Peutz-Jeghers Syndrome Patients Research Articles

Two missense STK11 gene variations impaired LKB1/adenosine monophosphate-activated protein kinase signaling in Peutz-Jeghers syndrome.

Peutz-Jeghers syndrome (PJS) is a rare hereditary neoplastic disorder mainly associated with serine/threonine kinase 11 (STK11/LKB1) gene mutations. Preimplantation genetic testing can protect a patient's offspring from mutated genes; however, some variations in this gene have been interpreted as variants of uncertain significance (VUS), which complicate reproductive decision-making in genetic counseling. To identify the pathogenicity of two missense variants and provide clinical guidance. Whole exome gene sequencing and Sanger sequencing were performed on the peripheral blood of patients with PJS treated at the Reproductive and Genetic Hospital of Citic-Xiangya. Software was employed to predict the protein structure, conservation, and pathogenicity of the two missense variation sites in patients with PJS. Additionally, plasmids were constructed and transfected into HeLa cells to observe cell growth. The differences in signal pathway expression between the variant group and the wild-type group were compared using western blot and immunohistochemistry. Statistical analysis was performed using one-way analysis of variance. P < 0.05 was considered statistically significant. We identified two missense STK11 gene VUS [c.889A>G (p.Arg297Gly) and c.733C>T (p.Leu245Phe)] in 9 unrelated PJS families who were seeking reproductive assistance. The two missense VUS were located in the catalytic domain of serine/threonine kinase, which is a key structure of the liver kinase B1 (LKB1) protein. In vitro experiments showed that the phosphorylation levels of adenosine monophosphate-activated protein kinase (AMPK) at Thr172 and LKB1 at Ser428 were significantly higher in transfected variation-type cells than in wild-type cells. In addition, the two missense STK11 variants promoted the proliferation of HeLa cells. Subsequent immunohistochemical analysis showed that phosphorylated-AMPK (Thr172) expression was significantly lower in gastric, colonic, and uterine polyps from PJS patients with missense variations than in non-PJS patients. Our findings indicate that these two missense STK11 variants are likely pathogenic and inactivate the STK11 gene, causing it to lose its function of regulating downstream phosphorylated-AMPK (Thr172), which may lead to the development of PJS. The identification of the pathogenic mutations in these two clinically characterized PJS patients has been helpful in guiding them toward the most appropriate mode of pregnancy assistance. These two missense variants can be interpreted as likely pathogenic variants that mediated the onset of PJS in the two patients. These findings not only offer insights for clinical decision-making, but also serve as a foundation for further research and reanalysis of missense VUS in rare diseases.

[Management of the Peutz-Jeghers Syndrome].

The current evidence to guide management of Peutz-Jeghers Syndrome (PJS) is sparse. Here we summarise the European guidelines that were published in 2021 by the EHTG (European Hereditary Tumour Group), extended with new evidence on some aspects of clinical management that have been generated since then. EHTG with this revised guideline has updated and extended their own previous expert opinion guideline from 2010. For this purpose, all published literature was systematically screened and the level of evidence determined by using the GRADE methodology (Grading of Recommendations Assessment. Development and Evaluation). This was followed by a Delphi process and the consensus for a statement was achieved if the voting committee reached ≥80% approval.The only other more recently published guidelines encountered only addressed the clinical management of gastrointestinal and pancreatic manifestations of PJS. These recommendations were reviewed and adopted, since no further relevant literature was identified in the systematic literature search. However, additional questions were identified and formulated into recommendations after following the described process. It may be stated that 10 years after the predecessor guideline, new evidence has been sparse. As with all rare diseases, a call for more collaborative studies must here be made in order to improve patient management by addressing open clinical questions and generating collaborative evidence with increased case numbers, both nationally and internationally. With the limited published evidence, these European guidelines are the most current reference for management of PJS patients.

Cancer Risk of Peutz-Jeghers Syndrome and Treatment Experience: A Chinese Medical Center.

Peutz-Jeghers syndrome (PJS), also known as hereditary mucocutaneous pigmented gastrointestinal polyposis, is a clinically rare autosomal dominant genetic disease, which falls into the category of hereditary colorectal cancer. There are ∼7,000 new cases of PJS in China every year, and 170,000 PJS patients may survive for a long time in society. PJS polyps are characterized by an early age of onset, difficult diagnosis and treatment, and easy recurrence. With repeated growth, polyps can lead to serious complications such as intestinal obstruction, intussusception, gastrointestinal bleeding, and cancerization, which cause serious clinical problems. Due to repeated hospitalization and endoscopic follow-up, PJS patients and their families suffer from great physical and mental pain and economic burden. With the in-depth understanding of PJS and the development and popularization of endoscopic techniques in the past decade, an integrated treatment modality based on endoscopy plus surgery has gradually become the preferred treatment in most hospitals, which greatly improves the quality of life of PJS patients. However, there is still a lack of effective drug prevention and cure means. In this paper, the current clinical treatment means for PJS polyps were summarized by literature review combined with the treatment experience of our medical center, with a focus on their clinical diagnosis, treatment, and cancer risk.

Survival, surveillance, and genetics in patients with Peutz-Jeghers syndrome: A nationwide study.

Peutz-Jeghers syndrome (PJS) is an autosomal dominant hereditary polyposis syndrome causing increased morbidity and mortality due to complications of polyposis and the development of cancer. STK11 is the only gene known to be associated with PJS, although in 10%-15% of patients fulfilling the diagnostic criteria no pathogenic variant (PV) is identified. The primary aim of this study was to identify the genetic etiology in all known PJS patients in Denmark and to estimate the risk of cancer, effect of surveillance and overall survival. We identified 56 patients (2-83 years old) with PJS. The detection rate of PVs was 96%, including three cases of mosaicism (6%). In two patients a variant was not detected. At the age of 40 years, the probabilities of cancer and death were 21% and 16%, respectively; at the age of 70 years these probabilities were 71% and 69%. Most cases of cancer (92%) were identified between the scheduled examinations in the surveillance program. These observations emphasize that PJS should be regarded as a general cancer predisposition syndrome, where improvement of clinical care is needed.

Clinical features, diagnosis, and treatment of Peutz-Jeghers syndrome: Experience with 566 Chinese cases.

Peutz-Jeghers syndrome (PJS) is a clinically rare disease with pigmented spots on the lips and mucous membranes and extremities, scattered gastrointestinal polyps, and susceptibility to tumors as clinical manifestations. Effective preventive and curative methods are still lacking. Here we summarize our experience with 566 Chinese patients with PJS from a Chinese medical center with regard to the clinical features, diagnosis, and treatment. To explore the clinical features, diagnosis, and treatment of PJS in a Chinese medical center. The diagnosis and treatment information of 566 cases of PJS admitted to the Air Force Medical Center from January 1994 to October 2022 was summarized. A clinical database was established covering age, gender, ethnicity, family history, age at first treatment, time and sequence of appearance of mucocutaneous pigmentation, polyp distribution, quantity, and diameter, frequency of hospitalization, frequency of surgical operations, etc. The clinical data was retrospectively analyzed using SPSS 26.0 software, with P < 0.05 considered statistically significant. Of all the patients included, 55.3% were male and 44.7% were female. Median time to the appearance of mucocutaneous pigmentation was 2 years, and median time from the appearance of mucocutaneous pigmentation to the occurrence of abdominal symptoms was 10 years. The vast majority (92.2%) of patients underwent small bowel endoscopy and treatment, with 2.3% having serious complications. There was a statistically significant difference in the number of enteroscopies between patients with and without canceration (P = 0.004, Z = -2.882); 71.2% of patients underwent surgical operation, 75.6% of patients underwent surgical operation before the age of 35 years, and there was a statistically significant difference in the frequency of surgical operations between patients with and without cancer (P = 0.000, Z = -5.127). At 40 years of age, the cumulative risk of intussusception in PJS was approximately 72.0%, and at 50 years, the cumulative risk of intussusception in PJS was approximately 89.6%. At 50 years of age, the cumulative risk of cancer in PJS was approximately 49.3%, and at 60 years of age, the cumulative risk of cancer in PJS was approximately 71.7%. The risk of intussusception and cancer of PJS polyps increases with age. PJS patients ≥ 10 years old should undergo annual enteroscopy. Endoscopic treatment has a good safety profile and can reduce the occurrence of polyps intussusception and cancer. Surgery should be conducted to protect the gastrointestinal system by removing polyps.

Alterations and clinical relevance of gut microbiota in patients with Peutz-Jeghers syndrome: A prospective study.

This case control study investigated the intestinal microbiota profile of patients with Peutz-Jeghers syndrome (PJS) and its association with polyp growth. 32 PJS patients (P group) and 35 healthy controls (H group) were enrolled. Clinical data of all patients including age, sex, number and size of polyps were recorded. Fecal samples of all participants were collected for gut microbiota analysis via 16s rRNA gene (regions V3-V4) sequencing. SPSS (ver. 22.0) and R software (ver. 3.1.0) were applied for the statistical analysis. The richness was comparable, while the overall structure of the gut microbiota differed significantly between the PJS and control group (weighted UniFrac, P=0.001; unweighted UniFrac, P=0.008). Significantly different abundance of 2 phyla, 7 families, and 18 genera were observed between 2 groups. 29 differentially enriched functional modules between 2 groups (FDR, P<0.05) were indentified. Morganella was positively associated with JPN (r=0.96, P< 0.001) and JPNG (r=0.78, P=0.04). Desulfovibrio was positively associated with JPNG (r = 0.87, P=0.01). Blautia was negatively associated with JPS (r= -0.85, P=0.02). Anaerostipes was negatively associated with JPN (r = -0.77, P<0.04), JPNG (r= -0.88, P<0.001) and JPS (r= -0.47, P< 0.04). Clostridium XVIII and Fusicatenibacter were negatively associated with JPN (r= -0.53, P=0.002) and JPS (r = -0.50, P=0.002) respectively. This study found remarkable differences in the gut microbiota of patients with PJS relative to healthy individuals, and associations between specific fecal bacteria and PJS clinical features. These findings may provide a new perspective for clinical practice.

STK11 Causative Variants and Copy Number Variations Identified in Thai Patients With Peutz-Jeghers Syndrome.

Introduction Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant inherited disorder caused by germline mutations in the serine-threonine kinase 11 (STK11) tumor suppressor gene. This syndrome is characterized by hamartomatous gastrointestinal polyps, mucocutaneous melanin pigmentation, and a higher risk of developing various cancers. Methods We summarized the clinical and molecular characteristics of five unrelated Thai patients with PJS. Denaturing high-performance liquid chromatography (DHPLC) screening, coupled with direct DNA sequencing and multiplex ligation-dependent probe amplification (MLPA), were applied for the molecular analysis of STK11. Results A total of four STK11 pathogenic changeswere identified in the five PJS patients, including two frameshift variants (a novel c.199dup, p.Leu67ProfsTer96 and a known c.834_835del, p.Cys278TrpfsTer6) and two types of copy number variations (CNV), exon 1 deletion and exons 2-3 deletion. Among reported STK11 exonic deletions, exon 1 and exons 2-3 deletions were found to be the two most commonly deleted exons. Conclusion All identified STK11 mutations were null mutations that were associated with more severe PJS phenotypes and cancers. This study broadens the phenotypic and mutational spectrum of STK11 in PJS.

Changes in the Gut Microbiome Associated with Intussusception in Patients with Peutz-Jeghers Syndrome.

Peutz-Jeghers syndrome (PJS) is a rare hereditary disorder characterized by intestinal polyposis, and intestinal intussusception is one of the most urgent complications. While it is known that imbalance of the gut microbiota is highly associated with intestinal disorders, the role of the gut microbiome in the pathogenesis of PJS has not been reported. In this study, we performed 16S rRNA sequencing on stools from 168 patients and 68 healthy family members who lived together to determine the gut microbiome composition of PJS patients. Metagenomics sequencing was further performed on the representative samples (61 PJS patients and 27 healthy family members) to analyze the functional changes. We found that the fecal microbiome of patients with PJS showed a greater variation in β-diversity. An enhancement of Escherichia coli and a reduction of Faecalibacterium prausnitzii was identified in PJS patients. Further reduction of Faecalibacterium prausnitzii was the characteristic microbial change observed in patients with intussusception. Functional analysis revealed that the abundance of propanoate metabolism was enriched in PJS patients and further enriched in those with intussusception. Escherichia coli was the major contributor to the enrichment of this metabolism pathway, which was associated with the abnormal expression of methylglyoxal synthase (encoded by mgsA) and phosphate acetyltransferase (encoded by pta). Our findings showed a distinct gut microbiome signature in PJS patients and identified the connection between the gut microbiome and intussusception. Alterations in the gut microbiome might be involved in the pathogenesis of PJS and may serve as biomarkers for gastrointestinal surveillance. IMPORTANCE Recent research has established a link between the gut microbiome and polyps and neoplasia, and antibiotic use influences the microbiome and the development of colorectal polyps. Familial adenomatous polyposis (FAP), which is characterized by the early development of benign precursor lesions (polyps), is associated with enterotoxigenic Bacteroides fragilis and Escherichia coli biofilms. However, the relationship between the gut microbiome and the pathophysiology of PJS has not yet been established. In this study, we found that PJS patients had a distinct microbiome composition, with a greater variation in β-diversity, an increase in Escherichia coli, and a decrease in Faecalibacterium prausnitzii. A further reduction of Faecalibacterium prausnitzii was observed in patients with intussusception. Moreover, PJS involved increased propanoate metabolism as well as abnormal mgsA and pta expression. These findings may contribute to a better understanding of the etiology of PJS and improve disease control strategies.

Massive gastric polyposis in Peutz-Jeghers Syndrome – a case report

Peutz-Jeghers Syndrome (PJS) is a rare autosomal dominant disorder equally affecting males and females with an incidence of 1/25,000 – 1/300,000 births. It is characterised by the development of hamartomatous polyps of the digestive tract, a lifetime risk of colorectal cancer and other gastrointestinal malignancies, as well as non-gastrointestinal cancers such as breast and ovarian cancers. Intestinal polyposis is very common in PJS, however, gastric polyps occur in less than 20% of patients with massive polyposis rarely reported. We report a case of massive gastric polyposis in an elderly PJS patient with concurrent and prior intestinal polyps and multiple occurrences of intussusception. The gastric polyps were present in the fundus through to the gastro-eosophageal junction. Microscopy demonstrated arborising branches of smooth muscle covered by disorganised mucosa – consistent with PJS polyps. The largest gastric polyp showed architectural complexity and nuclear atypia suggestive of high-grade dysplasia. An intrapolyp adenocarcinoma had been biopsied from the gastric fundus two months prior but no residual invasion was present in the gastrectomy specimen. It is important for pathologists to be aware of the association between PJS and gastric polyps in which dysplasia and malignancy can develop.

Peutz-Jeghers Syndrome: Lessons to be Learned in the Clinical Diagnosis.

Peutz-Jeghers Syndrome (PJS) is an autosomal dominant disease presenting with hamartomatous polyps in the gastrointestinal tract and hyperpigmented macules on lips and oral mucosa. The incidence of this syndrome is approximately 1 in 1,20,000 births. In this article, we are presenting 11 cases of PJS which were misdiagnosed and patients were compelled to visit hospital repeatedly. All these cases were diagnosed based on clinical suspicion, family history, and histopathological examination of specimens. Most of the cases presented with intussusception and required emergency surgical management. PJS can be diagnosed by the presence of microscopically confirmed hamartomatous polyps and a minimum of two of the following clinical criteria: Family history, mucocutaneous melanotic spots, and small bowel polyps with bleeding per rectally. The diagnosis can be missed if the melanotic spots on the face are missed. Routine investigations, imaging, and endoscopy were done in all cases. PJS patients need regular follow-up due to chance of recurrence of symptoms and susceptibility to cancer. PJS needs a high index of suspicion for diagnosis in cases of recurrent abdominal pain with bleeding per rectum. Proper family history and meticulous clinical examination for melanosis are very important to prevent the misdiagnosis of these cases.

S1583 Surveillance With Double Balloon Enteroscopy in Adult Patients With Peutz-Jeghers Syndrome: A Single Center Experience

Introduction: Peutz-Jeghers syndrome (PJS) is an inherited polyposis syndrome caused by mutation in the STK11 gene, and characterized by hamartomatous polyps throughout the gastrointestinal tract, most often in the small bowel (60-90%) and colon (50-64%). Presenting symptoms in PJS are often related to symptomatic polyps, including intestinal obstruction, abdominal pain, and bloody stools. For PJS patients, current recommendations support screening upper endoscopy, colonoscopy, and video capsule endoscopy at age 8-10, and if no polyps identified then again at age 18. Small bowel screening is recommended every 2-3 years. Deep enteroscopy, via antegrade or retrograde balloon enteroscopy, is often required for clearance of larger polyps visualized on video capsule endoscopy (VCE). The optimal follow-up strategy and modality of screening and surveillance of small bowel polyps is controversial. We aimed to evaluate if proactively performing deep enteroscopy vs serial VCE in adult PJS patients reduces risk of requiring subsequent surgical intervention. Methods: We retrospectively collected data from adult patients over 18 years of age with Peutz-Jeghers syndrome who underwent deep balloon enteroscopy for small bowel surveillance. Patients within this subset underwent proactive screening with antegrade double balloon enteroscopy performed approximately every one to 2 years. Data collected included number of prior small bowel surgeries before onset of and during deep enteroscopy surveillance, and complications. Results: Thirteen patients underwent deep enteroscopy from 2010 through 2021. Average number of prior small bowel surgeries was 1.9 (SD 1.4), average number of balloon enteroscopies during surveillance period 2.8 (SD 1.4), and average number of surgeries during balloon enteroscopy surveillance 0.46 (SD 0.66). There was a significant difference between number of surgeries before and during surveillance period (P=0.002). Conclusion: The initial standard screening modality for small bowel polyps and malignancy, VCE, can be complicated by increased risk of capsule retention given likelihood of prior surgery and possibility of obstructing polyps. Additionally, within the PJS cohort, there is a high yield for pathology which may ultimately require therapeutic deep enteroscopy anyhow. Our study, though small, does indicate that on a proactive balloon enteroscopy surveillance protocol there is a significantly lower risk of requiring small bowel surgery.

S1571 Device-Assisted Enteroscopy (DAE) in the Surveillance of Intestinal Polyposis in Peutz-Jeghers Syndrome

Introduction: Peutz-Jeghers Syndrome (PJS) is an autosomal dominant, genetic disorder characterized by the formation of hamartomatous polyps in the gastrointestinal tract. These polyps are a source of significant morbidity and mortality in this population due to associated complications of intestinal obstruction, bleeding, and malignant transformation. Surveillance of intestinal polyposis in patients with PJS has not been extensively studied, although centers which perform a significant volume of device-assisted enteroscopies (DAEs) encounter multiple cases each year. With the progressive adoption of DAE, examination of the deep small bowel for monitoring and prophylactic polypectomy has the potential to prevent complications of PJS and minimize the need for repeated laparotomy. Methods: After obtaining IRB approval, electronic health records were used to identify all DAEs performed on patients with PJS at 3 US referral centers (LSU, Duke, and UMass) between January 1, 2007 and January 1, 2020. Electronic medical records were reviewed to collect and analyze multiple data points. Primary endpoints included the complications associated with DAE performed for removal of intestinal hamartomas and the rate of laparotomy in PJS patients prior to and after index DAE. Secondary data points included patient characteristics, procedural details, and size/location/distribution of small bowel hamartomas. Results: Twenty-four patients met our inclusion criteria. Of these, 18 (75%) had previously undergone small bowel surgery for complications related to small bowel hamartomas. Between 2007 - 2020, a total of 46 DAEs were performed in these patients with an average of one surveillance exam every 2.5 years. A total of 131 polypectomies were performed during our study period with an observed complication rate of 1.5%, including one bowel perforation requiring surgery. Only one patient underwent surgery related to small bowel hamartomas following initial DAE surveillance exam over a total of 366 years of aggregated follow-up (Figure). Conclusion: Endoscopic management of small bowel polyps in patients with PJS using DAE is an effective strategy for prophylactic removal of hamartomas. DAE surveillance and endoscopic polypectomy is safe and may decrease the need for repeated laparotomy due to complications from intestinal hamartomas in patients with PJS.Figure 1.: Hamartomatous polyp in the ileum removed with saline injection-lift technique and hot snare polypectomy

High risk and early onset of cancer in Chinese patients with Peutz-Jeghers syndrome.

Peutz-Jeghers syndrome (PJS) is an autosomal dominant inherited disorder associated with a predisposition to a variety of cancers. Previous studies that have evaluated the cancer spectrum and risk of this rare disease have primarily been based on small data sets or heterogeneous cohorts from different countries. Here, we report the results of a large homogeneous cohort of Chinese PJS patients who were followed prospectively from 2006 to July 2021, and clinical data before 2006 were retrospectively collected. A total of 412 PJS patients (56.55% males) from 208 families were enrolled, contributing 12,798 person-years of follow-up. A total of 113 cancers were diagnosed in 109 patients (26.46%). The median age at the first cancer diagnosis was 40 years. In particular, patients born after the 1980s were diagnosed with cancer at an earlier median age of 30.5 years. The cumulative cancer risk was sharply increased to 30.9% at age 40 years; this high cancer risk age was 10 years earlier than that reported in previous Western studies, and increased to 76.2% at an age of 60 years. The most common cancer was gastrointestinal (GI) cancer (64.6%), in which colorectal cancer constituted a significantly larger proportional distribution (32.74%), when compared with previous investigations (11.1%−20.83%). There was some evidence that overrepresentation point variants in domain XI of STK11 may be associated with GI cancers. Furthermore, the incidences of gynecological and lung cancers were second only to that of GI cancer in this cohort. These results may provide novel insight for justifying surveillance to detect cancers at an earlier phase to improve clinical outcomes. Furthermore, the potential STK11 genotype-phenotype association could be the basis for future genetic counseling.

Genetic alternation in Peutz-Jeghers Syndrome (PJS) and its Diagnostic Method

Peutz-Jegers Syndrome (PJS) autosomal dominant disorder characterized by melanin spots, colon polyps and increased risk of cancer, especially due to mucosal skin pigmentation of the red edges of the lips, and gastrointestinal hematogenous polyposis. PJS was first reported in 1895. PJS can caused with or without mutation. Polyps have also been seen in the ureter, airway body system, and gastrointestinal system. The most common location is jejunum. DBE is an enteroscopy technique that enables the evaluation and treatment of the small bowel. Cancers of the colon, stomach, small intestine, pancreas, breast, and other organs are more common in PJS patients. PJS has a strong link with several malignancies like adenoma malignum (ADM) and a rare ovary tumor called sex cord tumor with annular tubules (SCTATs) in female PJS patients. Key words: Peutz-Jeghers Syndrome; intraoperative enteroscopy; dual-balloon enteroscopy

Lung cancer as a predominant feature in a patient with Peutz–Jeghers syndrome: Case report

Peutz–Jeghers syndrome (PJS) is characterized by mucocutaneous pigmentation and gastrointestinal hamartomatous polyposis, which can lead to intussusception. PJS patients face high lifetime risks for various cancer types, with the majority of patients being diagnosed with tumors along the gastrointestinal tract. Herein, we present the case of a 34‐year‐old man who carried a germline STK11 pathogenic variant, while lacking the cardinal features of PJS syndrome. Interestingly, he was diagnosed with lung adenocarcinoma despite being a never‐smoker. Tumor testing revealed clinically relevant molecular alterations, including the known germline pathogenic variant STK11, a KRAS somatic pathogenic variant, and FGFR3 gene amplification. Treatment with standard chemotherapy and immunotherapy did not have a clinical benefit. Due to clinical deterioration, the patient deceased 18 months after his initial diagnosis prior to having the chance for targeted therapy. Identification of rare hereditary cancer syndromes and the respective presence of tumor biomarkers can provide important alternatives to targeted treatments, including immunotherapy in patients with tumors unresponsive to conventional treatment protocols. This case highlights that although only a small proportion of lung cancer diagnoses will be due to hereditary predisposition, STK11 germline carriers should be under close surveillance for early detection of lung cancer.

Detection and analysis of common pathogenic germline mutations in Peutz-Jeghers syndrome.

BACKGROUNDDifferent types of pathogenic mutations may produce different clinical phenotypes, but a correlation between Peutz-Jeghers syndrome (PJS) genotype and clinical phenotype has not been found. Not all patients with PJS have detectable mutations of the STK11/LKB1 gene, what is the genetic basis of clinical phenotypic heterogeneity of PJS? Do PJS cases without STK11/LKB1 mutations have other pathogenic genes? Those are clinical problems that perplex doctors.AIMThe aim was to investigate the specific gene mutation of PJS, and the correlation between the genotype and clinical phenotype of PJS.METHODSA total of 24 patients with PJS admitted to the Air Force Medical Center, PLA (formerly the Air Force General Hospital, PLA) from November 1994 to January 2020 were randomly selected for inclusion in the study. One hundred thirty-nine common hereditary tumor-related genes including STK11/LKB1 were screened and analyzed for pathogenic germline mutations by high-throughput next-generation sequencing (NGS). The mutation status of the genes and their relationship with clinical phenotypes of PJS were explored.RESULTSTwenty of the 24 PJS patients in this group (83.3%) had STK11/LKB1 gene mutations, 90% of which were pathogenic mutations, and ten had new mutation sites. Pathogenic mutations in exon 7 of STK11/LKB1 gene were significantly lower than in other exons. Truncation mutations are more common in exons 1 and 4 of STK11/LKB1, and their pathogenicity was significantly higher than that of missense mutations. We also found SLX4 gene mutations in PJS patients.CONCLUSIONPJS has a relatively complicated genetic background. Changes in the sites responsible for coding functional proteins in exon 1 and exon 4 of STK11/LKB1 may be one of the main causes of PJS. Mutation of the SLX4 gene may be a cause of genetic heterogeneity in PJS.

Intussusception in Peutz-Jeghers Syndrome: Management of Unusual Acute Abdominal Presentation.

Peutz-Jeghers syndrome (PJS) is an autosomal dominant familial hamartomatous polyposis syndrome characterized by multiple gastrointestinal hamartomatous polyps and mucocutaneous melanin pigmentation. We report two cases, with no family history, presenting as emergency, one with perforation peritonitis due to spontaneous bowel disruption and another with bowel gangrene due to severe bowel congestion secondary to intussusception. Histological examination showed features of hamartomatous polyposis; other clinical features in these patients were suggestive of the diagnosis of Peutz-Jeghers syndrome. Given the multitude of carcinoma that these patients are susceptible to, aggressive screening protocols are recommended. Close monitoring and follow-up are essential in PJS patients for the prevention of potential complications, early detection of related malignancies due theirincreased risk for both intestinal and extraintestinal malignancies.

Double intussusception in a teenage child with Peutz-Jeghers syndrome: A case report

BACKGROUNDPeutz-Jeghers syndrome (PJS) is a genetic disorder characterized by the development of gastrointestinal hamartomatous polyps and mucocutaneous melanin pigmentation. Patients with PJS are at risk of complications such as intussusception. Intussusception is a condition where one segment of the intestine invaginates into another, causing intestinal obstruction. We report a PJS patient who was diagnosed with double intussusception in a single setting. CASE SUMMARYA 16-year-old teenage male PJS patient presented with a history of colicky abdominal pain, vomiting, blood in stools, loss of appetite, and weight loss. On abdominal examination, a vague mass was palpable over the right upper quadrant. Contrast-enhanced computed tomography (CT) of the abdomen was performed and an intussusception involving the jejunum and rectosigmoid junction was observed. The patient subsequently underwent a laparotomy and intussusception involving the jejunum and another over the ileum was noted intra-operatively. Bowel resection and an endoscopic polypectomy were performed, followed by a primary anastomosis. The patient was discharged well and reviewed again one month later, and was noted to be well.CONCLUSIONPJS patients have a high risk of intussusception and can be diagnosed accurately by endoscopic surveillance or radiologically with abdominal CT or magnetic resonance imaging. The mainstay of treatment is surgical intervention followed by endoscopic surveillance with periodic polypectomy.

The Management of Peutz-Jeghers Syndrome: European Hereditary Tumour Group (EHTG) Guideline.

The scientific data to guide the management of Peutz–Jeghers syndrome (PJS) are sparse. The available evidence has been reviewed and discussed by diverse medical specialists in the field of PJS to update the previous guideline from 2010 and formulate a revised practical guideline for colleagues managing PJS patients. Methods: Literature searches were performed using MEDLINE, Embase, and Cochrane. Evidence levels and recommendation strengths were assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE). A Delphi process was followed, with consensus being reached when ≥80% of the voting guideline committee members agreed. Recommendations and statements: The only recent guidelines available were for gastrointestinal and pancreatic management. These were reviewed and endorsed after confirming that no more recent relevant papers had been published. Literature searches were performed for additional questions and yielded a variable number of relevant papers depending on the subject addressed. Additional recommendations and statements were formulated. Conclusions: A decade on, the evidence base for recommendations remains poor, and collaborative studies are required to provide better data about this rare condition. Within these restrictions, multisystem, clinical management recommendations for PJS have been formulated.

A biannual pancreatic cancer surveillance program identifies a high prevalence of intraductal papillary mucinous neoplasms: accelerated malignant transformation in Peutz-Jeghers syndrome

Presenter: Yifan Wang MD | McGill University Background: Individuals with a family history of pancreatic adenocarcinoma (PC) or with a germline mutation in a PC susceptibility gene are at higher risk of developing PC. Surveillance of high-risk individuals (HRIs) may allow earlier detection of PC and its precursor lesions. Since advanced-stage PCs have been reported despite annual surveillance, shorter interval surveillance may be justified. Methods: From 2013 to 2020, asymptomatic HRIs were enrolled in a PC surveillance program alternating between magnetic resonance imaging and endoscopic ultrasound every 6 months. Results: Of 75 HRIs enrolled, 43 (57.3%) had a germline mutation in a PC susceptibility gene (GS), and 32 (42.7%) had a familial pancreatic cancer (FPC) pedigree. Branch-duct intraductal papillary mucinous neoplasms (BD-IPMNs) were identified in 26 (34.7%) individuals, but only 2 developed progressive lesions. Despite biannual surveillance, one patient with Peutz-Jeghers syndrome (PJS) developed locally advanced PC arising from a BD-IPMN. Whole genome sequencing of this patient’s PC and of a second PJS-associated PC from the kindred revealed that both tumours were driven by biallelic inactivation of STK11 in a KRAS-independent manner. From a review of 3,853 patients across two PC registries, we identified one additional PJS patient with PC. Importantly, all 3 PJS patients developed advanced PC consistent with malignant transformation of an underlying BD-IPMN in < 6 months. The other surveillance patient with a progressive lesion had FPC and underwent resection of a mixed-type IPMN which harboured polyclonal KRAS mutations. Furthermore, we found that colloid-type PCs, which develop from IPMNs, display COSMIC signature 17. Conclusion: Biannual PC surveillance identifies a high rate of BD-IPMNs in HRIs, but only a minority of these progress to PC. Our findings suggest that BD-IPMNs in patients with PJS are at risk of rapid malignant transformation. In PJS individuals, a lower threshold for resection of BD-IPMNs may be more effective than shortening surveillance intervals.