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Johan G A Offerhaus - One of the best experts on this subject based on the ideXlab platform.
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absence of smad9v90m mutation in Juvenile Polyposis Syndrome
Journal of Clinical Pathology, 2017Co-Authors: Lysanne Graafmans, Francis M Giardiello, Folkert H M Morsink, Johan G A Offerhaus, Lodewijk A A BrosensAbstract:Juvenile Polyposis Syndrome (JPS) is a rare autosomal dominant disease characterised by multiple distinct hamartomatous polyps in the gastrointestinal tract and an increased risk of colorectal cancer.1 A germline mutation in SMAD4 or BMPR1A is found in approximately 50%–60% of patients with JPS, suggesting existence of other genes that predispose to JPS.2 ,3 We investigated the recently reported SMAD9v90m mutation in our well-defined and genetically characterised cohort of patients with JPS. The diagnosis of JPS is based on one of the following clinical criteria: (1) more than three to …
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smad4 immunohistochemistry reflects genetic status in Juvenile Polyposis Syndrome
Clinical Cancer Research, 2010Co-Authors: Danielle Langeveld, Francis M Giardiello, Folkert H M Morsink, Johan G A Offerhaus, Arnout W Van Hattem, Wendy W J De Leng, Fiebo Ten J W KateAbstract:Purpose: Juvenile Polyposis Syndrome (JPS) can be caused by a germline defect of the SMAD4 gene. Somatic inactivation of SMAD4 occurs in pancreatic and colorectal cancers and is reflected by loss of SMAD4 immunohistochemistry. Here, SMAD4 immunohistochemistry as a marker of SMAD4 gene status and the role of SMAD4 in the adenoma-carcinoma sequence in neoplastic progression in JPS are studied. Experimental Design: Twenty polyps with a SMAD4 germline defect and 38 control polyps were studied by SMAD4 immunohistochemistry. Inactivation of the SMAD4 wild-type allele was studied in dysplastic epithelium and in areas with aberrant SMAD4 expression. APC , β-catenin, p53, and K-ras were studied to evaluate the adenoma-carcinoma sequence. Results: Nine of 20 polyps with a SMAD4 germline defect showed loss of epithelial SMAD4 expression. Loss of heterozygosity of SMAD4 was found in five polyps and a somatic stop codon mutation was found in two polyps without loss of heterozygosity. Remarkably, somatic inactivation of epithelial SMAD4 did not always coincide with dysplasia and aberrant p53 staining was found in four of six dysplastic polyps with normal SMAD4 staining. One K-ras mutation was found in nine Juvenile polyps with dysplasia. No evidence for Wnt activation was found. Conclusions: SMAD4 immunohistochemistry mirrors genetic status and provides a specific adjunct in the molecular diagnosis of JPS. However, epithelial SMAD4 inactivation is not required for polyp formation and is not obligatory for neoplastic progression in JPS. Instead, different routes to neoplasia in JPS caused by germline SMAD4 mutation seem to be operative, including somatic loss of SMAD4 and p53 inactivation without somatic loss of SMAD4 . Clin Cancer Res; 16(16); 4126–34. ©2010 AACR.
Carol A Burke - One of the best experts on this subject based on the ideXlab platform.
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prevalence of thoracic aortopathy in patients with Juvenile Polyposis Syndrome hereditary hemorrhagic telangiectasia due to smad4
American Journal of Medical Genetics Part A, 2015Co-Authors: Brandie Heald, Carol A Burke, L. Laguardia, Margaret Omalley, Christina Rigelsky, Rocio Moran, Kenneth G ZahkaAbstract:Hereditary hemorrhagic telangiectasia (HHT) is characterized by abnormal vascular structures that may present as epistaxis, telangiectasias, and/or arteriovenous malformations. The genes associated with HHT (ACVRL1, ENG, and SMAD4) are members of the TGFβ pathway. Other Syndromes associated with abnormalities in TGFβ signaling include Marfan Syndrome, Loeys-Dietz Syndrome and related disorders. These disorders have aortic disease as a prominent finding. While there are case reports of patients with HHT and aortopathy (dilatation/aneurysm, dissection, and rupture), this has not been systematically investigated. We conducted a retrospective chart review to determine the prevalence of aortopathy in an HHT cohort. Patients from a single institution were identified who met the Curacao Criteria for a clinical diagnosis of HHT and/or had a mutation in ACVRL1, ENG, or SMAD4 and underwent echocardiogram. Two-dimensional echocardiograms were reviewed by a single pediatric cardiologist, and data were collected on demographics, genotype, HHT features, aortic root measurements, past medical history, and family history. Z scores and nomograms were utilized to identify abnormal results. Twenty-six patients from 15 families (one ACVRL1, four ENG, eight SMAD4, and two clinical diagnoses) were included in the analysis. Aortopathy was found in 6/26 (23%) patients; all had SMAD4 mutations. In our cohort, 6/16 (38%) SMAD4 mutation carriers had evidence of aortopathy. These data suggest that aortopathy could be part of the spectrum of SMAD4-induced HHT manifestations. Routine aortic imaging, including measurements of the aorta, should be considered in patients with SMAD4 mutations to allow for appropriate medical and surgical recommendations.
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genotype defined cancer risk in Juvenile Polyposis Syndrome
British Journal of Surgery, 2014Co-Authors: Erman Aytac, Brandie Heald, Carol A Burke, Matthew F. Kalady, L. Laguardia, B Sulu, M Omalley, Feza H Remzi, James M ChurchAbstract:Background Germline mutations in SMAD4 and BMPR1A disrupt the transforming growth factor β signal transduction pathway, and are associated with Juvenile Polyposis Syndrome. The effect of genotype on the pattern of disease in this Syndrome is unknown. This study evaluated the differential impact of SMAD4 and BMPR1A gene mutations on cancer risk and oncological phenotype in patients with Juvenile Polyposis Syndrome. Methods Patients with Juvenile Polyposis Syndrome and germline SMAD4 or BMPR1A mutations were identified from a prospectively maintained institutional registry. Medical records were reviewed and the clinical patterns of disease were analysed. Results Thirty-five patients had germline mutations in either BMPR1A (8 patients) or SMAD4 (27). Median follow-up was 11 years. Colonic phenotype was similar between patients with SMAD4 and BMPR1A mutations, whereas SMAD4 mutations were associated with larger polyp numbers (number of patients with 50 or more gastric polyps: 14 versus 0 respectively). The numbers of patients with rectal polyps was comparable between BMPR1A and SMAD4 mutation carriers (5 versus 17). No patient was diagnosed with cancer in the BMPR1A group, whereas four men with a SMAD4 mutation developed gastrointestinal (3) or extraintestinal (1) cancer. The gastrointestinal cancer risk in patients with Juvenile Polyposis Syndrome and a SMAD4 mutation was 11 per cent (3 of 27). Conclusion The SMAD4 genotype is associated with a more aggressive upper gastrointestinal malignancy risk in Juvenile Polyposis Syndrome.
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The prevalence of hereditary hemorrhagic telangiectasia in Juvenile Polyposis Syndrome
Diseases of the Colon and Rectum, 2012Co-Authors: Margaret O'malley, James Church, Joseph Parambil, Brandie Heald, Matthew F. Kalady, L. Laguardia, Charis Eng, Carol A BurkeAbstract:BACKGROUND: Juvenile Polyposis Syndrome is a dominant GI Polyposis Syndrome defined by ≥ 5 GI Juvenile polyps or ≥ 1 Juvenile polyps with a family history of Juvenile Polyposis. Mutations in BMPR1A or SMAD4 are found in 50% of individuals. Hereditary hemorrhagic telangiectasia is a dominant disorder characterized by epistaxis, visceral arteriovenous malformations, and telangiectasias. Hereditary hemorrhagic telangiectasia is diagnosed when ≥ 3 criteria including clinical manifestations or a family history, are present. A Juvenile Polyposis-hereditary hemorrhagic telangiectasia overlap Syndrome has previously been reported in 22% of patients with Juvenile Polyposis due to a SMAD4 mutation.\n\nOBJECTIVE: Our objective was to determine the prevalence and clinical manifestations of hereditary hemorrhagic telangiectasia by Curacao criteria in our Juvenile Polyposis SMAD4 patients.\n\nDESIGN, PATIENTS, AND SETTING: This was a cohort study of Juvenile Polyposis patients in our inherited colon cancer registries. Hereditary hemorrhagic telangiectasia manifestations were obtained from medical records, patient contact, and/or prospective hereditary hemorrhagic telangiectasia screening. The Curacao criteria was used for diagnosis of hereditary hemorrhagic telangiectasia (≥ 3 criteria diagnostic; 2 criteria suspect of).\n\nMAIN OUTCOME MEASURES: Prevalence and clinical manifestations of hereditary hemorrhagic telangiectasia in Juvenile Polyposis SMAD4 patients.\n\nRESULTS: Forty-one Juvenile Polyposis families were identified. Genetic testing was available for individuals within 18 families. SMAD4 mutations were found in 21 relatives in 9 families. Eighty-one percent of SMAD4 patients had hereditary hemorrhagic telangiectasia and 14% were suspected of having hereditary hemorrhagic telangiectasia. Epistaxis and asthma are the most common symptoms in our overlap patients. Symptomatic and subclinical arteriovenous malformations were noted near universally.\n\nLIMITATIONS: There was a single, tertiary referral center.\n\nCONCLUSIONS: Nearly all Juvenile Polyposis SMAD4 patients have the overlap Syndrome. The clinical implications and need for hereditary hemorrhagic telangiectasia screening are important factors for genetic testing in Juvenile Polyposis. Health care providers must be cognizant of the Juvenile Polyposis-hereditary hemorrhagic telangiectasia overlap Syndrome and the implications for management of these patients.
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the prevalence of hereditary hemorrhagic telangiectasia in Juvenile Polyposis Syndrome patients with smad4 mutations
Hereditary Cancer in Clinical Practice, 2011Co-Authors: Margaret Omalley, Joseph Parambil, Matthew F. Kalady, L. Laguardia, Charis Eng, James M Church, Brandie Leach, Carol A BurkeAbstract:Background Juvenile Polyposis Syndrome (JPS) is defined by the presence of ≥ 5 colorectal Juvenile polyps or any number of Juvenile polyps in an individual with a family history of JPS. Genetic alterations including either point mutations or large rearrangements in BMPR1A or SMAD4 are found in 50% of affected individuals. Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant disease diagnosed upon the presence of epistaxis, visceral arteriovenous malformations (AVM) or mucutaneous telangiectasias. HHT is diagnosed when there are ≥ 3 manifestations and is suspected when there are at least 2 manifestations. Most HHT cases are caused by a germline mutation in ALK1 or ENG ,m embers of the TGFb signaling pathway. Approximately 22% of patients with Juvenile Polyposis Syndrome (JPS) due to a SMAD4 mutation have been reported to also have HHT [1]. Most prior publications have few patients and no systematic approach to screening, so the true incidence of the combined JPS/HHT Syndrome is not known. Our aim was to determine the prevalence of HHT in our patients with JPS with a SMAD4 mutation including those who underwent systematic screening for AVM’s. Methods JPS patients were identified from a comprehensive Polyposis database using Cologene© software. Families carrying a germline SMAD4 mutation were studied by screening affected patients for cutaneous telangiectases and with cardiac bubble ECHO, CAT scan chest, or MRI of brain for other AVMs. Results
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smad4 mutation and the combined Syndrome of Juvenile Polyposis Syndrome and hereditary haemorrhagic telangiectasia
Thorax, 2010Co-Authors: Nithya K Iyer, Brandie Leach, Carol A Burke, Joseph ParambilAbstract:Juvenile Polyposis Syndrome (JPS) and hereditary haemorrhagic telangiectasia (HHT) are autosomal dominant disorders with characteristic clinical phenotypes. Recently, reports of the combined Syndrome of JPS and HHT have been described in individuals with mutations in the SMAD4 gene, whose product—SMAD4—is a critical intracellular effector in the signalling pathway of transforming growth factor β (TGFβ). This report describes a 24-year-old man who presented to the Respiratory Institute after colectomy for JPS with a SMAD4 mutation and who was subsequently diagnosed to have HHT with asymptomatic cerebral and pulmonary arteriovenous malformations (AVMs). Patients with JPS due to a SMAD4 mutation should be screened for the vascular lesions associated with HHT, especially occult AVMs in visceral organs, which may potentially present catastrophically with serious medical consequences.
Brandie Heald - One of the best experts on this subject based on the ideXlab platform.
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exome sequencing reveals germline smad9 mutation that reduces phosphatase and tensin homolog expression and is associated with hamartomatous Polyposis and gastrointestinal ganglioneuromas
Gastroenterology, 2015Co-Authors: Joanne Ngeow, Brandie Heald, Wanfeng Yu, Lamis Yehia, Farshad Niazi, Jinlian Chen, Xuhua Tang, Todd Romigh, Lisa Tuckerkellogg, Haiwei SongAbstract:Hamartomatous Polyposis Syndromes (HPS) account for a small but appreciable proportion of inherited gastrointestinal cancer predisposition Syndromes; patients with HPS have an increased risk for colon and extracolonic malignancies. We present a unique case of familial Juvenile Polyposis Syndrome associated with gastrointestinal ganglioneuromas of unknown etiology. The patient was tested for HPS-associated genes, but no mutation was detected. Exome sequencing identified a germline heterozygous mutation in SMAD9 (SMAD9V90M). This mutation was predicted to be an activating mutation. HEK cells transfected to express SMAD9V90M had reduced expression of phosphatase and tensin homolog; this reduction was also observed in a polyp from the patient. We have therefore identified a new susceptibility locus for HPS. Patients with hamartomatous Polyposis in the colon associated with ganglioneuromatosis should be referred for genetic assessments.
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prevalence of thoracic aortopathy in patients with Juvenile Polyposis Syndrome hereditary hemorrhagic telangiectasia due to smad4
American Journal of Medical Genetics Part A, 2015Co-Authors: Brandie Heald, Carol A Burke, L. Laguardia, Margaret Omalley, Christina Rigelsky, Rocio Moran, Kenneth G ZahkaAbstract:Hereditary hemorrhagic telangiectasia (HHT) is characterized by abnormal vascular structures that may present as epistaxis, telangiectasias, and/or arteriovenous malformations. The genes associated with HHT (ACVRL1, ENG, and SMAD4) are members of the TGFβ pathway. Other Syndromes associated with abnormalities in TGFβ signaling include Marfan Syndrome, Loeys-Dietz Syndrome and related disorders. These disorders have aortic disease as a prominent finding. While there are case reports of patients with HHT and aortopathy (dilatation/aneurysm, dissection, and rupture), this has not been systematically investigated. We conducted a retrospective chart review to determine the prevalence of aortopathy in an HHT cohort. Patients from a single institution were identified who met the Curacao Criteria for a clinical diagnosis of HHT and/or had a mutation in ACVRL1, ENG, or SMAD4 and underwent echocardiogram. Two-dimensional echocardiograms were reviewed by a single pediatric cardiologist, and data were collected on demographics, genotype, HHT features, aortic root measurements, past medical history, and family history. Z scores and nomograms were utilized to identify abnormal results. Twenty-six patients from 15 families (one ACVRL1, four ENG, eight SMAD4, and two clinical diagnoses) were included in the analysis. Aortopathy was found in 6/26 (23%) patients; all had SMAD4 mutations. In our cohort, 6/16 (38%) SMAD4 mutation carriers had evidence of aortopathy. These data suggest that aortopathy could be part of the spectrum of SMAD4-induced HHT manifestations. Routine aortic imaging, including measurements of the aorta, should be considered in patients with SMAD4 mutations to allow for appropriate medical and surgical recommendations.
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genotype defined cancer risk in Juvenile Polyposis Syndrome
British Journal of Surgery, 2014Co-Authors: Erman Aytac, Brandie Heald, Carol A Burke, Matthew F. Kalady, L. Laguardia, B Sulu, M Omalley, Feza H Remzi, James M ChurchAbstract:Background Germline mutations in SMAD4 and BMPR1A disrupt the transforming growth factor β signal transduction pathway, and are associated with Juvenile Polyposis Syndrome. The effect of genotype on the pattern of disease in this Syndrome is unknown. This study evaluated the differential impact of SMAD4 and BMPR1A gene mutations on cancer risk and oncological phenotype in patients with Juvenile Polyposis Syndrome. Methods Patients with Juvenile Polyposis Syndrome and germline SMAD4 or BMPR1A mutations were identified from a prospectively maintained institutional registry. Medical records were reviewed and the clinical patterns of disease were analysed. Results Thirty-five patients had germline mutations in either BMPR1A (8 patients) or SMAD4 (27). Median follow-up was 11 years. Colonic phenotype was similar between patients with SMAD4 and BMPR1A mutations, whereas SMAD4 mutations were associated with larger polyp numbers (number of patients with 50 or more gastric polyps: 14 versus 0 respectively). The numbers of patients with rectal polyps was comparable between BMPR1A and SMAD4 mutation carriers (5 versus 17). No patient was diagnosed with cancer in the BMPR1A group, whereas four men with a SMAD4 mutation developed gastrointestinal (3) or extraintestinal (1) cancer. The gastrointestinal cancer risk in patients with Juvenile Polyposis Syndrome and a SMAD4 mutation was 11 per cent (3 of 27). Conclusion The SMAD4 genotype is associated with a more aggressive upper gastrointestinal malignancy risk in Juvenile Polyposis Syndrome.
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The prevalence of hereditary hemorrhagic telangiectasia in Juvenile Polyposis Syndrome
Diseases of the Colon and Rectum, 2012Co-Authors: Margaret O'malley, James Church, Joseph Parambil, Brandie Heald, Matthew F. Kalady, L. Laguardia, Charis Eng, Carol A BurkeAbstract:BACKGROUND: Juvenile Polyposis Syndrome is a dominant GI Polyposis Syndrome defined by ≥ 5 GI Juvenile polyps or ≥ 1 Juvenile polyps with a family history of Juvenile Polyposis. Mutations in BMPR1A or SMAD4 are found in 50% of individuals. Hereditary hemorrhagic telangiectasia is a dominant disorder characterized by epistaxis, visceral arteriovenous malformations, and telangiectasias. Hereditary hemorrhagic telangiectasia is diagnosed when ≥ 3 criteria including clinical manifestations or a family history, are present. A Juvenile Polyposis-hereditary hemorrhagic telangiectasia overlap Syndrome has previously been reported in 22% of patients with Juvenile Polyposis due to a SMAD4 mutation.\n\nOBJECTIVE: Our objective was to determine the prevalence and clinical manifestations of hereditary hemorrhagic telangiectasia by Curacao criteria in our Juvenile Polyposis SMAD4 patients.\n\nDESIGN, PATIENTS, AND SETTING: This was a cohort study of Juvenile Polyposis patients in our inherited colon cancer registries. Hereditary hemorrhagic telangiectasia manifestations were obtained from medical records, patient contact, and/or prospective hereditary hemorrhagic telangiectasia screening. The Curacao criteria was used for diagnosis of hereditary hemorrhagic telangiectasia (≥ 3 criteria diagnostic; 2 criteria suspect of).\n\nMAIN OUTCOME MEASURES: Prevalence and clinical manifestations of hereditary hemorrhagic telangiectasia in Juvenile Polyposis SMAD4 patients.\n\nRESULTS: Forty-one Juvenile Polyposis families were identified. Genetic testing was available for individuals within 18 families. SMAD4 mutations were found in 21 relatives in 9 families. Eighty-one percent of SMAD4 patients had hereditary hemorrhagic telangiectasia and 14% were suspected of having hereditary hemorrhagic telangiectasia. Epistaxis and asthma are the most common symptoms in our overlap patients. Symptomatic and subclinical arteriovenous malformations were noted near universally.\n\nLIMITATIONS: There was a single, tertiary referral center.\n\nCONCLUSIONS: Nearly all Juvenile Polyposis SMAD4 patients have the overlap Syndrome. The clinical implications and need for hereditary hemorrhagic telangiectasia screening are important factors for genetic testing in Juvenile Polyposis. Health care providers must be cognizant of the Juvenile Polyposis-hereditary hemorrhagic telangiectasia overlap Syndrome and the implications for management of these patients.
Charis Eng - One of the best experts on this subject based on the ideXlab platform.
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The prevalence of hereditary hemorrhagic telangiectasia in Juvenile Polyposis Syndrome
Diseases of the Colon and Rectum, 2012Co-Authors: Margaret O'malley, James Church, Joseph Parambil, Brandie Heald, Matthew F. Kalady, L. Laguardia, Charis Eng, Carol A BurkeAbstract:BACKGROUND: Juvenile Polyposis Syndrome is a dominant GI Polyposis Syndrome defined by ≥ 5 GI Juvenile polyps or ≥ 1 Juvenile polyps with a family history of Juvenile Polyposis. Mutations in BMPR1A or SMAD4 are found in 50% of individuals. Hereditary hemorrhagic telangiectasia is a dominant disorder characterized by epistaxis, visceral arteriovenous malformations, and telangiectasias. Hereditary hemorrhagic telangiectasia is diagnosed when ≥ 3 criteria including clinical manifestations or a family history, are present. A Juvenile Polyposis-hereditary hemorrhagic telangiectasia overlap Syndrome has previously been reported in 22% of patients with Juvenile Polyposis due to a SMAD4 mutation.\n\nOBJECTIVE: Our objective was to determine the prevalence and clinical manifestations of hereditary hemorrhagic telangiectasia by Curacao criteria in our Juvenile Polyposis SMAD4 patients.\n\nDESIGN, PATIENTS, AND SETTING: This was a cohort study of Juvenile Polyposis patients in our inherited colon cancer registries. Hereditary hemorrhagic telangiectasia manifestations were obtained from medical records, patient contact, and/or prospective hereditary hemorrhagic telangiectasia screening. The Curacao criteria was used for diagnosis of hereditary hemorrhagic telangiectasia (≥ 3 criteria diagnostic; 2 criteria suspect of).\n\nMAIN OUTCOME MEASURES: Prevalence and clinical manifestations of hereditary hemorrhagic telangiectasia in Juvenile Polyposis SMAD4 patients.\n\nRESULTS: Forty-one Juvenile Polyposis families were identified. Genetic testing was available for individuals within 18 families. SMAD4 mutations were found in 21 relatives in 9 families. Eighty-one percent of SMAD4 patients had hereditary hemorrhagic telangiectasia and 14% were suspected of having hereditary hemorrhagic telangiectasia. Epistaxis and asthma are the most common symptoms in our overlap patients. Symptomatic and subclinical arteriovenous malformations were noted near universally.\n\nLIMITATIONS: There was a single, tertiary referral center.\n\nCONCLUSIONS: Nearly all Juvenile Polyposis SMAD4 patients have the overlap Syndrome. The clinical implications and need for hereditary hemorrhagic telangiectasia screening are important factors for genetic testing in Juvenile Polyposis. Health care providers must be cognizant of the Juvenile Polyposis-hereditary hemorrhagic telangiectasia overlap Syndrome and the implications for management of these patients.
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the prevalence of hereditary hemorrhagic telangiectasia in Juvenile Polyposis Syndrome patients with smad4 mutations
Hereditary Cancer in Clinical Practice, 2011Co-Authors: Margaret Omalley, Joseph Parambil, Matthew F. Kalady, L. Laguardia, Charis Eng, James M Church, Brandie Leach, Carol A BurkeAbstract:Background Juvenile Polyposis Syndrome (JPS) is defined by the presence of ≥ 5 colorectal Juvenile polyps or any number of Juvenile polyps in an individual with a family history of JPS. Genetic alterations including either point mutations or large rearrangements in BMPR1A or SMAD4 are found in 50% of affected individuals. Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant disease diagnosed upon the presence of epistaxis, visceral arteriovenous malformations (AVM) or mucutaneous telangiectasias. HHT is diagnosed when there are ≥ 3 manifestations and is suspected when there are at least 2 manifestations. Most HHT cases are caused by a germline mutation in ALK1 or ENG ,m embers of the TGFb signaling pathway. Approximately 22% of patients with Juvenile Polyposis Syndrome (JPS) due to a SMAD4 mutation have been reported to also have HHT [1]. Most prior publications have few patients and no systematic approach to screening, so the true incidence of the combined JPS/HHT Syndrome is not known. Our aim was to determine the prevalence of HHT in our patients with JPS with a SMAD4 mutation including those who underwent systematic screening for AVM’s. Methods JPS patients were identified from a comprehensive Polyposis database using Cologene© software. Families carrying a germline SMAD4 mutation were studied by screening affected patients for cutaneous telangiectases and with cardiac bubble ECHO, CAT scan chest, or MRI of brain for other AVMs. Results
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screening smad1 smad2 smad3 and smad5 for germline mutations in Juvenile Polyposis Syndrome
Gut, 1999Co-Authors: Steve Bevan, Charis Eng, R K S Phillips, Kelly Woodfordrichens, Paul Rozen, Joanne P Young, Malcolm G Dunlop, K Neale, David Markie, Miguel A RodriguezbigasAbstract:BACKGROUND AND AIMS Juvenile polyps occur in several Mendelian disorders, whether in association with gastrointestinal cancer alone (Juvenile Polyposis Syndrome, JPS) or as part of known Syndromes (Cowden, Gorlin, and Bannayan-Zonana) in association with developmental abnormalities, dysmorphic features, or extraintestinal tumours. Recently, some JPS families were shown to harbour germline mutations in the SMAD4 ( DPC4 ) gene, providing further evidence for the importance of the TGFβ signalling pathway in colorectal cancer. There remains, however, considerable, unexplained genetic heterogeneity in JPS. Other members of the SMAD family are excellent candidates for JPS, especially SMAD2 (which, like SMAD4 , is mutated somatically in colorectal cancers), SMAD3 (which causes colorectal cancer when “knocked out” in mice), SMAD5 , and SMAD1 . METHODS SMAD1 , SMAD2 , SMAD3 , and SMAD5 were screened for germline mutations in 30 patients with JPS and without SMAD4 mutations. RESULTS No mutations were found in any of these genes. A G–A C89Y polymorphism with possible effects on protein function was found in SMAD3 , but the frequencies of the G and A alleles did not differ between patients with JPS and controls. CONCLUSIONS It remains to be determined whether or not this polymorphism is involved in a minor predisposition to colorectal or other carcinomas. SMAD4 may be the only member of the SMAD family which causes JPS when mutant in the germline. The other genes underlying JPS remain to be identified.
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mutations in dpc4 smad4 cause Juvenile Polyposis Syndrome but only account for a minority of cases
Human Molecular Genetics, 1998Co-Authors: Richard S Houlston, Charis Eng, Kelly Woodfordrichens, Paul Rozen, Joanne P Young, Malcolm G Dunlop, David Markie, Stephen Bevan, Andrew Williams, Miguel A RodriguezbigasAbstract:Juvenile polyps are present in a number of Mendelian disorders, sometimes in association only with gastrointestinal cancer [Juvenile Polyposis Syndrome (JPS)] and sometimes as part of known Syndromes (Cowden, Gorlin and Banayan-Zonana) in association with developmental abnormalities, dysmorphic features or extra-intestinal tumours. Recently, a gene for JPS was mapped to 18q21.1 and the candidate gene DPC4 (SMAD4) was shown to carry frameshift mutations in some JPS families. We have analysed eight JPS families for linkage to DPC4. Overall, there was no evidence for linkage to DPC4; linkage could be excluded in two of the eight pedigrees and was unlikely in two others. We then tested these eight families and a further 13 familial and sporadic JPS cases for germline mutations in DPC4. Just one germline DPC4 mutation was found (in a familial JPS patient from a pedigree unsuitable for linkage analysis). Like all three previously reported germline mutations, this variant occurred towards the C-terminus of the DPC4 protein. However, our patient's mutation is a missense change (R361C); somatic missense mutations in DPC4 have been reported previously in tumours. We therefore confirm DPC4 as a cause of JPS, but show that there is considerable remaining, uncharacterized genetic heterogeneity in this disease.
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molecular classification of the inherited hamartoma Polyposis Syndromes clearing the muddied waters
American Journal of Human Genetics, 1998Co-Authors: Charis EngAbstract:The autosomal dominantly inherited hamartoma Polyposis Syndromes comprise Juvenile Polyposis Syndrome or Juvenile Polyposis coli (JPS; OMIM 174900), Cowden Syndrome (CS; OMIM 158350), Bannayan-Ruvalcaba-Riley Syndrome (BRR; OMIM 153480), and Peutz-Jeghers Syndrome (PJS; OMIM 174900). The molecular basis of these Syndromes has remained elusive until recently, in part because of the often subtle clinical distinctions among them. Since the risk of organ-specific cancers in each Syndrome is different, a more reliable and objective means of differentiating among these Syndromes would be desirable, such as one based on molecular diagnosis.
Joseph Parambil - One of the best experts on this subject based on the ideXlab platform.
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The prevalence of hereditary hemorrhagic telangiectasia in Juvenile Polyposis Syndrome
Diseases of the Colon and Rectum, 2012Co-Authors: Margaret O'malley, James Church, Joseph Parambil, Brandie Heald, Matthew F. Kalady, L. Laguardia, Charis Eng, Carol A BurkeAbstract:BACKGROUND: Juvenile Polyposis Syndrome is a dominant GI Polyposis Syndrome defined by ≥ 5 GI Juvenile polyps or ≥ 1 Juvenile polyps with a family history of Juvenile Polyposis. Mutations in BMPR1A or SMAD4 are found in 50% of individuals. Hereditary hemorrhagic telangiectasia is a dominant disorder characterized by epistaxis, visceral arteriovenous malformations, and telangiectasias. Hereditary hemorrhagic telangiectasia is diagnosed when ≥ 3 criteria including clinical manifestations or a family history, are present. A Juvenile Polyposis-hereditary hemorrhagic telangiectasia overlap Syndrome has previously been reported in 22% of patients with Juvenile Polyposis due to a SMAD4 mutation.\n\nOBJECTIVE: Our objective was to determine the prevalence and clinical manifestations of hereditary hemorrhagic telangiectasia by Curacao criteria in our Juvenile Polyposis SMAD4 patients.\n\nDESIGN, PATIENTS, AND SETTING: This was a cohort study of Juvenile Polyposis patients in our inherited colon cancer registries. Hereditary hemorrhagic telangiectasia manifestations were obtained from medical records, patient contact, and/or prospective hereditary hemorrhagic telangiectasia screening. The Curacao criteria was used for diagnosis of hereditary hemorrhagic telangiectasia (≥ 3 criteria diagnostic; 2 criteria suspect of).\n\nMAIN OUTCOME MEASURES: Prevalence and clinical manifestations of hereditary hemorrhagic telangiectasia in Juvenile Polyposis SMAD4 patients.\n\nRESULTS: Forty-one Juvenile Polyposis families were identified. Genetic testing was available for individuals within 18 families. SMAD4 mutations were found in 21 relatives in 9 families. Eighty-one percent of SMAD4 patients had hereditary hemorrhagic telangiectasia and 14% were suspected of having hereditary hemorrhagic telangiectasia. Epistaxis and asthma are the most common symptoms in our overlap patients. Symptomatic and subclinical arteriovenous malformations were noted near universally.\n\nLIMITATIONS: There was a single, tertiary referral center.\n\nCONCLUSIONS: Nearly all Juvenile Polyposis SMAD4 patients have the overlap Syndrome. The clinical implications and need for hereditary hemorrhagic telangiectasia screening are important factors for genetic testing in Juvenile Polyposis. Health care providers must be cognizant of the Juvenile Polyposis-hereditary hemorrhagic telangiectasia overlap Syndrome and the implications for management of these patients.
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the prevalence of hereditary hemorrhagic telangiectasia in Juvenile Polyposis Syndrome patients with smad4 mutations
Hereditary Cancer in Clinical Practice, 2011Co-Authors: Margaret Omalley, Joseph Parambil, Matthew F. Kalady, L. Laguardia, Charis Eng, James M Church, Brandie Leach, Carol A BurkeAbstract:Background Juvenile Polyposis Syndrome (JPS) is defined by the presence of ≥ 5 colorectal Juvenile polyps or any number of Juvenile polyps in an individual with a family history of JPS. Genetic alterations including either point mutations or large rearrangements in BMPR1A or SMAD4 are found in 50% of affected individuals. Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant disease diagnosed upon the presence of epistaxis, visceral arteriovenous malformations (AVM) or mucutaneous telangiectasias. HHT is diagnosed when there are ≥ 3 manifestations and is suspected when there are at least 2 manifestations. Most HHT cases are caused by a germline mutation in ALK1 or ENG ,m embers of the TGFb signaling pathway. Approximately 22% of patients with Juvenile Polyposis Syndrome (JPS) due to a SMAD4 mutation have been reported to also have HHT [1]. Most prior publications have few patients and no systematic approach to screening, so the true incidence of the combined JPS/HHT Syndrome is not known. Our aim was to determine the prevalence of HHT in our patients with JPS with a SMAD4 mutation including those who underwent systematic screening for AVM’s. Methods JPS patients were identified from a comprehensive Polyposis database using Cologene© software. Families carrying a germline SMAD4 mutation were studied by screening affected patients for cutaneous telangiectases and with cardiac bubble ECHO, CAT scan chest, or MRI of brain for other AVMs. Results
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smad4 mutation and the combined Syndrome of Juvenile Polyposis Syndrome and hereditary haemorrhagic telangiectasia
Thorax, 2010Co-Authors: Nithya K Iyer, Brandie Leach, Carol A Burke, Joseph ParambilAbstract:Juvenile Polyposis Syndrome (JPS) and hereditary haemorrhagic telangiectasia (HHT) are autosomal dominant disorders with characteristic clinical phenotypes. Recently, reports of the combined Syndrome of JPS and HHT have been described in individuals with mutations in the SMAD4 gene, whose product—SMAD4—is a critical intracellular effector in the signalling pathway of transforming growth factor β (TGFβ). This report describes a 24-year-old man who presented to the Respiratory Institute after colectomy for JPS with a SMAD4 mutation and who was subsequently diagnosed to have HHT with asymptomatic cerebral and pulmonary arteriovenous malformations (AVMs). Patients with JPS due to a SMAD4 mutation should be screened for the vascular lesions associated with HHT, especially occult AVMs in visceral organs, which may potentially present catastrophically with serious medical consequences.
