantly reduce their quality of life. Hamartomatous polyps in the small bowel may cause bleeding, intestinal obstruction, and intussusception. Novel diagnostic and therapeutic endoscopic procedures such as small-bowel capsule endoscopy and balloon-assisted enteroscopy have been developed in recent years. SUMMARY: Under these circumstances, there is growing concern about the management of PJS in Japan, and there are no practice guidelines available. To address this situation, the guideline committee was organized by the Research Group on Rare and Intractable Diseases granted by the Ministry of Health, Labour and Welfare with specialists from multiple academic societies. The present clinical guidelines explain the principles in the diagnosis and management of PJS together with four clinical questions and corresponding recommendations based on a careful review of the evidence and involved incorporating the concept of the Grading of Recommendations Assessment, Development and Evaluation system. KEY MESSAGES: Herein, we present the English version of the clinical practice guidelines of PJS to promote seamless implementation of accurate diagnosis and appropriate management of pediatric, adolescent, and adult patients with PJS.

Paediatric polyposis syndromes: burden of disease and current concepts.

PURPOSE OF REVIEW: Polyposis syndromes are rare but significant entities that often present during childhood and adolescence. Polyposis syndromes should remain high on the differential diagnoses for any child presenting with rectal bleeding, protein-losing enteropathy or intussusception in the setting of multiple polyps in the gastrointestinal tract. There are three primary paediatric polyposis syndromes: Juvenile polyposis syndrome (JPS), Familial adenomatous polyposis (FAP) and Peutz-Jeghers syndrome (PJS). This review will cover recent guidelines for these conditions and advances in genetic testing. RECENT FINDINGS: The first set of paediatric guidelines were released in 2019 by the European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) for FAP, JPS and PJS. Even with advances in genetic testing, a significant proportion of patients with polyposis syndromes have no identifiable genetic mutations. Recent research has shown that polyps behave differently in patients with and without disease-causing variants, emphasizing the role of genetic testing in the diagnosis and management of polyposis syndromes. SUMMARY: Polyposis syndromes in the paediatric population are growing due to increased recognition and advances in genetic testing. A timely diagnosis and surveillance of a paediatric polyposis syndrome are pivotal for the management of disease burden and early identification of cancers within the gastrointestinal tract and beyond. Paediatricians, paediatric gastroenterologists, paediatric oncologists and paediatric surgeons should be familiar with the presentation and comorbidities of polyposis syndromes in children and adolescents. Further research into genotype-phenotype correlations is needed to tailor the care for paediatric patients with polyposis syndromes.

Guidelines for the management of hereditary colorectal cancer from the British Society of Gastroenterology (BSG)/Association of Coloproctology of Great Britain and Ireland (ACPGBI)/United Kingdom Cancer Genetics Group (UKCGG).

Heritable factors account for approximately 35% of colorectal cancer (CRC) risk, and almost 30% of the population in the UK have a family history of CRC. The quantification of an individual's lifetime risk of gastrointestinal cancer may incorporate clinical and molecular data, and depends on accurate phenotypic assessment and genetic diagnosis. In turn this may facilitate targeted risk-reducing interventions, including endoscopic surveillance, preventative surgery and chemoprophylaxis, which provide opportunities for cancer prevention. This guideline is an update from the 2010 British Society of Gastroenterology/Association of Coloproctology of Great Britain and Ireland (BSG/ACPGBI) guidelines for colorectal screening and surveillance in moderate and high-risk groups; however, this guideline is concerned specifically with people who have increased lifetime risk of CRC due to hereditary factors, including those with Lynch syndrome, polyposis or a family history of CRC. On this occasion we invited the UK Cancer Genetics Group (UKCGG), a subgroup within the British Society of Genetic Medicine (BSGM), as a partner to BSG and ACPGBI in the multidisciplinary guideline development process. We also invited external review through the Delphi process by members of the public as well as the steering committees of the European Hereditary Tumour Group (EHTG) and the European Society of Gastrointestinal Endoscopy (ESGE). A systematic review of 10 189 publications was undertaken to develop 67 evidence and expert opinion-based recommendations for the management of hereditary CRC risk. Ten research recommendations are also prioritised to inform clinical management of people at hereditary CRC risk.

Hereditary Cancer Syndromes-A Primer on Diagnosis and Management, Part 2: Gastrointestinal Cancer Syndromes.

Hereditary causes due to mutations and defects in certain genes account for roughly 5% to 10% of all colorectal cancers. These inherited syndromes have been associated with a 60% to 100% lifetime risk for development of colorectal cancer, depending on the genetic syndrome, and many also carry an increased risk for multiple extracolonic malignancies. In this second part of a review series on hereditary cancer syndromes, the focus will be to provide guidance on the features and management of the most commonly encountered hereditary colorectal cancers and polyposis conditions including Lynch syndrome, familial adenomatous polyposis, MUTYH-associated polyposis, and hamartomatous polyposis.

Device-assisted enteroscopy: An update on techniques, clinical indications and safety.

After more than 15 years since its introduction into clinical practice, indications for device-assisted enteroscopy have greatly expanded. Alongside the consolidated indications such as the diagnosis and treatment of small bowel bleeding, Crohn's disease, hereditary polyposis, small-bowel tumors and complicated celiac disease, device-assisted enteroscopy is nowadays largely used to perform endoscopic retrograde cholangiopancreatography in patients with altered anatomy, stent placement, retrieval of foreign bodies, direct insertion of jejunal feeding tubes, and in selected cases of incomplete colonoscopy. This has been made possible by the technical improvements of the enteroscopes and accessories and by the widespread use of the method. Device-assisted enteroscopy endotherapy currently offers a safe and effective alternative to major surgery and often represents the preferred option for treatment of small-bowel pathology. Its safety profile is favourable even in the elderly patient, provided that it is performed in high-volume and experienced centers. The evolution of the enteroscopy technique is a challenge for the future and could be facilitated by the new enteroscopes models. These prototypes need a thorough clinical and safety assessment especially for the complex therapeutic procedures. Large prospective, multicenter studies should be performed to assess whether the use of device-assisted enteroscopy leads to improved patients' long-term outcomes.

Management of Peutz-Jeghers Syndrome in Children and Adolescents: A Position Paper From the ESPGHAN Polyposis Working Group.

Peutz-Jeghers syndrome (PJS) is a well-described inherited syndrome, characterized by the development of gastrointestinal polyps, and characteristic mucocutaneous freckling. Development of small bowel intestinal polyps may lead to intussusception in children may require emergency laparotomy with potential loss of bowel. Gastrointestinal polyps may lead to bleeding and anemia. This European Society for Paediatric Gastroenterology Hepatology and Nutrition position paper provides a guide for diagnosis, assessment, and management of PJS in children and adolescents and guidance on avoiding complications from PJS or from the endoscopic procedures performed on these patients.This is the first position paper regarding PJS published by European Society for Paediatric Gastroenterology Hepatology and Nutrition. Literature from PubMed, Medline, and Embase was reviewed and in the absence of evidence, recommendations reflect the opinion of pediatric and adult experts involved in the care of polyposis syndromes. Because many of the studies that form the basis for the recommendations were descriptive and/or retrospective in nature, some of the recommendations are based on expert opinion. This position paper will be helpful in the appropriate management and timing of procedures in children and adolescents with PJS.

[Diagnosis and treatment for 46 cases of Peutz-Jeghers syndrome].

OBJECTIVE: To explore the clinical features, pathological features, gene test results, diagnosis, treatment and prognosis of Peutz-Jeghers syndrome(PJS).
 Methods: We retrospectively analyzed clinical data of 46 hospitalized cases of PJS during 2007 and 2017.
 Results: All 46 patients had mucocutaneous melanin pigmentation and multiple gastrointestinal polyposis. The pigmentation was first noticed often within 5 years old, and 14 cases had family history. The clinical manifestations mainly included black spots, abdominal pain, hematochezia, and anemia. Histological examinations showed that 20 patients were classified as hamartomatous polyps,18 as adenomatous polyps, 14 as inflammatory polyps, and 10 as zigzag polyps. Eleven patients sequenced a panel of 20 genes previously associated with colorectal cancer (CRC) by next-generation sequencing, and the results showed 5 patients with gene mutations, and 3 of them with intussusception and surgical histories were found to have pathogenic germline mutations in the STK11 gene. Endoscopic treatment was the main therapy, but endoscopy combined with laparoscopy or surgical treatment was performed when complications occurred or the polyp was too large. Malignant tumors were found in 3 patients during follow-up.
 Conclusion: PJS is a hereditary disease which is characterized by spots of the skin or mucosa and gastrointestinal multiple polyps. The main pathological features are hamartoma and adenoma. The risks for intussusception and surgical operation are found to be high in the patients with pathogenic germline mutations in the STK11 gene. Endoscopic treatment is the main therapy. PJS patients should be followed up regularly due to the increasing risk for cancer and being easily to relapse.

A Peutz-Jeghers syndrome family associated with sinonasal adenocarcinoma: 28 years follow up report.

Peutz-Jeghers syndrome (PJS) is a rare hereditary disorder characterized by hamartomatous polyps in both of the gastrointestinal tract and mucosal pigmentation. It could increase in risk of intestinal and extra-intestinal neoplasms. We here described three cases of sinonasal polyposis in a PJS family and two developed sinonasal type adenocarcinoma. Genetic study revealed a germline STK11/LKB1 mutation on codon 179 (c.C536G, p.P179R) of exon 4. LOH analysis of the LKB1 locus confirms this to be a deleterious mutation. Sinonasal polyposis with malignant transformation could be encountered in PJS patients. Regular follow-up was recommended for the risk of malignant changes in nasal polyps.

Oral mucosal stigmata in hereditary-cancer syndromes: From germline mutations to distinctive clinical phenotypes and tailored therapies.

Numerous familial tumor syndromes are associated with distinctive oral mucosal findings, which may make possible an early diagnosis as an efficacious marker for the risk of developing visceral malignancies. In detail, Familial Adenomatous Polyposis (FAP), Gardner syndrome, Peutz-Jeghers syndrome, Cowden Syndrome, Gorlin Syndrome, Lynch/Muir-Torre Syndrome and Multiple Endocrine Neoplasia show specific lesions of the oral mucosa and other distinct clinical and molecular features. The common genetic background of the above mentioned syndromes involve germline mutations in tumor suppressor genes, such as APC, PTEN, PTCH1, STK11, RET, clearly implied in both ectodermal and mesodermal differentiation, being the oral mucosal and dental stigmata frequently associated in the specific clinical phenotypes. The oral and maxillofacial manifestations of these syndromes may become visible several years before the intestinal lesions, constituting a clinical marker that is predictive for the development of intestinal polyps and/or other visceral malignancies. A multidisciplinary approach is therefore necessary for both clinical diagnosis and management of the gene-carriers probands and their family members who have to be referred for genetic testing or have to be investigated for the presence of visceral cancers.

Familial colorectal cancer syndromes: an overview of clinical management.

Familial colorectal cancer syndromes pose a complex challenge to the treating clinician. Once a syndrome is recognized, genetic testing is often required to confirm the clinical suspicion. Management from that point is usually based on disease-specific guideline recommendations targeting risk reduction for the patient and their relatives through surgery, surveillance and chemoprophylaxis. The aim of this paper is to provide an up-to-date summary of the most common familial syndromes and their medical and surgical management, with specific emphasis on evidence-based interventions that improve patient outcome, and to present the information in a manner that is easily readable and clinically relevant to the treating clinician.

ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes.

This guideline presents recommendations for the management of patients with hereditary gastrointestinal cancer syndromes. The initial assessment is the collection of a family history of cancers and premalignant gastrointestinal conditions and should provide enough information to develop a preliminary determination of the risk of a familial predisposition to cancer. Age at diagnosis and lineage (maternal and/or paternal) should be documented for all diagnoses, especially in first- and second-degree relatives. When indicated, genetic testing for a germline mutation should be done on the most informative candidate(s) identified through the family history evaluation and/or tumor analysis to confirm a diagnosis and allow for predictive testing of at-risk relatives. Genetic testing should be conducted in the context of pre- and post-test genetic counseling to ensure the patient's informed decision making. Patients who meet clinical criteria for a syndrome as well as those with identified pathogenic germline mutations should receive appropriate surveillance measures in order to minimize their overall risk of developing syndrome-specific cancers. This guideline specifically discusses genetic testing and management of Lynch syndrome, familial adenomatous polyposis (FAP), attenuated familial adenomatous polyposis (AFAP), MUTYH-associated polyposis (MAP), Peutz-Jeghers syndrome, juvenile polyposis syndrome, Cowden syndrome, serrated (hyperplastic) polyposis syndrome, hereditary pancreatic cancer, and hereditary gastric cancer.

Polyposis syndromes in children and adolescents: a case series data analysis.

BACKGROUND: Polyposis syndromes in children are distinct entities clinically and pathologically. These syndromes have multiple genetic characteristics, with development of polyps at various sites of the gastrointestinal (GI) tract, and are associated with an increased risk of colon cancer. They are relatively rare, and have mostly been characterized in the adult population, whereas little epidemiologic data have been reported in children. AIMS: The aim of this study was to summarize the pediatric experience collected over a period of 11 years on polyposis syndromes in three major Israeli tertiary centers. PATIENTS AND METHODS: Medical records of children below 18 years old and their families, diagnosed with polyposis syndromes between 1999 and 2010, were reviewed. The data included disease presentation, genetic profile, surveillance, and treatment. RESULTS: Fifty patients with polyposis syndromes were identified. The most frequent syndrome was familial adenomatous polyposis (FAP) in 33 children (66%), of whom 25 children (75.7%) had a known mutation. The mean age at presentation was 10.6±3.9 years (range 4-17 years). Most children were examined because of a family history of a polyposis syndrome (42 children, 84%). Among symptomatic children (32 children), the most frequent complaint was rectal bleeding (42%), followed by abdominal pain (22%), intussusception (10%), and diarrhea (4%). The youngest symptomatic patient was 4 years old at presentation, with rectal bleeding.All patients underwent multiple colonoscopies and upper GI endoscopies according to specific guidelines. Thirteen children underwent colonic surgery (39%); nine children had FAP. Adenocarcinoma of the colon was diagnosed in a 12.5-year-old child. CONCLUSION: In this cohort study, FAP was the most common type of polyposis syndrome diagnosed in this pediatric population. Colon cancer was present at the onset of symptoms in a 12.5-year-old patient with FAP. We therefore recommend strict adherence to the hereditary GI cancer guidelines to prevent morbidity and mortality in FAP and other inherited polyposis syndromes.

Rectal carcinoma in a young female patient with Peutz-Jeghers syndrome: a case report.

OBJECTIVE: To report a case of rectal cancer in a patient with Peutz-Jeghers syndrome (PJS). CLINICAL PRESENTATION AND INTERVENTION: A 20-year-old woman with intermittent bloody stool of 4 months was admitted for examination. Gastroendoscopy revealed multiple polyps involving the stomach, small intestine, colon and a rectal adenocarcinoma. A diagnosis of PJS was made based on intestinal polyps with characteristic pathology and melanotic macules on the lips. After surgery and chemotherapy upon follow-up at 8 months, the patient did not have any signs of recurrence. CONCLUSION: This case showed that rectal carcinoma should be considered for young patients with PJS.

[Digestive tract polyposes]. / Polypózy trávicího traktu.

The article provides an overview of hereditary polyposis syndromes of the digestive tract and genetic mechanisms in greater detail. A brief summary of the basic symptoms of the condition, including extra gastrointestinal signs, is given. Significant diagnostic procedures are listed. The therapy for these disease conditions is either operative or endoscopic.

Hyperamylasemia and pancreatitis following spiral enteroscopy.

BACKGROUND: Acute pancreatitis is a significant potential complication with double-balloon enteroscopy. Hyperamylasemia is frequently observed after both double-balloon enteroscopy and single-balloon enteroscopy but often without associated pancreatitis. Whether the same phenomenon occurs with spiral enteroscopy is currently unknown. AIMS: To determine the incidence of pancreatitis and hyperamylasemia following spiral enteroscopy. METHODS: A prospective cohort study of consecutive patients undergoing proximal spiral enteroscopy was conducted. Serum amylase levels were measured immediately before and following the procedure, combined with observation for clinical signs of pancreatitis. RESULTS: A total of 32 patients underwent proximal spiral enteroscopy, with a mean total procedure time of 51 min (range 30 min to 100 min) and mean depth of insertion of 240 cm (range 50 cm to 350 cm). The diagnostic yield was 50%, with 31% of all procedures being therapeutic. While no patients exhibited signs that raised suspicion of pancreatitis, hyperamylasemia was common (20%). Hyperamylasemia was not significantly associated with procedure duration or depth of insertion but was linked to patients with Peutz-Jeghers syndrome and with the use of propofol sedation, suggesting that it may be more common in difficult cases. CONCLUSIONS: Postprocedural hyperamylasemia occurred frequently with proximal spiral enteroscopy, while no associated pancreatitis was observed. This finding suggests that hyperamylasemia may not necessarily reflect pancreatic injury nor portend a risk for pancreatitis.

[Peutz-Jeghers syndrome : not only a polyposis!]. / Peutz-Jeghers-Syndrom : Nicht immer nur eine Polyposis!

The clinical signs of the Peutz-Jeghers syndrome are often overlooked in daily clinical practice. Early diagnosis is enormously relevant for the patient's outcome. Therefore, it is very important not only to think of the well-known manifestation of the gastrointestinal polyposis but also to consider the various other processes which can influence the prognosis remarkably as for instance ovarian and testicular tumors when a mutation of the serine-threonine kinase gene STK11 (chromosome 19p13.3) is present.

Double-balloon endoscopy in clinical practice: where are we now?

Double-balloon endoscopy (DBE) was developed in 2000 for the diagnosis and treatment of small bowel diseases. Although use rates still differ between Eastern and Western countries, DBE quickly reached a broad global diffusion. Together with capsule endoscopy (CE), DBE represented 'a revolution' for the management of small bowel diseases because of its therapeutic capabilities. At present, the main indications for DBE in clinical practice are obscure gastrointestinal bleeding, Crohn's disease and familial polyposis. In the setting of obscure gastrointestinal bleeding, DBE seems to have similar diagnostic performances as capsule endoscopy, but it allows for a more definitive diagnosis and the treatment of identified lesions. The main contribution of DBE in the management of Crohn's disease patients is its therapeutic capabilities. Indeed, several recently published studies have suggested that endoscopic dilation of small bowel strictures can delay or, in the near future, could even replace surgical interventions. Also, for patients with familial polyposis syndromes, DBE can represent a viable alternative to small bowel surgery. The complication rate of DBE appears to be low; major complications, such as pancreatitis, bleeding and perforation, have been reported in approximately 1% of all diagnostic DBE whereas the complication rate for therapeutic procedures is about 5%.