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.

[The course and clinical manifestations of Peutz-Jeghers syndrome in the Russian population].

BACKGROUND: Peutz-Jeghers syndrome (PJS) is a rare hereditary syndrome characterized by the growth of hamartomatous polyps in the gastrointestinal tract, perioral pigmentation and an increased risk of malignant neoplasms. The syndrome is caused by a pathogenic variant in the STK11 gene. AIM: To assess the clinical picture and treatment of Russian patients with PJS. MATERIALS AND METHODS: A retrospective analysis of 30 patients from 25 families with an established diagnosis of PJS who were in the Ryzikh State Scientific Center for Coloproctology from 2011 to 2021 was carried out. All patients underwent instrumental examination, including esophagogastroduodenoscopy, colonoscopy, X-ray examination of the small intestine/CT-enterography, in the absence of invaginates - video capsule endoscopy, as well as molecular genetic examination for the presence of pathogenic variants in the STK11 gene. All removed polyps were subjected to the histological examination. RESULTS: The analysis of the clinical picture allowed us to establish the following data: the first complaints in patients were noted in childhood and adolescence, while the median age was 11 [7; 19] (0.5-24) years; pathogenic variants in the STK11 gene were identified in 26 (87%) cases, among which 10 were described for the first time; during the initial examination, polyps in the small intestine were detected in all 30 (100%) patients, in the stomach - in 23/30 (77%) patients, and in the colon - in 21/30 (70%); with an age, an increase in the number of polyps in all parts of the gastrointestinal tract was noted; before the diagnosis operations were performed urgently for intestinal obstruction; after the diagnosis of PJS, when polyps were detected in the gastrointestinal tract, endoscopic polypectomies were performed; if endoscopic removal of hamartomatous polyps was impossible, patients were operated as planned; malignant diseases of the predominantly reproductive system were detected in 8/30 (27%) patients. The median age of cancer detection was 52 [31; 52] (17-59) years. CONCLUSION: Russian patients with PJS have population-specific features in the clinical picture of the course of the disease, which dictates the need to develop their own recommendations for monitoring and treatment of such patients.

Ultrasound Color Pattern of Colonic Hamartomatous Polyps.

Colonic hamartomatous polyps are clinically benign tumors. Colonic hamartomas are polypoid lesions that are rare in adults and most commonly encountered in infants and children. We report an unusual case of giant colonic hamartomatous polyps that were found incidentally during a medical workup for acute lower gastrointestinal bleeding in a 26-year-old woman. We present the color Doppler ultrasound, computed tomography scan, and endoscopic pattern of colonic hamartomatous polyps.

Report of a case combining solitary Peutz-Jeghers polyp, colitis cystica profunda, and high-grade dysplasia of the epithelium of the colon.

BACKGROUND: Colitis cystica profunda is a rare nonneoplastic disease defined by the presence of intramural cysts that contain mucus, usually situated in the rectosigmoid area, which can mimic various malignant lesions and polyps. Its etiology still remains not fully elucidated, and several mechanisms such as congenital, post-traumatic, and infectious have been implicated in the development of this rare entity. CASE PRESENTATION: Herein, we describe a unique case of colitis cystica profunda in the setting of Peutz-Jeghers-type polyp of the sigmoid colon, associated with high-grade dysplasia of the overlying epithelium in a 48-year-old female patient, who presented to the emergency room with signs of intestinal obstruction. To the best of our insight, this is the first manifestation ever reported in the literature regarding the coexistence of solitary Peutz-Jeghers-type polyp, colitis cystica profunda, and high-grade dysplasia of the epithelium of the colon. CONCLUSIONS: The purpose of this case report is to highlight colitis cystica profunda and its clinical significance. An uncommon nonneoplastic entity, many times masquerading as malignant lesion of the rectosigmoid area of the colon. Clinicians and pathologists should be aware of this benign condition that is found incidentally postoperatively in patients undergoing colectomies, leading to unnecessary increase of morbidity and mortality in these patients, who otherwise could have been cured with conservative treatment only.

Exome Sequencing Reveals Germline SMAD9 Mutation That Reduces Phosphatase and Tensin Homolog Expression and Is Associated With Hamartomatous Polyposis and Gastrointestinal Ganglioneuromas.

Hamartomatous polyposis syndromes (HPS) account for a small but appreciable proportion of inherited gastrointestinal cancer predisposition syndromes; patients with HPS have an increased risk for colon and extracolonic malignancies. We present a unique case of familial juvenile polyposis syndrome associated with gastrointestinal ganglioneuromas of unknown etiology. The patient was tested for HPS-associated genes, but no mutation was detected. Exome sequencing identified a germline heterozygous mutation in SMAD9 (SMAD9(V90M)). This mutation was predicted to be an activating mutation. HEK cells transfected to express SMAD9(V90M) had reduced expression of phosphatase and tensin homolog; this reduction was also observed in a polyp from the patient. We have therefore identified a new susceptibility locus for HPS. Patients with hamartomatous polyposis in the colon associated with ganglioneuromatosis should be referred for genetic assessments.

Cronkhite‒Canada syndrome as inflammatory hamartomatous polyposis: new evidence from whole transcriptome sequencing of colonic polyps.

BACKGROUND: Cronkhite-Canada syndrome (CCS) is a rare, nonhereditary disease characterized by diffuse gastrointestinal polyposis and ectodermal abnormalities. Although it has been proposed to be a chronic inflammatory condition, direct evidence of its pathogenesis is lacking. This study aims to investigate the pathophysiology of CCS by analyzing transcriptomic changes in the colonic microenvironment. METHODS: Next-generation sequencing-based genome-wide transcriptional profiling was performed on colonic hamartomatous polyps from four CCS patients and normal colonic mucosa from four healthy volunteers. Analyses of differential expression and multiple enrichment analyses were conducted from the molecular level to the cellular level. Quantitative real-time PCR (qRT-PCR) was carried out to validate the sequencing accuracy in samples from six CCS patients and six healthy volunteers. RESULTS: A total of 543 differentially expressed genes were identified, including an abundance of CC- and CXC-chemokines. Innate immune response-related pathways and processes, such as leukocyte chemotaxis, cytokine production, IL-17, TNF, IL-1 and NF-kB signaling pathways, were prominently enhanced in CCS colonic polyps. Upregulation of wound healing, epithelial-mesenchymal transition, Wnt, and PI3K-Akt signaling pathways were also observed. Enrichment analyses at different levels identified extracellular structure disorganization, dysfunction of the gut mucosal barrier, and increased angiogenesis. Validation by qRT-PCR confirmed increased expression of the LCN2, IL1B, CXCL1, and CXCL3 genes in CCS colonic polyps. CONCLUSIONS: This case-control whole transcriptome analysis of active CCS colonic hamartomatous polyps revealed intricate molecular pathways, emphasizing the role of the innate immune response, extracellular matrix disorganization, inflammatory cell infiltration, increased angiogenesis, and potential epithelial to mesenchymal transition. These findings supports CCS as a chronic inflammatory condition and sheds light on potential therapeutic targets, paving the way for more effective and personalized management of CCS in the future.

Somatic STK11 mosaicism in a Turkish patient with Peutz-Jeghers syndrome.

Peutz-Jeghers syndrome (PJS) is an autosomal dominant disorder, caused by germline variants in the serine/threonine kinase 11 (STK11) gene. However, mosaic variants in STK11 gene have been rarely described. A 25-year-old woman diagnosed with PJS due to multiple hamartomatous polyps in the gastrointestinal tract was referred to our clinic. In the molecular diagnosis, the patient was evaluated using the STK11 gene sequence analysis and multiplex ligation-dependent probe amplification (MLPA) method, which suggested no pathogenic variant to account for the clinical picture. Given that the clinical findings of the patient were consistent with those of PJS, the raw data from next-generation sequencing (NGS) were re-examined for mosaicism which led to the detection of a novel mosaic c.920 + 1G > T variant in STK11 gene with a rate of 23% (1860x). Deep read-level NGS was performed on buccal mucosa and polyp samples to determine mosaicism levels in other tissues. Variant frequencies were 29% (710x) and 31% (1301x), respectively. Mosaicism should be considered in cases with clear clinical diagnostic criteria, such as PJS, where the pathogenic variant cannot be detected by sequence analysis and MLPA methods. Identification of mosaicism in these patients is very important as it can have an impact on patient follow-up and genetic counseling for relatives.

Ulcerative Colitis or Not? A Case of Dysplasia, Gastrointestinal Bleeding, and Juvenile Polyposis in a 27-Year-Old Man.

Juvenile polyposis syndrome lies within the family of hamartomatous polyposis syndromes characterized by polyps that appear benign but harbor an increased risk of colorectal and gastric cancer. This 27-year-old man with severe ulcerative colitis was discovered to have concomitant juvenile polyposis syndrome during diagnostic workup for gastrointestinal bleeding. The implications of this rare association complicate both diagnostic and treatment modalities since both diseases confer an increased risk of cancer.

Peutz-Jeghers Syndrome: A Comprehensive Review of Genetics, Clinical Features, and Management Approaches.

A relatively rare inherited condition known as Peutz-Jeghers syndrome (PJS) causes mucocutaneous pigmentation and gastrointestinal hamartomatous polyps. These polyps are non-cancerous, but the presence of PJS significantly increases the chances of developing various types of cancers, such as colorectal, pancreatic, gastric, and breast cancer. The purpose of this review article is to give an abbreviated summary of what is currently known about this syndrome, covering its clinical symptoms, pathophysiology, genetics, and management. PJS also raises the risk of getting many malignancies, especially gastrointestinal and pelvic cancers. Symptoms of the gastrointestinal tract brought on by hamartomatous polyps are frequent and include stool blockage, bleeding, and stomach pain. The pigmentation commonly appears as prominent bluish-black macules and frequently affects the skin and mucous membranes. Small macules and large regions of lentiginous pigmentation are both possible. Numerous areas, including the perioral area, buccal mucosa, fingers, and lips, exhibit pigmentation. Bowel obstruction and intussusception risk can be decreased by early identification and routine surveillance of gastrointestinal polyps. The gene serine/threonine kinase 11 (STK11) controls several biological functions, including cell polarity, growth, and proliferation. Genetic counseling is recommended for the affected individuals and their families. This can help assess the risk of passing on the condition to future generations and provide information about available reproductive options. Regular surveillance is crucial for managing the syndrome and reducing the risk of cancer development. Other syndromes and extra-gastrointestinal characteristics, such as somatic tumor polyps outside the gastrointestinal tract, are also linked to this syndrome.

PTEN mosaicism with features of Cowden syndrome.

We present the first known case of somatic PTEN mosaicism causing features of Cowden syndrome (CS) and inheritance in the subsequent generation. A 20-year-old woman presented for genetics evaluation with multiple ganglioneuromas of the colon. On examination, she was found to have a thyroid goiter, macrocephaly, and tongue papules, all suggestive of CS. However, her reported family history was not suspicious for CS. A deleterious PTEN mutation was identified in blood lymphocytes, 966A>G, 967delA. Genetic testing was recommended for her parents. Her 48-year-old father was referred for evaluation and was found to have macrocephaly and a history of Hashimoto's thyroiditis, but no other features of CS. Site-specific genetic testing carried out on blood lymphocytes showed mosaicism for the same PTEN mutation identified in his daughter. Identifying PTEN mosaicism in the proband's father had significant implications for the risk assessment/genetic testing plan for the rest of his family. His result also provides impetus for somatic mosaicism in a parent to be considered when a de novo PTEN mutation is suspected.

Hamartomatous polyps: Diagnosis, surveillance, and management.

Hereditary polyposis syndrome can be divided into three categories: Ade-nomatous, serrated, and hamartomatous polyps. Hamartomatous polyps, malformations of normal tissue presenting in a disorganized manner, are characterized by an autosomal dominant inheritance pattern. These syndromes exhibit hamartomatous gastrointestinal polyps in conjunction to extra-intestinal manifestations, which require conscientious and diligent monitoring. Peutz-Jeghers syndrome, Cowden syndrome, and juvenile polyposis syndrome are the most common displays of hamartomatous polyposis syndrome (HPS). Diagnosis can be pursued with molecular testing and endoscopic sampling. Early identification of these autosomal dominant pathologies allows to optimize malignancy sur-veillance, which helps reduce morbidity and mortality in both the affected patient population as well as at-risk family members. Endoscopic surveillance is an important pillar of prognosis and monitoring, with many patients eventually requiring surgical intervention. In this review, we discuss the diagnosis, surveillance, and management of HPS.

Atypical Peutz-Jeghers Syndrome Presenting With a Huge Jejunojejunal Intussusception in a Young Male: A Case Report.

Intussusception is considered one of the rare causes of intestinal obstruction in adults compared to pediatric patients. It usually presents with non-specific clinical manifestations ranging from mild recurrent abdominal pain to severe acute abdominal pain. The non-specificity of its symptoms makes it difficult to diagnose preoperatively. As 90% of adult intussusceptions are due to a pathological lead point, this prompts the underlying medical condition to be identified. We herein report a rare case of a 21-year-old male with atypical clinical features of Peutz-Jegher syndrome (PJS), presenting with jejunojejunal intussusception as a result of a hamartomatous intestinal polyp. A preliminary diagnosis of intussusception was made after an abdominal computed tomography (CT) scan and was confirmed intraoperatively. Postoperatively, the patient's condition improved steadily, and he was discharged with a referral to the gastroenterologist for further assessment.

A case of sporadic Peutz-Jeghers syndrome presenting as multiple intussusceptions.

Peutz-Jeghers syndrome (PJS) is an autosomal dominant mutation of the STK11/LKB1 gene on chromosome 19 often characterized by mucocutaneous pigmentation, hamartomatous polyps, anemia, gastrointestinal bleeding and intussusception. We present the case of a 21-year-old female with no pertinent family history who received the diagnosis of PJS after presenting to the hospital with two episodes intussusception. Patients with PJS have an increased lifetime risk of developing stomach, small bowel, colon, pancreatic, breast, cervical, uterus and testicular cancer requiring religious surveillance at an early age.

Classification of the canonical splice alteration MUTYH c.934-2A > G is likely benign based on RNA and clinical data.

MUTYH-associated polyposis (MAP) is an autosomal recessive disorder characterized by the development of multiple adenomatous colonic polyps and an increased lifetime risk of colorectal cancer. Germline biallelic pathogenic variants in MUTYH are responsible for MAP. The MUTYH c.934-2A > G (NM_001128425.1) variant, which is also known as c.850-2A > G for NM_001048174.2, has been identified in our laboratory in more than 800 patients, including homozygous and compound heterozygote carriers. The variant was initially classified as a variant of uncertain significance (VUS) because of lack of a MAP phenotype in biallelic carriers. In two unrelated female patients who were heterozygous carriers of this variant, further testing by RNA sequencing identified an aberrant transcript with a deletion of 9 nt at the start of exon 11 (MUTYH r.934_942del9). This event is predicted to lead to an in-frame loss of three amino acids in a noncritical domain of the protein. This was the only splice defect identified in these patients that was not present in the controls, and the aberrant transcript is derived exclusively from the variant allele, strongly supporting the cause of this splice defect as being the intronic variant, MUTYH c.934-2A > G. The splicing analysis demonstrating a small in-frame skipping of three amino acids in a noncritical domain, along with the absence of a MAP phenotype in our internal cohort of biallelic carriers, provides evidence that the variant is likely benign and not of clinical significance.

Small bowel polyp resection using device-assisted enteroscopy in Peutz-Jeghers Syndrome: Results of a specialised tertiary care centre.

INTRODUCTION: Enteroscopy resection of small bowel polyps in Peutz-Jeghers syndrome has only been described in small case series. Herein, we aimed to assess the efficacy of enteroscopy resection of small bowel polyps within a specialised tertiary care centre and the impact on intraoperative enteroscopy. METHODS: This was an observational single-centre study. All adult Peutz-Jeghers syndrome patients followed in the Predisposition Digestive Ile-de-France network who underwent an endoscopic resection of at least one small bowel polyp ≥ 1 cm by enteroscopy between 2002-2015 were included. Small bowel polyps were detected under a dedicated screening programme by previous capsule endoscopy and/or magnetic resonance enterography, performed every 2-3 years. Complete treatment was defined as the absence of polyps ≥ 1 cm after conventional endoscopic resection. Intraoperative enteroscopy or surgical resection were indicated in incomplete treatments. The overall complete treatment rate including conventional enteroscopy and intraoperative enteroscopy was also considered. RESULTS: Endoscopic resection of 216 small bowel polyps (median: 8.6 per patient, size: 6-60 mm) was performed by 50 enteroscopies in 25 patients (mean age: 36 years, range: 18-71, 56% male) with small bowel polyp ≥ 1 cm. Twenty-three patients (92%) underwent 42 screening capsule endoscopies and 14 (57%) had 23 magnetic resonance enterographies during a median follow-up of 60 months. Complete treatment was achieved in 76%. Intraoperative enteroscopy and surgical resection were performed in four (16%) and two (8%) patients. Intraoperative enteroscopy improved by 16% the complete treatment rate and the overall rate was 92%. The complication rate was 6%. CONCLUSION: This long-term study confirmed the efficacy and safety of endoscopic resection of small bowel polyps in Peutz-Jeghers syndrome. Intraoperative enteroscopy can be a complementary approach in selected cases.

Recurrent intestinal obstruction in a patient of Peutz-Jeghers syndrome.

Peutz-Jeghers syndrome is a rare hamartomatous polyposis syndrome characterized by the presence of intestinal polyps and mucocutaneous melanotic pigmentations. It is associated with various gastrointestinal and extraintestinal malignancies. This case report deals with the clinical presentation, investigations, operative findings, and outcome of a patient harboring this disease. A 45-year-old female presented to us with intermittent colicky abdominal pain for the last 6 months and a single episode of melena 1 month back. She had a previous history of resection of a jejunal growth 22 years back. The histopathology report was suggestive of papillary adenocarcinoma. On examination, hyperpigmented macules were seen on her lips and buccal mucosa. Laparotomy revealed multiple polyps mainly in the proximal small intestine and a focus of ileoileal intussusception. A limited resection was done.

A case report of hamartomatous polyposis in an individual with Neurofibromatosis type 1.

Even in well-described genetic syndromes, such as neurofibromatosis type 1, expansion of the phenotype should be considered as a possible explanation for atypical presentations. However, it is critical to complete the evaluation for a potential dual diagnosis, as there could be significant prognostic and management implications.

The role of inherited genetic variants in colorectal polyposis syndromes.

Colorectal carcinoma (CRC) is the third most common cancer in men and the second most common cancer in women across the world. Most CRCs occur sporadically, but in 15-35% of cases, hereditary factors are important. Some patients with an inherited predisposition to CRC will be diagnosed with a "genetic polyposis syndrome" such as familial adenomatous polyposis (FAP), MUTYH-associated polyposis (MAP), polymerase proofreading associated polyposis (PPAP), NTHL1-associated polyposis, MSH3-associated polyposis or a hamartomatous polyposis syndrome. Individuals with ≥10 colorectal polyps have traditionally been referred for genetic diagnostic testing to identify APC and MUTYH mutations which cause FAP and MAP respectively. Mutations are found in most patients with >100 adenomas but in only a minority of those with 10-100 adenomas. The reasons that diagnostic laboratories are not identifying pathogenic variants include mutations occurring outside of the open reading frames of genes, individuals exhibiting generalized mosaicism and the involvement of additional genes. It is important to identify patients with an inherited polyposis syndrome, and to define the mutations causing their polyposis, so that the individuals and their relatives can be managed appropriately.

Genetic analysis and clinical description of Greek patients with Peutz-Jeghers syndrome: Creation of a National Registry.

Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant disorder caused by germline mutations in the STK11 tumor suppressor gene. PJS patients face a cumulative cancer risk as high as 93% for all sites combined. The present study reports the spectrum of STK11 mutations in eight families with clinical diagnosis of PJS, summarizes the clinical characteristics of sixteen mutation carriers and launches a National Registry for PJS in Greece. STK11 loss-of-function (LoF) mutations were detected in 87.5% of index patients. Carriers presented with their first manifestation at a median age of 24.9 years, while early-onset breast cancer was the most frequent malignancy observed, highlighting the need for breast surveillance. Out of the deleterious STK11 mutations identified, two were novel: c.375_376delGT and c.676_679dupAACG, with 57.2% of these potentially occurring de novo. Using all available clinical and genetic data, the National Registry for Greek PJS was established in an attempt to better characterize the syndrome and raise awareness among patients and clinicians (available at https://www.peutzjeghersgreece.org). This is the first comprehensive genetic analysis and clinical characterization of Greek PJS patients, where a high incidence of breast cancer was observed and the first attempt to centralize all data in a National Registry.

Clinical manifestations and STK11 germline mutations in Taiwanese patients with Peutz-Jeghers syndrome.

BACKGROUNDS: Clinical manifestations and molecular basis of Taiwanese patients with Peutz-Jeghers syndrome (PJS) were investigated to add the knowledge of phenotype and genotype of the disease. METHODS: Based on the Pathology Data Bank and the Colorectal Cancer Register, we collected their clinical data. The entire coding sequence of the STK11 gene was amplified and analyzed by sequencing using the genomic DNA. RESULTS: Fifteen patients diagnosed with PJS from 11 unrelated families were collected until 2015. The median age at the onset of symptoms was 19 years with intussusception as the most frequent presenting symptom. Ten patients developing 11 cancers at various anatomical sites, including two cases of sinonasal cancer, two lung cancers, two breast cancers, two rectal cancers, two gynecological cancers and one small bowel cancer. Five of the deceased patients had died of cancers. The median age of diagnosis of first cancer in the probands was 32 years. Seventy patients (7 of 10) diagnosed before age of 40. Mutations found in eight families included five novel mutations (exon 6, c.843 ins G; exon 8, c.2065 delete A; exon 8, c.G923A, nonsense; exon 6, c.748dupA; and mTOR c.5107dupA) and three previously reported mutations. The other three PJS families without detectable STK11 mutations did not develop malignancies so far. CONCLUSION: This is the first comprehensive study of patients with Peutz-Jeghers syndrome in the Taiwanese. We have demonstrated that the phenotype of Peutz-Jeghers syndrome varies greatly among the patients. Patients with detectable STK11 mutations have very high risk of developing cancers.