OBJECTIVE: A constitutional disease-causing variant (DCV) in the SMAD4 or BMPR1A genes is present in 40%-60% of patients with juvenile polyposis syndrome (JPS). The aim of this study was to characterize the clinical course and polyp burden in children with DCV-positive JPS compared to DCV-negative JPS. METHODS: Demographic, clinical, genetic, and endoscopic data of children with JPS were compiled from eight international centers in the ESPHGAN/NASPGHAN polyposis working group. RESULTS: A total of 124 children with JPS were included: 69 (56%) DCV-negative and 55 (44%) DCV-positive (53% SMAD4 and 47% BMPR1A) with a median (interquartile range) follow-up of 4 (2.8-6.4) years. DCV-positive children were diagnosed at an older age compared to DCV-negative children [12 (8-15.7) years vs. 5 (4-7) years, respectively, p < 0.001], had a higher frequency of family history of polyposis syndromes (50.9% vs. 1.4%, p < 0.001), experienced a greater frequency of extraintestinal manifestations (27.3% vs. 5.8%, p < 0.001), and underwent more gastrointestinal surgeries (16.4% vs. 1.4%, p = 0.002). The incidence rate ratio for the development of new colonic polyps was 6.15 (95% confidence interval 3.93-9.63, p < 0.001) in the DCV-positive group compared to the DCV-negative group, with an average of 12.2 versus 2 new polyps for every year of follow-up. There was no difference in the burden of polyps between patients with SMAD4 and BMPR1A mutations. CONCLUSIONS: This largest international cohort of pediatric JPS revealed that DCV-positive and DCV-negative children exhibit distinct clinical phenotype. These findings suggest a potential need of differentiated surveillance strategies based upon mutation status.
- MeSH
- dědičné nádorové syndromy * genetika MeSH
- dítě MeSH
- fenotyp * MeSH
- lidé MeSH
- mladiství MeSH
- mutace * MeSH
- následné studie MeSH
- předškolní dítě MeSH
- protein Smad4 * genetika MeSH
- receptory morfogenetických kostních proteinů typu I * genetika MeSH
- střevní polypóza * genetika vrozené MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
Kolorektálny karcinóm je v súčasnosti jedným z najčastejších nádorových ochorení vyskytujúcich sa v rozvinutých krajinách. Pochopenie molekulárnych princípov jeho vzniku patrí opätovne v poslednom čase medzi priority v oblasti onkogenetického výskumu. Kolorektálny karcinóm je zároveň aj vhodným modelom pre štúdium kancerogenézy z dôvodu dobrej dostupnosti prekanceróznych lézií a tiež z dôvodu existencie viacerých jasne popísaných hereditárnych foriem ako familiárna adenomatózna polypóza a Lynchov syndróm. Klasický model kolorektálnej tumorigenézy, popísaný Fearonom a Vogelsteinom, predstavuje tradičnú cestu vývoja kolorektálneho karcinómu zo sekvencie adenóm‑karcinóm. Tento model bol postavený na dôkladnej analýze mutácií v jednotlivých morfologických štádiách kancerogenézy, ktorých progresívna akumulácia vedie k malígnej transformácii kolonického epitelu. V posledných rokoch bol však prijatý aj alternatívny model vývoja kolorektálneho karcinómu zo seratovaných prekurzorov. Táto cesta vývoja, nazývaná aj seratovaná cesta, priniesla nový pohľad na kolorektálnu tumorigenézu. V súčasnosti sa predpokladajú minimálne tri molekulárne cesty kolorektálnej tumorigenézy: 1. cesta chromozómovej instability reprezentovaná dedičnou formou familiárnej adenomatóznej polypózy; 2. mutátorová cesta s mismach repair fenotypom reprezentovaná dedičnou formou Lynchovho syndrómu, ale aj časťou sporadických kolorektálných karcinomov; a 3. hypermetylačná seratovaná cesta charakterizovaná vysokou frekvenciou hypermetylácie CpG ostrovčekov promótorových oblastí určitých génov (CIMP+).
Colorectal cancer is currently one of the most frequent cancers in developed countries. Understanding the molecular principles of its pathogenesis has recently come into focus of many oncogenetic studies. Colorectal cancer also represents an ideal model for the study of molecular basis of cancerogenesis owing to the wide availability of its precursor lesions and the existence of several notorious genetic predispositions such as familial adenomatous polyposis and Lynch syndrome. The classical model of colorectal tumorigenesis, described by Fearon and Vogelstein, suggested the idea of a conventional progression from adenoma to carcinoma. It was based on a careful analysis of mutations occurring within particular stages of carcinogenesis with regards to their stepwise accumulations leading to neoplastic transformation of the colonic epithelium. Recently, new evidence has pointed to an alternative model of colorectal tumorigenesis introducing the concept of serrated precursors. This alternative pathway, known as the serrated pathway, has provided a new perspective on colorectal cancer development. Nowadays, three molecular pathways leading to colorectal tumorigenesis are recognized: 1. the chromosomal instability pathway typified by familial adenomatous polyposis; 2. the mutator pathway characterized by inactivation of DNA mismatch repair genes such as in Lynch syndrome or a number of sporadic colorectal cancers; 3. the hypermethylation serrated neoplasia pathway characterized by excessive methylation of some CpG islands in the promoter region of certain genes (positive CpG islands methylator phenotype) (CIMP+). Key words: colorectal cancer – colorectal tumorigenesis – Lynch syndrome – microsatellite instability – hypermethylation phenotype The author declares she has no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 14. 7. 2016 Accepted: 8. 9. 2016
- Klíčová slova
- hypermetylační fenotyp, mutátorové geny,
- MeSH
- chromozomální nestabilita MeSH
- dědičné nepolypózní kolorektální nádory * diagnóza genetika MeSH
- epigeneze genetická MeSH
- geny APC MeSH
- imunohistochemie MeSH
- karcinogeneze * MeSH
- kolorektální nádory * etiologie genetika MeSH
- lidé MeSH
- metylace DNA MeSH
- mikrosatelitní nestabilita MeSH
- nádorová transformace buněk MeSH
- polypy tlustého střeva genetika MeSH
- střevní polypóza genetika MeSH
- tumor supresorové geny MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
- MeSH
- celiakie diagnóza MeSH
- Crohnova nemoc diagnóza MeSH
- dítě MeSH
- dospělí MeSH
- financování organizované MeSH
- gastrointestinální krvácení diagnóza MeSH
- idiopatické střevní záněty diagnóza MeSH
- kapslová endoskopie metody normy MeSH
- lidé MeSH
- střevní polypóza diagnóza genetika MeSH
- tenké střevo patologie MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé MeSH
Peutz-Jeghersov syndróm je vzácne autozomálne dominantne dedičné ochorenie charakterizované hamartomatóznymi polypmi tráviaceho traktu, mukokutánnymi pigmentáciami a zvýšeným rizikom malígneho ochorenia. Diagnostika sa opiera o prítomnosť mukokutánnych pigmentácii, histologické vyšetrenie polypov s nálezom typických hamartómov a o genetickú analýzu. Mutácia tumorsupresorového génu STK11 kódujúci serín-treonín kinázu 11 je zatiaľjedinou známou príčinou Peutz-Jeghersovho syndrómu. Doposiaľ bolo popísaných vyše 145 typov mutácií tohto génu pravdepodobne zodpovedných za veľkú variabilitu jeho fenotypového prejavu. Liečba ochorenia spočíva v pravidelnom endoskopickom alebo chirurgickom odstraňovaní polypov a v špecifickom onkologickom screeningu v snahe znížiť riziko vzniku závažných komplikácií polypózy a zabrániť rozvoju pokročilých foriem onkologických ochorení.
Peutz-Jeghers syndrome is a rare autosomal dominant inherited disease characterized by hamartomatous polyps of the gastrointestinal tract, by mucocutaneous pigmentations and an increased risk of intestinal and extraintestinal tumours. Diagnosis of Peutz-Jeghers syndrome requires mucocutaneous lesions, histological finding of typical hamartomas and genetic analysis. Mutation of gene STK 11, a tumour suppressor gene coding protein serine/threonine kinase 11, is the only known cause of Peutz-Jeghers syndrome. 145 mutations of the gene have been described so far, which is probably the reason for the large phenotypic variability. The treatment strategy is based on regular endoscopic or surgical polypectomy and a special oncological screening programme to prevent severe complications of polyposis and the development of an advanced form of malignancies.
- Klíčová slova
- hamartomatózny polyp, STK11/LKB1, gén kódujúci serín, treonín kinázu, Peutz-Jeghers,
- MeSH
- chemoprofylaxe metody MeSH
- diagnostické techniky molekulární využití MeSH
- fenotyp MeSH
- genetické testování metody MeSH
- genotyp MeSH
- hamartom epidemiologie genetika patologie MeSH
- karcinom MeSH
- Peutzův-Jeghersův syndrom diagnóza genetika terapie MeSH
- střevní polypóza diagnóza genetika terapie MeSH
- Publikační typ
- přehledy MeSH
Cowden syndrome is an inherited disease characterized by mucocutaneous lesions, gastrointestinal hamartomatous polyposis and an increased risk of breast, thyroid and endometrial carcinomas. Despite well described phenotypic expression of this disease, it is not easy to determine correct clinical diagnosis. In this case report we present a clinical history of a patient with Cowden syndrome. When he was 22 years old, he was found to have polyposis of gastrointestinal tract. The diagnosis of Peutz-Jeghers syndrome was established. Owing to intensive belly spasms, as a 36-year-old he was sent to another gastroenterological department where the thorough gastrointestinal tract examination was performed. We found glycogenic acanthosis of the esophagus; diffuse polyposis with large polyps within the stomach, and polyposis with small polyps in duodenum, colon, and rectum. We also noted the presence of excessive mucocutaneous papillomatosis of the lips and subtle skin lesions. Possible Cowden syndrome diagnosis was suggested. The same year he underwent plastic operation of the lips. During surgery, diffuse nodularity of the trachea was also noted. After plastic operation and assessment of Cowden syndrome as a possible diagnosis, he was recommended for a genetic examination. Diagnosis of Cowden syndrome was confirmed by sequencing analysis of the PTEN gene (phosphatase and tensin homolog deleted on chromosome 10). We found 'c.825_840delAAATACATTCTTCATA' deletion. This case affirmed that, for establishment of a correct diagnosis, especially for rare clinically overlapping syndromes, molecular testing is usually the only reliable method.
- MeSH
- delece genu MeSH
- dospělí MeSH
- financování organizované MeSH
- fosfohydroláza PTEN genetika MeSH
- kůže patologie MeSH
- lidé MeSH
- nádory rtu genetika komplikace patologie MeSH
- papilom genetika komplikace patologie MeSH
- střevní polypóza genetika komplikace patologie MeSH
- syndrom mnohočetného hamartomu genetika komplikace patologie MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
