暂无摘要。

OBJECTIVE: In this case-control study we aimed to investigate the intestinal microbiota profile of patients with Peutz-Jeghers syndrome (PJS) and its association with polyp growth.
METHODS: Thirty-two PJS patients and 35 healthy controls were enrolled. Fecal samples of all participants were collected for gut microbiota analysis via 16S rRNA gene (regions V3-V4) sequencing. SPSS version 22.0 and R software version 3.1.0 were used for the statistical analysis.
RESULTS: The richness was comparable, while the overall structure of the gut microbiota differed significantly between the PJS and control groups (weighted UniFrac, P = 0.001; unweighted UniFrac, P = 0.008). Significantly different abundances of two phyla, seven families, and 18 genera as well as twenty-nine differentially enriched functional modules (false discovery rate, P < 0.05) between the two groups were identified. Morganella was positively associated with the median number of polyps (JPN; r = 0.96, P < 0.001) and number of newly discovered polyps in the jejunum between two recent endoscopic resections (JPNG; r = 0.78, P = 0.04). Desulfovibrio was positively associated with JPNG (r = 0.87, P = 0.01). Blautia was negatively associated with the median maximum size of polyps in the jejunum (JPS). Anaerostipes was negatively associated with JPN, JPNG and JPS. Clostridium XVIII and Fusicatenibacter were negatively associated with JPN and JPS, respectively.
CONCLUSIONS: We found remarkably different gut microbiota of patients with PJS compared to healthy individuals and associations between specific fecal bacteria and clinical features of PJS. These findings may provide a new perspective for the management of PJS in clinical practice.

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.

There have been little research on the cancer risks of patients with Peutz-Jeghers syndrome (PJS) in Korea. We aimed to investigate the clinical features of PJS patients and their cancer incidence rate.
Patients with PJS from nine medical centers were enrolled. In those patients diagnosed with cancer, data obtained included the date of cancer diagnosis, the tumor location, and the cancer stage. The cumulative risks of gastrointestinal cancers and extra-gastrointestinal cancers were calculated using the Kaplan-Meier method.
A total of 96 PJS patients were included. The median age at diagnosis of PJS was 23.4 years. Cancer developed in 21 of the 96 patients (21.9%). The age of PJS diagnosis was widely distributed (0.9 to 72.4 years). The most common cancers were gastrointestinal cancer (n = 12) followed by breast cancer (n = 6). The cumulative lifetime cancer risk was calculated to be 62.1% at age 60. The cumulative lifetime gastrointestinal cancer risk was 47.1% at age 70. The cumulative lifetime extra- gastrointestinal cancer risk was 40.3% at age 60.
PJS onset may occur at any age and the risks of gastrointestinal and extra-gastrointestinal cancer are high. Thorough surveillance of PJS patients for malignancies is vital.

We retrospectively investigated 14 Japanese patients with Peutz-Jeghers (PJ) syndrome who were treated in six hospitals to determine the prevalence of cancer in Japanese patients with PJ syndrome. The study included seven males and seven females. The mean age at the time of diagnosis of PJ syndrome was 28.1 years (range 2-60 years). Hamartomatous polyps were observed in 13 (92.9%) patients, mucocutaneous pigmentation in 11 (78.6%), and positive family history in six patients (42.9%). The mean observation period after the diagnosis of PJ syndrome was 10.1 years (range 0-34 years). Although one patient died of cancer of unknown primary origin, the remaining 13 patients included in the study completed their last follow-up at each hospital. Cancers were detected in six patients (42.9%), including cancer of the uterine cervix (N=3), breast cancer (N=1), duodenal cancer (N=1), transverse colon cancer (N=1), and cancer of unknown primary origin (N=1). One patient presented with both cervical cancer and breast cancer. No patient presented with pancreatic cancer. This study highlights that patients with PJ syndrome are at high risk for intestinal and extra-intestinal cancers, such as uterine and breast cancer. Routine surveillance for intestinal and extra-intestinal malignancies is warranted in patients with PJ syndrome.

Peutz-Jeghers syndrome is a rare hereditary syndrome characterized by presence of hamartoma polyps in intestinal tract and usually by mucocutaneous pigmentation. Clinical-genetic characteristics of Russian patients with Peutz-Jeghers syndrome were studied for the first time. Four germline mutations in STK11gene were found in probands from six families and three of them had not been described previously. Clinical pattern of disease in Russian patients included: frequent polyposis of colon and stomach (62,5% and 75%, respectively) along with small bowel; frequent presence of malignant tumors (62,5%). These clinical aspects can help physicians to find out Peutz-Jeghers syndrome. Molecular-genetic testing of individuals should be recommended.

The present study aims to identify the genotype-phenotype correlation in children with Peutz-Jeghers Syndrome (PJS) through the analysis of STK11 gene mutations in the context of clinical and pathological characteristics.
In this observational cohort study, the clinical characteristics of 18 families diagnosed with pediatric PJS were collected. Genomic DNA from the peripheral blood of affected children and their family members was collected. The coding region of STK11 was amplified by PCR and screened for mutation by Sanger sequencing. The families that were negative for STK11 mutation were further assessed by multiplex ligation-dependent probe amplification (MLPA).
Initial presentation in affected children was at 1.6 to 14.2 years and included anemia in 8 patients whereas 6 presented for screening by virtue of family history. All patients underwent endoscopy, colonoscopy, and polypectomy. Polyps were distributed throughout the gastrointestinal (GI) tract, including the small intestine, stomach, colon, and rectum.In the 18 pediatric PJS families, STK11 mutations were detected in 8 families by Sanger sequencing, and large deletions were detected in 3 by MLPA, respectively. Nine of the 11 STK11 mutations were de novo, 3 were novel (c.419T>C:p.L140P, c.314T>G:p.L105X), and (c.488_489insACGG p.L164fs).
Although the main clinical features of pediatric PJS were similar to those of PJS cases in adults, a high frequency of STK11 de novo mutations were encountered in our population of patients with PJS.

Peutz-Jeghers syndrome is a rare autosomal dominant inherited disorder characterized by mucocutaneous pigmentation and hamartomatous gastrointestinal polyposis. A growing body of evidence has shown that Peutz-Jeghers syndrome could cause an increased risk of various cancers, yet the range of cancer risk estimates was wide among different studies. In this retrospective cohort study, 336 patients with Peutz-Jeghers syndrome in China were enrolled. The clinical characteristics, cancer spectrum, relative cancer risks, and cumulative cancer risks were analyzed. In total, 52 patients were diagnosed of cancer in the follow-up period, at a median age of 41 years (range: 21-67). The relative risk for cancer in Peutz-Jeghers syndrome patients was 63.858 (confidence interval: 47.514-85.823), and the cumulative cancer risk at the age of 60 years was 55%. Colorectal cancer was the most common cancer for Peutz-Jeghers syndrome patients (relative risk: 237.918, confidence interval: 154.417-366.572) and the cumulative cancer risk at the age of 60 years was 28%. There was a statistically significant difference in the cumulative cancer risk between patients with family history and those without family history, as well as between patients living in rural area and those living in urban areas ( p < 0.05), while no significant effects of gender and intussusception history on the cumulative cancer risk was found ( p > 0.05). Hopefully, our study may contribute to the management of this rare disorder and establishment of related surveillance projects, especially in China.

Hamartomatous polyps (HPs) in the gastrointestinal (GI) tract are rare compared to other types of GI polyps, yet they are the most common type of polyp in children. The symptoms are usually rectal bleeding, abdominal pain, obstipation, anaemia, and/or small bowel obstruction. The polyps are typically removed concurrently with endoscopy when located in the colon, rectum, or stomach, whereas polyps in the small bowel are removed during push-enteroscopy, device-assisted enteroscopy, or by surgery. HPs can be classified as juvenile polyps or Peutz-Jeghers polyps based on their histopathological appearance. Patients with one or a few juvenile polyps are usually not offered clinical follow-up as the polyp(s) are considered not to harbour any malignant potential. Nevertheless, it is important to note that juvenile polyps and HPs are also found in patients with hereditary hamartomatous polyposis syndromes (HPS). Patients with HPS have an increased risk of cancer, recurrences of polyps, and extraintestinal complications. The syndromes are important to diagnose, as patients should be offered surveillance from childhood or early adolescence. The syndromes include juvenile polyposis syndrome, Peutz-Jeghers syndrome, and the PTEN hamartoma tumour syndrome. Currently, the HPS diagnoses are based on clinical criteria and are often assisted with genetic testing as candidate genes have been described for each syndrome. This thesis is based on six scientific papers. The overall aim of the studies was to expand the knowledge on clinical course and molecular genetics in patients with HPs and HPS, and to investigate research participants\' attitude towards the results of extensive genetic testing.   Paper I: In the first paper we investigated the occurrence, anatomic distribution, and other demographics of juvenile polyps in the colon and rectum in Denmark in 1995-2014. Based on the Danish Pathology Data Bank we found that 1772 patients had 2108 JPs examined in the period, and we calculated the incidence of juvenile polyps to be between 1:45,000 and 1:65,000. The majority of patients with juvenile polyps were adults and 1% fulfilled to diagnostic criteria of JPS. The majority of patients had a single juvenile polyp. Paper II: In this paper we conducted a review of the HPS based on the current literature. Paper III: We investigated the hypothesis that patients with one or few HPs may have a HPS based on genetic screening. We de-signed a panel of 26 genes associated with HPS and used targeted next generation sequencing in 77 patients with mainly one juvenile polyp. We detected several germ line variants, among them three in ENG, two in BMPR1A, one in PTEN, and one in SMAD4. Although some of the detected variants have been reported previously none could be classified as definitely pathogenic or likely pathogenic according to our variant classification scheme and thus we concluded that genetic screening of patients with one or few JPs are not indicated. Paper IV: In Paper IV we investigated one of the ethical aspects of next generation sequencing: the issue whether research participants in NGS studies should be offered the possibility of not re-ceiving information on incidental genetic findings (the \"opting out possibility\"). We conducted semi-structures interviews in 127 research participants, and found that the majority (61%) wanted information on all incidentals findings, while 36% wanted information on actionable incidental findings. Only 3% did not want information on incidental findings at all. Paper V: In this paper we wanted to gather information on all Danish patients with Peutz-Jeghers syndrome in order to investigate the phenotype and genotype. Through Danish registers we detected 43 patients of which 14 had deceased. We calculated the prevalence of Peutz-Jeghers syndrome to be approximately one in 195,000 individuals. The median age at diagnosis was 29 years with obstruction of the small bowel as the most frequent presenting symptom. We noted 18 cancer occurrences in the population in both the GI tract and at extraintestinal sites, demonstrating that these patients are predisposed to cancer at various anatomical sites. The study also underlined the wide phenotypic expression of the syndrome.   Paper VI: In the last paper we identified patients with juvenile polyposis syndrome, who carry a SMAD4 mutation, and described their genotype and phenotype. We especially investigated whether these patients have symptoms of both juvenile polyposis syndrome and hereditary hemorrhagic telangiectasia. We identified 14 Danish patients. Most of these had symptoms of both conditions and one had aortic root dilatation. Thus, this group of patients requires a multidisciplinary follow-up program.

Peutz-Jeghers syndrome (PJS) is caused by the germline mutations in serine/threonine kinase 11 (STK11) gene. The aim of the present study was to investigate the spectrum of STK11 gene mutations using multiplex ligation-dependent probe amplification (MLPA) assay in combination with direct sequencing in Chinese children with PJS.
Nine children who met the clinical criteria for PJS and 2 presumed patients with PJS were enrolled in the present study. Patients\' clinical information on polyp characteristics, polyp-related complications, family histories, and so on were reviewed and analyzed. After obtaining informed consent, we performed a mutation analysis of STK11 gene in 11 Chinese patients using MLPA assay and direct sequencing.
By means of MLPA method, we detected exonic deletions in 5 patients. In details, 1 patient had the complete deletion of all 10 exons, 3 patients showed deletions of promoter region and exon 1, and 1 patient had exon deletions from 1 to 9. By direct sequencing of the coding region of STK11 gene, we identified point mutations in 4 patients at c.548T>G/p.Leu183Arg, c.580G>T/p.Asp194Tyr, c.152_153insGG/Asp53GlyfsX12, and c.631delC/Arg211GlyfsX76, respectively, and 3 of them are novel mutations. We failed to find any mutation in left 2 patients who met the clinical criteria of PJS.
MLPA plus direct sequencing revealed large genomic deletions of STK11 gene in Chinese children with PJS and increased the detecting rate of STK11 gene mutations in Chinese patients with PJS. MLPA combined with direct sequencing could serve as a better strategy for the genetic diagnosis of PJS in Chinese population.