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Peutz-Jeghers syndrome (PJS), also known as periorificial lentiginosis, is a rare autosomal dominant inherited disease with an incidence of 1/200,000 live-borns. Mutations in the serine-threonine kinase 11 (STK11) gene are considered the major cause of PJS. The most frequent complication at young age is recurrent intussusception due to multiple ham...
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Peutz-Jeghers syndrome (PJS) is an autosomal dominant inherited disorder characterized by intestinal hamartomatous polyps in association with mucocutaneous pigmentations. Main symptoms of PJS in childhood are abdominal pain, obstruction, intussusception, and bleeding from hamartomatous polyps. PJS carries a high risk of gastrointestinal cancer with...
Citations
... Intussusception is a commonly encountered condition in children, with approximately 90% of cases classified as idiopathic [5]. Indeed, factors such as food allergies [6], virus infections [7], and genetic predispositions [8][9][10] can all contribute to recurrent intussusception. Moreover, recurrence of intussusception occurs in approximately 10% of children following successful non-surgical reduction, with a higher risk observed, especially in children aged above one year [11]. ...
... Gut Pathogens (2024) 16:28 intussusception. Although genetic diseases such as SAMD9 mutation, Peutz-Jeghers syndrome, and Schaff-Yang syndrome may be associated with intussusception [8][9][10], our case did not exhibit typical presentations of these diseases. Notably, the case patient presented with the unusual occurrence of four episodes of intussusception, each manifesting at different recurrent locations, suggesting the presence of underlying unresolved causes. ...
Background
Intussusception, a common cause of abdominal pain in children, often lacks clear underlying causes and is mostly idiopathic. Recurrence, though rare, raises clinical concerns, with rates escalating after each episode. Factors like pathological lead points and Henoch-Schönlein purpura (HSP) are associated with recurrent cases. On the other hand, the prevalence of Helicobacter pylori (H. pylori), often asymptomatic, in children has been declining. Although its infection is reported to be linked with HSP, its role in recurrent intussusception remains unexplored. Further research is needed to understand the interplay among H. pylori (culprit pathogen), HSP (trigger), and intractable intussusception so as to develop effective management strategies.
Case presentation
A two-year-old girl experienced four atypical episodes of intussusception at distinct locations, which later coincided with HSP. Despite treatment with steroids, recurrent intussusception persisted, suggesting that HSP itself was not a major cause for intractable presentations. Subsequent identification of H. pylori infection and treatment with triple therapy resulted in complete resolution of her recalcitrant intussusception.
Conclusion
This instructive case underscored a sequence wherein H. pylori infection triggered HSP, subsequently resulting in recurrent intussusception. While H. pylori infection is not common in young children, the coexistence of intractable intussusception and steroid-resistant recurrent HSP necessitates consideration of H. pylori infection as a potential underlying pathogen.
... The presence of Lynch syndrome (EPCAM, MLH1, MSH2, MSH6, and PMS2), juvenile polyposis syndrome (SMAD4 and BMPR1A) and Peutz-Jeghers syndrome (STK11) have been linked to elevated gastrointestinal cancer risk [11][12][13]. There are also other less-commonly reported hereditary cancer predisposition syndromes (HCPS) that are associated with either high or moderate GC risk, such as hereditary breast and ovarian cancer syndrome (BRCA1/2), Li-Fraumeni syndrome (TP53), Cowden syndrome (PTEN), Ataxia-telangiectasia (ATM), and Bloom syndrome (BLM) [10]. ...
Gastric cancer is a major challenge in modern oncology due to its high detection rate and prevalence. While sporadic cases make up the majority of gastric cancer, hereditary gastric cancer is caused by germline mutations in several genes linked to different syndromes. Thus, identifying hereditary forms of gastric cancer is considered crucial globally. A survey study using NGS-based analysis was conducted to determine the frequency of different types of hereditary gastric cancer in the yet-unstudied Kyrgyz population. The study cohort included 113 patients with diagnosed gastric cancer from Kyrgyzstan. The age of patients was 57.6 ± 8.9. Next-generation sequencing analysis of genomic DNA was performed using a custom Roche NimbleGen enrichment panel. The results showed that 6.2% (7/113) of the patients had pathogenic or likely pathogenic genetic variants. Additionally, 3.5% (4/113) of the patients carried heterozygous pathogenic/likely pathogenic variants in high penetrance genes, such as TP53, POLD1, RET, and BRCA2. Moreover, 2.7% (3/113) of the patients carried heterozygous mutations in genes linked to autosomal recessive conditions, specifically PALB2, FANCA, and FANCD2. We have not identified any genetic variants in hereditary GC-associated genes: CDH1, STK11, SMAD4, BMPRIA, APC, MLH1, and others. Our study included patients with sporadic features of GC. The use of recognized criteria (NCCN, Gastric Cancer, Version 2.2022) would increase the number of identified genetic variants in hereditary GC-associated genes. Further research is required to determine the clinical relevance of the genetic variants identified in the current study.
... S11 and S12) and used 3D convolutions to enable the network to recognize key structural regions that may not be apparent from sequence alone (Fig. 3A). As an example, we show PrimateAI-3D predictions for STK11 (Fig. 3B), the tumor suppressor gene responsible for Peutz-Jeghers hereditary polyposis syndrome (68)(69)(70)(71), with each amino acid position colored by the average PrimateAI-3D score at that position. Common primate variants used for training and annotated ClinVar pathogenic variants from separate parts of the linear sequence form distinct clusters in 3D space. ...
Personalized genome sequencing has revealed millions of genetic differences between individuals, but our understanding of their clinical relevance remains largely incomplete. To systematically decipher the effects of human genetic variants, we obtained whole-genome sequencing data for 809 individuals from 233 primate species and identified 4.3 million common protein-altering variants with orthologs in humans. We show that these variants can be inferred to have nondeleterious effects in humans based on their presence at high allele frequencies in other primate populations. We use this resource to classify 6% of all possible human protein-altering variants as likely benign and impute the pathogenicity of the remaining 94% of variants with deep learning, achieving state-of-the-art accuracy for diagnosing pathogenic variants in patients with genetic diseases.
... S11 and S12) and used 3D-convolutions to enable the network to recognize key structural regions that may not be apparent from sequence alone (Fig. 3A). As an example, we show PrimateAI-3D predictions for STK11 (Fig. 3B), the tumor suppressor gene responsible for Peutz-Jeghers hereditary polyposis syndrome (68)(69)(70)(71), with each amino acid position colored by 20 the average PrimateAI-3D score at that position. Common primate variants used for training and annotated ClinVar pathogenic variants from separate parts of the linear sequence form distinct clusters in 3D space. ...
Personalized genome sequencing has revealed millions of genetic differences between individuals, but our understanding of their clinical relevance remains largely incomplete. To systematically decipher the effects of human genetic variants, we obtained whole genome sequencing data for 809 individuals from 233 primate species, and identified 4.3 million common protein-altering variants with orthologs in human. We show that these variants can be inferred to have non-deleterious effects in human based on their presence at high allele frequencies in other primate populations. We use this resource to classify 6% of all possible human protein-altering variants as likely benign and impute the pathogenicity of the remaining 94% of variants with deep learning, achieving state-of-the-art accuracy for diagnosing pathogenic variants in patients with genetic diseases.
One Sentence Summary
Deep learning classifier trained on 4.3 million common primate missense variants predicts variant pathogenicity in humans.
... Graphite particles resemble those of amalgam particles. 11 They present clinically as a localized flat, blue-gray lesion of variable dimensions. The gingiva and alveolar mucosa are the most common sites, but these lesions may also involve the floor of the mouth and the buccal mucosa. ...
... It is associated with germline mutations in the LKB1/STK11 gene, located on the short arm of the chromosome. 11 Characterized by intestinal hamartomatous polyps in association with mucocutaneous melanocytic macules. It appears as pigmented macules, often confluent and varying in size and shades of brown, appear in almost all cases periorally and on the lips and buccal mucosae. ...
Background
Oral pigmentation can be either normal or abnormal discolouration of the oral mucosa. Objective: To help clinicians establish a better approach towards the care of patients with pigmented oral lesions and to establish early diagnosis and treatment of such conditions. Data source: Works of literature concerning oral pigmentations, clinical features and treatment were reviewed thoroughly from renowned electronic databases such as PubMed, Medline, Google Scholar, and Cochrane Library and personal clinical experience in managing such conditions. The following words were used for the search: oral pigmentation, aetiology, and clinical presentations. Findings: Oral pigmentation presents in various clinical patterns that can range from just physiologic changes to oral manifestations of systemic diseases and malignancies. Oral pigmentation may be physiological or pathological. Knowledge of the different presentations of oral pigmented lesions is quite crucial to improve and mastering the skill of differential diagnosis, definitive diagnosis and prompt treatment. The deposition of pigments in oral tissues may be due to various etiological factors. It can arise from intrinsic and extrinsic factors and can be physiological or pathological. Conclusion: A good understanding of the various presentations of oral pigmented lesions would aid in the proper diagnosis and treatment of the condition.
... Other hereditary CRC syndromes worth noting include Peutz-Jeghers syndrome (PJS) caused by a mutation in Serine/threonine kinase 11 (STK11), usually presenting as multiple benign hamartomatous polyps [42,43], and MUTYH-associated polyposis (MAP) inherited in an autosomal recessive pattern characterized by biallelic germline mutations in MutY DNA glycosylase (MUTYH), a gene having a role in base excision repair (BER) [26,44]. Familial adenomatous polyposis (FAP), a well-studied disease with an autosomal dominant inheritance, has been reported to be caused by insertions and deletions in the adenomatous polyposis coli (APC) tumor suppressor gene [45]. ...
Colorectal cancer (CRC) is the 3rd most common malignant neoplasm worldwide, with more than two million new cases diagnosed yearly. Despite increasing efforts in screening, many cases are still diagnosed at a late stage, when mortality is high. This paper briefly reviews known genetic causes of CRC (distinguishing between sporadic and familial forms) and discusses potential and confirmed nucleic acid biomarkers obtainable from liquid biopsies, classified by their molecular features, focusing on clinical relevance. We comment on advantageous aspects such as better patient compliance due to blood sampling being minimally invasive, the possibility to monitor mutation characteristics of sporadic and hereditary CRC in a disease showing genetic heterogeneity, and using up- or down-regulated circulating RNA markers to reveal metastasis or disease recurrence. Current difficulties and thoughts on some possible future directions are also discussed. We explore current evidence in the field pointing towards the introduction of personalized CRC management.
... Other hereditary CRC syndromes worth noting include Peutz-Jeghers syndrome (PJS) caused by a mutation in Serine/threonine kinase 11 (STK11), usually presenting as multiple benign hamartomatous polyps [42,43], and MUTYH-associated polyposis (MAP) inherited in an autosomal recessive pattern characterized by biallelic germline mutations in MutY DNA glycosylase (MUTYH), a gene having a role in base excision repair (BER) [26,44]. Familial adenomatous polyposis (FAP), a well-studied disease with an autosomal dominant inheritance, has been reported to be caused by insertions and deletions in the adenomatous polyposis coli (APC) tumor suppressor gene [45]. ...
... In normoxic conditions, the enhanced HIF1a protein stability has been observed in acute or chronic depletion of AMPKa [7,29], but the relationship between AMPK and HIF1a remained unclear in HCC. We first 50 were calculated by nonlinear regression using log (inhibitor) vs. normalized response-variable slope model (GRAPHPAD Prism software). Symbols, mean; error bars, SD (n = 3). ...
... LKB1 and mammalian target of rapamycin (mTOR) are the most well-known upstream and downstream regulators of AMPK, respectively [49]. The germline mutation of LKB1 showed high correlation with Peutz-Jeghers syndrome, usually coupled with multiple gastrointestinal hamartoma polyps [50]. mTOR is known to facilitate cancer cell growth and can be inhibited by AMPK [51]. ...
Hepatocellular carcinoma (HCC) is characterized by rapid growth, early vascular invasion and high metastasis. Currently available FDA‐approved drugs show low therapeutic efficacy, limiting HCC treatment to chemotherapy. We designed and synthesized a novel small molecule, SCT‐1015, that allosterically activated adenosine monophosphate‐activated protein kinase (AMPK) to suppress the aerobic glycolysis in HCC. SCT‐1015 was shown to bind the AMPK α‐ and β‐subunit interface, thereby exposing the kinase α domain to the upstream kinases, resulting in the increased AMPK activity. SCT‐1015 dramatically reduced HCC cell growth in vitro and tumor growth in vivo. We further found that AMPK formed protein complexes with hypoxia‐inducible factor 1‐alpha (HIF1α), and that SCT‐1015‐activated AMPK promoted hydroxylation of HIF1α (402P and 564P), resulting in HIF1α degradation by the ubiquitin‐proteasome system. With declined HIF1α abundance, many glycolysis‐related enzymes were down‐regulated, suppressing aerobic glycolysis and promoting oxidative phosphorylation. These results indicated that SCT‐1015 channelled HCC cells into an unfavourable metabolic status. Overall, we reported SCT‐1015, as a direct activator of AMPK signaling that held therapeutic potential in HCC.
... Le syndrome de Peutz-Jeghers (PJ) est une maladie génétique autosomique dominante et de pénétrance quasi complète liée à une mutation inactivatrice du gène STK11 (Sérine/Thréonine Kinase 11) [65]. Celui-ci code pour une protéine éponyme jouant un rôle dans la polarité cellulaire et en tant que suppresseur de tumeur en limitant la prolifération lorsque les ressources énergétiques de la cellule sont réduites. ...
Résumé
Environ 23 % des cancers annexiels sont liés à un syndrome héréditaire, dont la majorité est représentée par les mutations des gènes BRCA et le syndrome de Lynch, responsable de tumeurs épithéliales. Cependant, le pathologiste doit également faire face à d’autres syndromes plus rares, prédisposant à une tumeur de l’ovaire, plutôt non épithéliale. Les tumeurs ovariennes dans le cadre du syndrome des cancers sein/ovaire sont essentiellement des carcinomes séreux de haut grade, d’origine plutôt tubaire, alors que celles associées à un syndrome de Lynch sont en majorité des carcinomes de type endométrioïde et à cellules claires. Les tumeurs des cordons sexuels d’origine héréditaire sont représentées par les tumeurs de Sertoli–Leydig dans le cadre du syndrome DICER et les tumeurs des cordons sexuels à tubules annelés liées au syndrome de Peutz–Jeghers. Le carcinome à petites cellules de type hypercalcémiant peut être associé au syndrome de prédisposition aux tumeurs rhabdoïdes. Enfin de rares tumeurs germinales ont été rapportées dans le cadre du syndrome de l’ataxie télangiectasie. La reconnaissance de ces entités par le pathologiste est indispensable. Bien que les aspects morphologiques permettant de prédire une prédisposition familiale varient en fonction du gène en cause, leur diagnostic permet parfois de déclencher une consultation et enquête génétiques, modifiant la prise en charge à la fois de la patiente et de sa famille.
... The number of polyps in PJS is less than MAP syndrome and they exists since birth or early age (25). Germ line mutations in the STK11 (serine threonine kinase 11) gene, also called LKB1, a tumour suppressor gene present on chromosome 19p13.3 is the main cause behind this syndrome (26). Conformational change is seen in STK11 protein after mutations leading to decrease in its efficiency to control cell division with loss of kinase activity. ...
Colorectal cancer ranks as third most commonly found cancers in
human and being found both in male and female equally. All over the
world these cancers have been a major problem in public health sector.Chromosomal Instability is among the most common form of genomic stability constituting 85 % of all colorectal cancer, defined as the presence of numerical chromosome changes or multiple structural
aberrations of chromosomes.Asubset of colorectal cancers (10 to 20 %) has been linked to aberrant methylated CpG loci. CpG Island MethylatorPhenotype (CIMP) is characteristic of this subset.Determination of Microsatellite Stability Index status in CRC has prognostic and therapeutic implications and also for classification
and has become the need of the hour and its detection by various methods and implications in treatment demands much research so as to improve the prognosis of all types of colorectal cancers and hence provide a path for therapy.
