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2.
Eur J Hum Genet ; 32(6): 731-735, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38627541

ABSTRACT

Constitutional loss of SMAD4 function results in Juvenile Polyposis-Hereditary Haemorrhagic Telangiectasia Overlap Syndrome (JP-HHT). A retrospective multi-centre case-note review identified 28 patients with a pathogenic SMAD4 variant from 13 families across all Scottish Clinical Genetics Centres. This provided a complete clinical picture of the Scottish JP-HHT cohort. Colonic polyps were identified in 87% (23/28) and gastric polyps in 67% (12/18) of screened patients. Complication rates were high: 43% (10/23) of patients with polyps required a colectomy and 42% (5/12) required a gastrectomy. Colorectal cancer occurred in 25% (7/28) of patients, at a median age of 33 years. Pulmonary arteriovenous malformations were identified in 42% (8/19) of screened patients. 88% (23/26) and 81% (17/21) of patients exhibited JP and HHT features respectively, with 70% (14/20) demonstrating features of both conditions. We have shown that individuals with a pathogenic SMAD4 variant are all at high risk of both gastrointestinal neoplasia and HHT-related vascular complications, requiring a comprehensive screening programme.


Subject(s)
Intestinal Polyposis , Smad4 Protein , Telangiectasia, Hereditary Hemorrhagic , Humans , Smad4 Protein/genetics , Telangiectasia, Hereditary Hemorrhagic/genetics , Telangiectasia, Hereditary Hemorrhagic/pathology , Female , Male , Adult , Middle Aged , Intestinal Polyposis/genetics , Intestinal Polyposis/congenital , Intestinal Polyposis/pathology , Intestinal Polyposis/diagnosis , Adolescent , Scotland , Neoplastic Syndromes, Hereditary/genetics , Neoplastic Syndromes, Hereditary/pathology , Neoplastic Syndromes, Hereditary/diagnosis , Child , Mutation , Retrospective Studies , Aged
3.
World J Gastroenterol ; 30(8): 984-990, 2024 Feb 28.
Article in English | MEDLINE | ID: mdl-38516236

ABSTRACT

BACKGROUND: Cronkhite-Canada syndrome (CCS) is a rare, noninherited disease characterized by gastrointestinal polyposis with diarrhea and ectodermal abnormalities. CCS polyps are distributed through the whole digestive tract, and they are common in the stomach and colon but very uncommon in the esophagus. CASE SUMMARY: Here, we present a case of a 63-year-old man with skin hyperpigmentation accompanied by diarrhea, alopecia, and loss of his fingernails. Laboratory data indicated anemia, hypoalbuminemia, hypocalcemia, hypokalemia, and positive fecal occult blood. Endoscopy showed numerous polyps scattered throughout the digestive tract, including the esophagus. He was treated with nutritional support and glucocorticoids with remission of his symptoms. CONCLUSION: Comprehensive treatment led by hormonal therapy can result in partial or full remission of clinical symptoms. Treatment should be individualized for each patient according to their therapy response. Surveillance endoscopy is necessary for assessing mucosal disease activity and detecting malignant transformation.


Subject(s)
Endoscopy, Gastrointestinal , Intestinal Polyposis , Male , Humans , Middle Aged , Endoscopy, Gastrointestinal/adverse effects , Glucocorticoids/therapeutic use , Esophagus/pathology , Intestinal Polyposis/complications , Intestinal Polyposis/diagnosis , Intestinal Polyposis/therapy , Diarrhea/etiology
4.
Orphanet J Rare Dis ; 19(1): 35, 2024 Feb 01.
Article in English | MEDLINE | ID: mdl-38297356

ABSTRACT

BACKGROUND: Cronkhite-Canada syndrome (CCS) is a rare, nonhereditary disease characterized by diffuse gastrointestinal polyposis and ectodermal abnormalities. Although it has been proposed to be a chronic inflammatory condition, direct evidence of its pathogenesis is lacking. This study aims to investigate the pathophysiology of CCS by analyzing transcriptomic changes in the colonic microenvironment. METHODS: Next-generation sequencing-based genome-wide transcriptional profiling was performed on colonic hamartomatous polyps from four CCS patients and normal colonic mucosa from four healthy volunteers. Analyses of differential expression and multiple enrichment analyses were conducted from the molecular level to the cellular level. Quantitative real-time PCR (qRT-PCR) was carried out to validate the sequencing accuracy in samples from six CCS patients and six healthy volunteers. RESULTS: A total of 543 differentially expressed genes were identified, including an abundance of CC- and CXC-chemokines. Innate immune response-related pathways and processes, such as leukocyte chemotaxis, cytokine production, IL-17, TNF, IL-1 and NF-kB signaling pathways, were prominently enhanced in CCS colonic polyps. Upregulation of wound healing, epithelial-mesenchymal transition, Wnt, and PI3K-Akt signaling pathways were also observed. Enrichment analyses at different levels identified extracellular structure disorganization, dysfunction of the gut mucosal barrier, and increased angiogenesis. Validation by qRT-PCR confirmed increased expression of the LCN2, IL1B, CXCL1, and CXCL3 genes in CCS colonic polyps. CONCLUSIONS: This case-control whole transcriptome analysis of active CCS colonic hamartomatous polyps revealed intricate molecular pathways, emphasizing the role of the innate immune response, extracellular matrix disorganization, inflammatory cell infiltration, increased angiogenesis, and potential epithelial to mesenchymal transition. These findings supports CCS as a chronic inflammatory condition and sheds light on potential therapeutic targets, paving the way for more effective and personalized management of CCS in the future.


Subject(s)
Colonic Polyps , Intestinal Polyposis , Humans , Colonic Polyps/genetics , Colonic Polyps/pathology , Exome Sequencing , Epithelial-Mesenchymal Transition , Phosphatidylinositol 3-Kinases , Intestinal Polyposis/genetics , Intestinal Polyposis/pathology , Interleukin-1
5.
Endoscopy ; 56(2): 125-130, 2024 Feb.
Article in English | MEDLINE | ID: mdl-37699523

ABSTRACT

BACKGROUND: Large (≥20mm) adenomatous anastomotic polyps (LAAPs) are uncommon. Data pertaining to their prevalence, characteristics, and the efficacy of endoscopic resection (ER) are absent. A safe and effective strategy for ER would reduce morbidity and healthcare costs. METHODS: Large nonpedunculated colorectal polyps of ≥20mm (LNPCPs) referred for ER were prospectively studied. Multiple data points were recorded including anastomotic location, polyp morphology, resection modality, complications, and technical success. RESULTS: Over 7 years until November 2022, 2629 lesions were referred. Of these, 10 (0.4%) were LAAPs (median size 35 mm [interquartile range (IQR) 30-40mm]). All LAAPs were removed by piecemeal endoscopic mucosal resection (EMR), most (n=9; 90%) in combination with cold-forceps avulsion with adjuvant snare-tip soft coagulation (CAST). On comparison of the LAAP group with the conventional LNPCP group, CAST was more commonly used (90% vs. 9%; P<0.001) and deep mural injury (DMI) type II was more frequent (40% vs. 11%, P=0.003); however, significant DMI (III-V) did not occur. At 6 month (IQR 5.25-6 months) surveillance, there was no recurrence in any of the 10 cases. There were no serious adverse events. CONCLUSIONS: LAAPs present unique challenges owing to their location overlying an anastomosis. Despite these challenges they can be safely and effectively managed endoscopically without recurrence at endoscopic follow-up.


Subject(s)
Adenomatous Polyps , Colonic Polyps , Colorectal Neoplasms , Endoscopic Mucosal Resection , Intestinal Polyposis , Humans , Adenomatous Polyps/pathology , Endoscopic Mucosal Resection/adverse effects , Anastomosis, Surgical/adverse effects , Intestinal Polyposis/etiology , Retrospective Studies , Colonic Polyps/surgery , Colonic Polyps/pathology , Colonoscopy/adverse effects , Colorectal Neoplasms/pathology
6.
Clin J Gastroenterol ; 17(1): 23-28, 2024 Feb.
Article in English | MEDLINE | ID: mdl-37950802

ABSTRACT

A 50-year-old female was diagnosed with gastric hyperplastic polyps 7 years before and was followed up at another hospital. She was referred to our hospital because of the growth of gastric polyps and progression of anemia. She had no family history of polyposis. The polyps were observed only in the stomach, increased in size and number, and the erythematous edema got worse. Endoscopic mucosal resection (EMR) of the gastric polyp was performed. Pathologically, the gastric polyp was hamartomatous polyp, and the intervening mucosa between polyps showed no atypical structure without inflammation. Given that gastric juvenile polyposis (GJP) was clinically suspected, a genetic test using peripheral blood was performed. Target resequencing and Sanger sequencing analysis revealed a nonsense mutation in the SMAD4 gene at codon 169. The mutation was detected at a low frequency of 11%, and considered a mosaic mutation. Therefore, she was diagnosed with a sporadic GJP, and total gastrectomy was performed. Immunostaining of SMAD4 for the resected specimen showed a mixture of stained and unstained area in the epithelium of the polyp, indicating partial loss of SMAD4 expression. To our knowledge, this is the first reported case of GJP with a nonsense SMAD4 mutation at codon 169 in a mosaic pattern.


Subject(s)
Adenomatous Polyps , Intestinal Polyposis , Neoplastic Syndromes, Hereditary , Polyps , Stomach Neoplasms , Female , Humans , Middle Aged , Codon, Nonsense , Stomach Neoplasms/genetics , Stomach Neoplasms/surgery , Stomach Neoplasms/diagnosis , Smad4 Protein/genetics , Smad4 Protein/metabolism
7.
Mol Genet Genomic Med ; 12(1): e2348, 2024 Jan.
Article in English | MEDLINE | ID: mdl-38146137

ABSTRACT

BACKGROUND: Juvenile Polyposis Syndrome (JPS) is a rare autosomal dominant hereditary disorder characterized by the development of multiple hamartomatous gastrointestinal polyps. Here, we present a case of JPS with a mosaic variant in SMAD4. METHODS: Exome sequencing TRIO analysis, using germline DNA from the biological mother and father along with the index case (IC). RESULTS: A 46-year-old male with no family history of cancer presented with chronic iron deficiency anemia and was diagnosed with massive gastric polyposis (≥100 polyps). At the age of 59, he underwent a total gastrectomy, revealing numerous polyps occupying the entire gastric mucosa, including a 5 cm gastric hyperplastic polyp with high-grade dysplasia and focal adenocarcinoma. TRIO analysis identified the c.386A>C p.(Asn129Thr) variant in the SMAD4 gene at an allele frequency (AF) of 22%, suggesting its mosaic origin. Subsequently, the variant was found in heterozygosity in the IC's son, who exhibited two subcentimeter polyps in the colon and seven inflammatory gastric polyps with gastric inflammatory areas and hyperplasia, suggesting that the c.386A>C p.(Asn129Thr) variant in SMAD4 segregated with the phenotype. CONCLUSION: Our study provides evidence supporting the classification of the c.386A>C p.(Asn129Thr) variant in SMAD4 as a likely pathogenic variant. This finding contributes to improved accuracy in the diagnosis and genetic counseling of JPS.


Subject(s)
Adenomatous Polyps , Intestinal Polyposis/congenital , Neoplastic Syndromes, Hereditary , Stomach Neoplasms , Male , Humans , Middle Aged , Stomach Neoplasms/genetics , Neoplastic Syndromes, Hereditary/genetics , Neoplastic Syndromes, Hereditary/pathology , Smad4 Protein/genetics
9.
J Clin Invest ; 133(21)2023 11 01.
Article in English | MEDLINE | ID: mdl-37909332

ABSTRACT

Cronkhite-Canada Syndrome (CCS) is a rare, noninherited polyposis syndrome affecting 1 in every million individuals. Despite over 50 years of CCS cases, the etiopathogenesis and optimal treatment for CCS remains unknown due to the rarity of the disease and lack of model systems. To better understand the etiology of CCS, we generated human intestinal organoids (HIOs) from intestinal stem cells isolated from 2 patients. We discovered that CCS HIOs are highly proliferative and have increased numbers of enteroendocrine cells producing serotonin (also known as 5-hydroxytryptamine or 5HT). These features were also confirmed in patient tissue biopsies. Recombinant 5HT increased proliferation of non-CCS donor HIOs and inhibition of 5HT production in the CCS HIOs resulted in decreased proliferation, suggesting a link between local epithelial 5HT production and control of epithelial stem cell proliferation. This link was confirmed in genetically engineered HIOs with an increased number of enteroendocrine cells. This work provides a new mechanism to explain the pathogenesis of CCS and illustrates the important contribution of HIO cultures to understanding disease etiology and in the identification of novel therapies. Our work demonstrates the principle of using organoids for personalized medicine and sheds light on how intestinal hormones can play a role in intestinal epithelial proliferation.


Subject(s)
Colorectal Neoplasms , Intestinal Polyposis , Humans , Serotonin , Intestines , Organoids/pathology , Colorectal Neoplasms/pathology , Intestinal Polyposis/genetics , Intestinal Polyposis/pathology
15.
United European Gastroenterol J ; 11(8): 745-749, 2023 10.
Article in English | MEDLINE | ID: mdl-37498302

ABSTRACT

INTRODUCTION: The risk of cancer in patients with solitary colorectal juvenile polyps (JPs) is poorly investigated and several studies have reported polyps with dysplastic and adenomatous alterations. We aimed to investigate the long-term risk of cancer and mortality in these patients by merging data from national registers and comparing them to a matched control cohort. MATERIALS AND METHODS: Patients with a solitary JP were identified in The Danish National Pathology Register and Data Bank (DNPR). The included patients were matched on sex, age, and place of birth with 50 controls. The groups were then analyzed for risk of cancer using the Danish Cancer Registry and mortality using the Danish Cause of Death Registry. RESULTS: We identified 1781 patients with solitary JPs and matched them with 83,713 controls. The mean follow-up time was 7.65 years for cases and 7.36 years for controls. The risk of cancer, including colorectal cancer, did not differ for the two groups and when adjusting for sex and year of birth, the hazard ratio (HR) was 1.15 (confidence interval [CI] 95% 0.94-1.41, p = 0.162). There was no increased risk of death (HR: 1.07, CI 95% 0.88-1.30, p = 0.486). The risk did not differ for different age groups or sex. CONCLUSION: There is no increased risk of cancer or mortality for patients with solitary colorectal JPs. Thus, endoscopic follow-up may be safely omitted in these patients.


Subject(s)
Adenoma , Colorectal Neoplasms , Intestinal Polyposis , Humans , Cohort Studies , Intestinal Polyps , Intestinal Polyposis/pathology , Adenoma/pathology , Colorectal Neoplasms/epidemiology , Colorectal Neoplasms/pathology
19.
J Investig Med High Impact Case Rep ; 11: 23247096231179451, 2023.
Article in English | MEDLINE | ID: mdl-37278538

ABSTRACT

Cronkhite-Canada syndrome (CCS) is an acquired polyposis syndrome with gastrointestinal and extraintestinal manifestations. Given its rarity and lack of standard treatment, diagnosis and treatment are challenging. Steroid therapy and nutritional support are conventional treatments. There is no consensus on management of steroid-refractory cases. Here, we report the diagnosis and treatment course of a 54-year-old Asian male with CCS, whose initial treatment with prednisone 60 mg a day led to partial response and disease flare up during prednisone tapering. The use of infliximab and azathioprine led to promising remission of his symptoms.


Subject(s)
Intestinal Polyposis , Humans , Male , Middle Aged , Prednisone/therapeutic use , Intestinal Polyposis/drug therapy , Intestinal Polyposis/diagnosis , Intestinal Polyposis/pathology , Azathioprine/therapeutic use , Necrosis
20.
Fam Cancer ; 22(4): 429-436, 2023 10.
Article in English | MEDLINE | ID: mdl-37354305

ABSTRACT

Juvenile polyposis syndrome (JPS) is a hereditary hamartomatous polyposis syndrome characterized by gastrointestinal juvenile polyps and increased risk of gastrointestinal cancer. Germline pathogenic variants are detected in SMAD4 or BMPR1A, however in a significant number of patients with JPS, the etiology is unknown. From Danish registers, and genetic department and laboratories, we identified all patients in Denmark with a clinical diagnosis of JPS and/or a pathogenic variant in BMPR1A or SMAD4. In patients where no variant had been detected, we performed genetic analysis, including whole genome sequencing. We collected clinical information on all patients to investigate the phenotypic spectrum. Sixty-six patients (mean age 40 years) were included of whom the pathogenic variant was unknown in seven patients. We detected a pathogenic variant in SMAD4 or PTEN in additional three patients and thus ≈ 95% of patients had a pathogenic germline variant. Endoscopic information was available in fifty-two patients (79%) and of these 31 (60%) fulfilled the clinical criteria of JPS. In 41 patients (79%), other types of polyps than juvenile had been removed. Our results suggest that almost all patients with a clinical diagnosis of JPS has a pathogenic variant in mainly BMPR1A, SMAD4, and more rarely PTEN. However, not all patients with a pathogenic variant fulfil the clinical criteria of JPS. We also demonstrated a wide clinical spectrum, and that the histopathology of removed polyps varied.


Subject(s)
Gastrointestinal Neoplasms , Intestinal Polyposis , Neoplastic Syndromes, Hereditary , Polyps , Humans , Adult , Intestinal Polyposis/genetics , Neoplastic Syndromes, Hereditary/genetics , Germ-Line Mutation , Bone Morphogenetic Protein Receptors, Type I/genetics , Smad4 Protein/genetics , Whole Genome Sequencing
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