Gastrointestinal polyposis syndromes are primarily characterized by multiple polyps in the gastrointestinal tract, with their pathogenic mechanisms largely related to genetic factors and involving multiple signaling pathways. Adenomatous polyposis syndromes are mainly associated with APC gene variants, while some cases may arise from MUTYH gene variants. Peutz-Jeghers syndrome is primarily linked to STK11 gene variants. Juvenile polyposis syndrome is mainly associated with variants in the SMAD4 and BMPR1A genes. PTEN hamartoma tumor syndrome is predominantly caused by PTEN gene variants. Hereditary mixed polyposis syndrome is primarily related to variants of the GREM1 and BMPR1A genes. This article systematically summarizes the advances in genetic research on Gastrointestinal polyposis syndromes to enhance clinicians' understanding of these diseases and improve their diagnostic and therapeutic approaches.

Sessile serrated lesions (SSLs) are not uncommon entities per se, usually localised to the proximal half of the colon and are often flat on endoscopic examination. The presence of dysplasia associated with SSL and, even more so, invasion are considered rare, while dysplastic SSLs (SSL-D) very quickly transform into invasive carcinoma. MLH1 immunohistochemical reaction may help to establish the diagnosis of SSL-D. We present the case of an 88-year-old female patient who presented for colonoscopic resection of suspicious tumours in the coecum and transverse colon. Histological examination revealed medullary carcinoma in the coecum with MLH1 and PMS2 mismatch repair protein deficiency. The polyp removed from the transverse colon was histopathologically confirmed to be SSL with central low-grade dysplasia (SSL-D), confirmed by loss of MLH1, and submucosal invasion was seen at a single focus. A BRAF V600E sequencing was performed to rule out Lynch syndrome, which confirmed the presence of the mutation. Risk factors for SSL-D include older age, the presence of multiple synchronous SSLs and a size greater than 10 mm. In SSL-D, due to the high malignant transformation potential, a complete resection should always be sought. In the SSL – SSL-D – carcinoma sequence, the main driver mutations are in the BRAF and less frequently KRAS genes. In cases with numerous SSLs, the possibility of sessile polyposis syndrome, and less frequently MUTYH-associated polyposis and hereditary mixed polyposis syndrome should also be raised. In both SSL and colorectal carcinoma, microsatellite instability, CpG island methylation phenotype and the presence of BRAF V600E mutation are common. The mismatch repair status can be determined by immunohistochemistry using MLH1, PMS2, MSH2 and MSH6 reactions, the 2 tests complementing each other. Determination of mismatch repair status is crucial for the diagnosis of colorectal carcinoma and the potential indication of immune checkpoint inhibitor treatment. Orv Hetil. 2025; 166(11): 427–433. A sessilis serrated laesio (SSL) nem ritka entitás, általában a proximalis colonfélre lokalizálódik, és az endoszkópos vizsgálat során gyakran lapos megjelenésű. Az SSL-hez társuló dysplasia (SSL-D) és még inkább az invázió jelenléte azonban ritkaságnak számít, aminek oka, hogy ezek a laesiók ’low-grade’ dysplasia esetében is gyorsan alakulnak invazív carcinomává. MLH1-reakció segíthet az SSL-D diagnózisának felállításában. Munkánkban egy 88 éves nőbeteg esetét mutatjuk be, aki a coecum, illetve a colon transversum területén észlelt tumorgyanús elváltozások kolonoszkópos eltávolítására érkezett. Szövettani vizsgálat során a coecumban medullaris carcinoma került megállapításra, melyben MLH1 és PMS2 ’mismatch repair protein’ deficientia volt megfigyelhető. A colon transversumból eltávolított polypus szövettani vizsgálattal SSL-nek bizonyult, centrálisan ’low-grade’ dysplasiával (SSL-D), melyet az MLH1 vesztése is megerősített, továbbá egy látótérben submucosa-invázió is jelen volt. A Lynch-szindróma kizárására BRAF V600E szekvenálásos vizsgálat történt, mely a mutáció fennállását bizonyította. Az SSL-D rizikótényezői közé sorolható az idősebb életkor, több szinkrón SSL jelenléte, illetve a 10 mm-nél nagyobb méret. SSL-D esetében a nagy malignitási transzformációs potenciál miatt mindig törekedni kell a komplett resectióra. Az SSL – SSL-D – carcinoma szekvencia esetében a fő ’driver’ mutációk a BRAF és ritkábban a KRAS géneket érintik. Nagyszámú SSL esetén fel kell, hogy merüljön továbbá a sessilis polyposis szindróma, ritkábban a MUTYH-hoz társult polyposis és az öröklött kevert polyposis szindróma lehetősége is. Mind SSL-ben, mind colorectalis carcinomában gyakori a mikroszatellita-instabilitás, a CpG-sziget-metilációs fenotípus, illetve a BRAF V600E mutáció fennállta. A ’mismatch repair’ status meghatározható immunhisztokémiai módszerrel az MLH1, PMS2, MSH2 és MSH6 reakciók használatával, illetve PCR-módszerrel is. A két vizsgálat kiegészíti egymást. Az immunellenőrzőpont-gátló kezelés végett a ’mismatch repair’ status meghatározása kulcsfontosságú colorectalis carcinoma diagnózisa esetén. Orv Hetil. 2025; 166(11): 427–433.

Bone morphogenetic protein receptor type 1A (BMPR1A) is responsible for two individual Mendelian diseases: juvenile polyposis syndrome and hereditary mixed polyposis syndrome 2, which have overlapping phenotypes. This study aimed to elucidate whether these two syndromes are just two subtypes of a single syndrome rather than two isolated syndromes. We sequenced the BMPR1A gene in 186 patients with polyposis and colorectal cancer, and evaluated the clinicopathological features and phenotypes of the probands and their available relatives with BMPR1A mutations. BMPR1A germline mutations were found in six probands and their three available relatives. The numbers of frameshift, nonsense, splice-site, and missense mutations were one, one, two, and two, respectively; two of the six mutations were novel. Typical juvenile polyps were found in only three patients. Two patients had colorectal cancer rather than any polyps. Diseases in BMPR1A germline mutation carriers vary from mixed polyposis to sole colorectal cancer, and typical juvenile polyps do not always occur in these carriers. The variety of phenotypes reflected the features of BMPR1A-mutation carriers, which should be recognized as a spectrum of one syndrome. Genetic testing may be a good approach to identifying BMPR1A-related syndromes.

The gastrointestinal hamartomatous polyposis syndromes are rare, autosomal dominant disorders associated with an increased risk of benign and malignant intestinal and extraintestinal tumors. They include Peutz-Jeghers syndrome, juvenile polyposis syndrome, the PTEN hamartoma tumor syndrome (including Cowden's syndrome and Bannayan-Riley-Ruvalcaba syndrome), and hereditary mixed polyposis syndrome. Diagnoses are based on clinical criteria and, in some cases, confirmed by demonstrating the presence of a germline pathogenic variant. The best understood hamartomatous polyposis syndrome is Peutz-Jeghers syndrome, caused by germline pathogenic variants in the STK11 gene. The management is focused on prevention of bleeding and mechanical obstruction of the small bowel by polyps and surveillance of organs at increased risk for cancer. Juvenile polyposis syndrome is caused by a germline pathogenic variant in either the SMAD4 or BMPR1A genes, with differing clinical courses. Patients with SMAD4 pathogenic variants may have massive gastric polyposis, which can result in gastrointestinal bleeding and/or protein-losing gastropathy. Patients with SMAD4 mutations usually have the simultaneous occurrence of hereditary hemorrhagic telangiectasia (juvenile polyposis syndrome-hereditary hemorrhagic telangiectasia overlap syndrome) that can result in epistaxis, gastrointestinal bleeding from mucocutaneous telangiectasias, and arteriovenous malformations. Germline pathogenic variants in the PTEN gene cause overlapping clinical phenotypes (known as the PTEN hamartoma tumor syndromes), including Cowden's syndrome and related disorders that are associated with an increased risk of gastrointestinal and colonic polyposis, colon cancer, and other extraintestinal manifestations and cancers. Due to the relative rarity of the hamartomatous polyposis syndromes, recommendations for management are based on few studies. This U.S Multi-Society Task Force on Colorectal Cancer consensus statement summarizes the clinical features, assesses the current literature, and provides guidance for diagnosis, assessment, and management of patients with the hamartomatous polyposis syndromes, with a focus on endoscopic management.

The gastrointestinal hamartomatous polyposis syndromes are rare, autosomal dominant disorders associated with an increased risk of benign and malignant intestinal and extraintestinal tumors. They include Peutz-Jeghers syndrome, juvenile polyposis syndrome, the PTEN hamartoma tumor syndrome (including Cowden's syndrome and Bannayan-Riley-Ruvalcaba syndrome), and hereditary mixed polyposis syndrome. Diagnoses are based on clinical criteria and, in some cases, confirmed by demonstrating the presence of a germline pathogenic variant. The best understood hamartomatous polyposis syndrome is Peutz-Jeghers syndrome, caused by germline pathogenic variants in the STK11 gene. The management is focused on prevention of bleeding and mechanical obstruction of the small bowel by polyps and surveillance of organs at increased risk for cancer. Juvenile polyposis syndrome is caused by a germline pathogenic variant in either the SMAD4 or BMPR1A genes, with differing clinical courses. Patients with SMAD4 pathogenic variants may have massive gastric polyposis, which can result in gastrointestinal bleeding and/or protein-losing gastropathy. Patients with SMAD4 mutations usually have the simultaneous occurrence of hereditary hemorrhagic telangiectasia (juvenile polyposis syndrome-hereditary hemorrhagic telangiectasia overlap syndrome) that can result in epistaxis, gastrointestinal bleeding from mucocutaneous telangiectasias, and arteriovenous malformations. Germline pathogenic variants in the PTEN gene cause overlapping clinical phenotypes (known as the PTEN hamartoma tumor syndromes), including Cowden's syndrome and related disorders that are associated with an increased risk of gastrointestinal and colonic polyposis, colon cancer, and other extraintestinal manifestations and cancers. Due to the relative rarity of the hamartomatous polyposis syndromes, recommendations for management are based on few studies. This US Multi-Society Task Force on Colorectal Cancer consensus statement summarizes the clinical features, assesses the current literature, and provides guidance for diagnosis, assessment, and management of patients with the hamartomatous polyposis syndromes, with a focus on endoscopic management.