Abstract:Juvenile polyposis syndrome (JPS) is a clinically diagnosed hamartomatous polyposis syndrome that increases the risk of gastrointestinal cancer. Approximately 40%–50% of JPS is caused by a germline disease-causing variant (DCV) in the SMAD4 or BMPR1A genes. The aim of this study was to characterize the phenotype of DCV-negative JPS and compare it with DCV-positive JPS. Herein, we analyzed a cohort of 145 individuals with JPS from nine institutions, including both pediatric and adult centers. Data analyzed incl… Show more
“…Individuals with gastric polyposis, usually in association with pathogenic variants in SMAD4 are also at risk for gastric cancer, with the lifetime risk estimated to be at least 30% and median age of diagnosis is 58 years ; this has not been reported in association with BMPR1A pathogenic variants. 67,87–91 Estimates of gastrointestinal cancer risk range from 11% 68 to 55%, 89 but none of the studies are prospective long-term studies (which would lead to underestimates), and all are prone to referral-based ascertainment bias (overestimates). Question: At what age should colonoscopic and upper endoscopic surveillance begin in individuals identified with juvenile polyposis syndrome? Recommendation: We suggest initiating colonoscopic and upper endoscopic surveillance at age 12–15 years, or earlier if symptomatic. Surveillance should be repeated every 1–3 years depending on polyp burden.…”
Section: Juvenile Polyposis Syndromementioning
confidence: 99%
“…Individuals with gastric polyposis, usually in association with pathogenic variants in SMAD4 are also at risk for gastric cancer, with the lifetime risk estimated to be at least 30% and median age of diagnosis is 58 years; this has not been reported in association with BMPR1A pathogenic variants. 67,[87][88][89][90][91] Estimates of gastrointestinal cancer risk range from 11% 68 to 55%, 89 but none of the studies are prospective long-term studies (which would lead to underestimates), and all are prone to referral-based ascertainment bias (overestimates).…”
Section: Gastrointestinal Polyposis and Cancermentioning
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.
“…Individuals with gastric polyposis, usually in association with pathogenic variants in SMAD4 are also at risk for gastric cancer, with the lifetime risk estimated to be at least 30% and median age of diagnosis is 58 years ; this has not been reported in association with BMPR1A pathogenic variants. 67,87–91 Estimates of gastrointestinal cancer risk range from 11% 68 to 55%, 89 but none of the studies are prospective long-term studies (which would lead to underestimates), and all are prone to referral-based ascertainment bias (overestimates). Question: At what age should colonoscopic and upper endoscopic surveillance begin in individuals identified with juvenile polyposis syndrome? Recommendation: We suggest initiating colonoscopic and upper endoscopic surveillance at age 12–15 years, or earlier if symptomatic. Surveillance should be repeated every 1–3 years depending on polyp burden.…”
Section: Juvenile Polyposis Syndromementioning
confidence: 99%
“…Individuals with gastric polyposis, usually in association with pathogenic variants in SMAD4 are also at risk for gastric cancer, with the lifetime risk estimated to be at least 30% and median age of diagnosis is 58 years; this has not been reported in association with BMPR1A pathogenic variants. 67,[87][88][89][90][91] Estimates of gastrointestinal cancer risk range from 11% 68 to 55%, 89 but none of the studies are prospective long-term studies (which would lead to underestimates), and all are prone to referral-based ascertainment bias (overestimates).…”
Section: Gastrointestinal Polyposis and Cancermentioning
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.
“… 99 There are other further phenotypic differences in JPS between individuals with either a SMAD4 or BMPR1A PV, and those without an identified molecular explanation. 97 , 100 …”
Section: Introductionmentioning
confidence: 99%
“… 105 The number of gastric juvenile polyps can vary, ranging between a few (1–4 polyps), multiple (5–99 polyps) or massive (>100 polyps) – with “few” being most common in patients with BMPR1A PV and “multiple” in SMAD4 PV. 103 Gastrectomy may be required in a subset of JPS to due to the enormous polyp burden or cancer, 100 , 106 and there are reports of individuals with SMAD4 -related JPS presenting with massive gastric polyposis with obstructive symptoms and hypergastrinemia. 103 , 107 Further, SMAD4 PV have been identified in some cases of Ménétrier disease, which is characterized by hypertrophic gastropathy resulting in giant mucosal folds in the proximal part of the stomach.…”
Gastric cancer is one of the most significant causes of cancer-related morbidity and mortality worldwide. Recognized modifiable risk factors include
Helicobacter pylori
infection, geographic location, select dietary factors, tobacco use and alcohol consumption. In addition, multiple hereditary cancer predisposition syndromes are associated with significantly elevated gastric cancer risk. Endoscopic surveillance in hereditary gastric cancer predisposition syndromes has the potential to identify gastric cancer at earlier and more treatable stages, as well as to prevent development of gastric cancer through identification of precancerous lesions. However, much uncertainty remains regarding use of endoscopic surveillance in hereditary gastric cancer predisposition syndromes, including whether or not it should be routinely performed, the surveillance interval and age of initiation, cost-effectiveness, and whether surveillance ultimately improves survival from gastric cancer for these high-risk individuals. In this review, we outline the hereditary gastric cancer predisposition syndromes associated with the highest gastric cancer risks. Additionally, we cover current evidence and guidelines addressing hereditary gastric cancer risk and surveillance in these syndromes, along with current challenges and limitations that emphasize a need for continued research in this field.
“…It has recently been shown that phenotypic differences exist between individuals with and without a germline variant in BMPR1A or SMAD4 . For patients without a germline variant, this includes a younger age at presentation, polyps predominantly in the lower gastrointestinal tract, and lower risk of requiring colectomy or gastrectomy (5). It is likely that with time, additional genetic changes related to JPS predisposition will be discovered.…”
Juvenile polyposis syndrome (JPS) is a childhood polyposis syndrome with up to a 50% lifetime risk of gastrointestinal cancer. Germline pathogenic variants in BMPR1A and SMAD4 are responsible for around 40% of cases of JPS, but for the majority of individuals, the underlying genetic cause is unknown. We identified a family for which polyposis spanned four generations, and the proband had a clinical diagnosis of JPS. Next-generation sequencing was conducted, followed by Sanger sequencing confirmation. We identified an internal deletion of the FOCAD gene in all family members tested that altered the reading frame and is predicted to be pathogenic. We conclude that inactivation of the FOCAD gene is likely to cause JPS in this family.
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