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Ramsey ML, Heald B, Gokun Y, Baker J, Groce JR, Han S, Hart PA, Krishna SG, Lara LF, Lee PJ, Papachristou GI, Pearlman R, Poll S, Roberts ME, Stanich PP. Germline multigene panel testing in acute and chronic pancreatitis. PLoS One 2024; 19:e0307076. [PMID: 39172977 PMCID: PMC11341018 DOI: 10.1371/journal.pone.0307076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2024] [Accepted: 06/29/2024] [Indexed: 08/24/2024] Open
Abstract
BACKGROUND/OBJECTIVES Germline genetic testing is recommended for younger patients with idiopathic pancreatitis but there has been a lack of consensus in recommendations for those over age 35. We aimed to analyze the results of genetic testing among subjects of varying ages. METHODS Individuals who underwent germline multigene testing for pancreatitis susceptibility genes (CASR, CFTR, CPA1, CTRC, PRSS1, SPINK1) through a large commercial laboratory between 2017 and 2022 were included. Test results and information collected from test requisition forms were evaluated. Multivariable logistic regression models were performed to identify factors associated with a positive pancreatitis panel (pathogenic, likely pathogenic, and/or increased risk variants) in pancreatitis-related genes. RESULTS Overall, 2,468 subjects with primary indication of acute pancreatitis (AP) (n = 401), chronic pancreatitis (CP) (n = 631), pancreatic cancer (n = 128), or other indications (n = 1,308) completed germline testing. Among patients with AP or CP, the prevalence of any positive result for those <35 versus ≥35 years of age was 32.1% and 24.5% (p = 0.007), and the prevalence of a clinically meaningful result was 10.8% and 5.4%, respectively (p = 0.001). Positive family history of pancreatitis was associated with increased odds ratio (OR) of 8.59 (95% confidence interval (CI) 2.92-25.25) for a clinically significant panel result while each 5-year increase in age at test completion had lower odds (OR 0.89, 95% CI 0.83-0.95). CONCLUSIONS The highest prevalence of pathogenic variants is seen in younger individuals with a positive family history of pancreatitis. However, clinically meaningful results are identified in older subjects, suggesting that genetic counseling and testing should be considered for all age groups.
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Affiliation(s)
- Mitchell L. Ramsey
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America
| | - Brandie Heald
- Medical Affairs, Invitae Corporation, San Francisco, California, United States of America
| | - Yevgeniya Gokun
- Department of Biomedical Informatics, Center for Biostatistics, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America
| | - Josie Baker
- Division of Human Genetics, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America
| | - J. Royce Groce
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America
| | - Samuel Han
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America
| | - Phil A. Hart
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America
| | - Somashekar G. Krishna
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America
| | - Luis F. Lara
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America
| | - Peter J. Lee
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America
| | - Georgios I. Papachristou
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America
| | - Rachel Pearlman
- Division of Human Genetics, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America
| | - Sarah Poll
- Medical Affairs, Invitae Corporation, San Francisco, California, United States of America
| | - Maegan E. Roberts
- Division of Human Genetics, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America
| | - Peter P. Stanich
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America
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Panchoo AV, VanNess GH, Rivera-Rivera E, Laborda TJ. Hereditary pancreatitis: An updated review in pediatrics. World J Clin Pediatr 2022; 11:27-37. [PMID: 35096544 PMCID: PMC8771313 DOI: 10.5409/wjcp.v11.i1.27] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 08/08/2021] [Accepted: 11/28/2021] [Indexed: 02/06/2023] Open
Abstract
Hereditary Pancreatitis (HP) has emerged as a significant cause of acute, acute recurrent and chronic pancreatitis in the pediatric population. Given that it presents similarly to other causes of pancreatitis, a positive family history and/or isolation of a gene mutation are vital in its designation. Inheritance patterns remain complex, but mutations involving the PRSS1, SPINK1, CFTR and CTRC genes are commonly implicated. Since being first described in 1952, dozens of genetic alterations that modify the action of pancreatic enzymes have been identified. Among children, these variants have been isolated in more than 50% of patients with chronic pancreatitis. Recent research has noted that such mutations in PRSS1, SPINK1 and CFTR genes are also associated with a faster progression from acute pancreatitis to chronic pancreatitis. Patients with HP are at increased risk of developing diabetes mellitus, exocrine pancreatic insufficiency, and pancreatic adenocarcinoma. Management follows a multi-disciplinary approach with avoidance of triggers, surveillance of associated conditions, treatment of pancreatic insufficiency and use of endoscopic and surgical interventions for complications. With significant sequela, morbidity and a progressive nature, a thorough understanding of the etiology, pathophysiologic mechanisms, diagnostic evaluation, current management strategies and future research considerations for this evolving disease entity in pediatrics is warranted.
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Affiliation(s)
- Arvind Vasant Panchoo
- Division of Gastroenterology, Hepatology and Nutrition, The Children’s Hospital of San Antonio, San Antonio, TX 78207, United States
- Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, United States
| | - Grant H VanNess
- Faculty of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Edgardo Rivera-Rivera
- Department of Pediatric Gastroenterology, Parkview Health, Fort Wayne, IN 46845, United States
| | - Trevor J Laborda
- Division of Gastroenterology, Hepatology and Nutrition, The Children’s Hospital of San Antonio, San Antonio, TX 78207, United States
- Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, United States
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Al Droubi B, Altamimi E. Acute Pancreatitis in Jordanian Children: A Single Center Experience. Front Pediatr 2022; 10:908472. [PMID: 35844741 PMCID: PMC9283568 DOI: 10.3389/fped.2022.908472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 06/10/2022] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND There is still much to understand and discover regarding pediatric pancreatitis. The etiology, clinical presentation, and prognosis of pancreatitis differs considerably between young children and adults. The incidence of pancreatitis has been increasing; it is no longer as rare in children as previously thought and could cause significant morbidity and mortality when severe. METHODS In this retrospective study conducted at a tertiary care hospital in Jordan, we present a cohort of children with 64 episodes of acute pancreatitis. RESULTS While abdominal pain was the most common presenting complaint in our cohort (97%), the classical features of radiation to the back and relief by the forward-lean position were observed in only one-third of our patients. Compared to serum amylase, serum lipase had a higher sensitivity for detecting pancreatitis (98 vs. 67%). Abdominal ultrasound is a non-invasive, widely available imaging modality; when performed, it revealed an enlarged pancreas in almost 60% of the patients. However, abdominal ultrasonography is often limited by the presence of excessive bowel gas. Anatomical abnormalities were the most common etiologies of pancreatitis (29%), followed by idiopathic pancreatitis (21%), and biliary causes (21%). CONCLUSION In our cohort, serum lipase was a better diagnostic tool compared to serum amylase. Congenital biliary-pancreatic abnormalities were the most common causes of acute pancreatitis in our cohort. Almost half of these patients developed recurrent acute pancreatitis. The prevalence of pancreatic pseudocysts was 16.7%, and nearly half of them required an intervention.
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Affiliation(s)
- Belal Al Droubi
- Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan
| | - Eyad Altamimi
- Department of Pediatrics, Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan
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Diaz KE, Lucas AL. Familial Pancreatic Ductal Adenocarcinoma. THE AMERICAN JOURNAL OF PATHOLOGY 2019; 189:36-43. [PMID: 30558720 PMCID: PMC7073774 DOI: 10.1016/j.ajpath.2018.06.026] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/11/2018] [Revised: 05/21/2018] [Accepted: 06/11/2018] [Indexed: 12/11/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC), although a rare disease, has a poor prognosis. With 5-year overall survival of 8%, there is a critical need to detect PDAC early or at a premalignant stage. Current screening methods are largely imaging based, but a more focused screening approach based on modifiable and nonmodifiable risk factors may improve the efficacy and likely outcomes of screening. In addition, the pathologic mechanisms that lead to the development of PDAC are discussed in an effort to further understand the targets of pancreatic cancer screening. The focus of this article will be inherited pancreatic cancer syndromes and familial pancreatic cancer, which together compose up to 10% of PDAC. Understanding the methods and targets of PDAC screening in high-risk individuals may translate to improved morbidity and mortality.
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Affiliation(s)
- Kelly E Diaz
- Samuel Bronfman Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Aimee L Lucas
- Samuel Bronfman Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York; Henry D. Janowitz Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.
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Abstract
Recurrent acute pancreatitis (RAP) is a clinically significant problem globally. The etiology remains unclear in approximately 10% to 15% of patients despite a thorough workup. Data on natural history and efficacy of treatments are limited. We aimed to establish criteria for diagnosis, evaluate the causative factors, and arrive at a consensus on the appropriate workup and management of patients with RAP. The organizing committee was formed, and a set of questions was developed based on the current evidence, controversies, and topics that needed further research. After a vetting process, these topics were assigned to a group of experts from around the world with special interest in RAP. Data were presented as part of a workshop on RAP organized as a part of the annual meeting of the America Pancreatic Association. Pretest and Posttest questions were administered, and the responses were tabulated by the current Grades of Recommendation Assessment, Development and Evaluation system. The consensus guidelines were established in the format of a diagnostic algorithm. Several deficiencies were identified with respect to data on etiology, treatment efficacies, and areas that need immediate research.
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Carrera S, Sancho A, Azkona E, Azkuna J, Lopez-Vivanco G. Hereditary pancreatic cancer: related syndromes and clinical perspective. Hered Cancer Clin Pract 2017; 15:9. [PMID: 28670351 PMCID: PMC5490219 DOI: 10.1186/s13053-017-0069-6] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2017] [Accepted: 06/21/2017] [Indexed: 02/07/2023] Open
Abstract
Pancreatic cancer is a very aggressive disease with a poor prognosis. The majority of them are attributed to sporadic causes, especially to many modifiable risk factors such as tobacco or alcohol abuse. The principal histologic subtype of pancreatic cancer is ductal adenocarcinoma. Pancreatic neuroendocrine tumors, which constitute a more indolent entity, represent second type of pancreatic cancer in terms of incidence. Individuals with a family history of pancreatic cancer carry an increased risk of developing the disease, which may be related to an underlying hereditary component. Unfortunately, in the majority of these families the suspected germline genetic cause responsible of the disease will not be identified, but approximately in a 20% of the cases a hereditary cancer predisposition syndrome with increased risk of pancreatic cancer development can be recognized. This review will be focused on the leading hereditary cancer syndromes related to pancreatic ductal adenocarcinoma and pancreatic neuroendocrine tumors. Additionally, we will try to explain clinical aspects related to the identification of germline mutations in pancreatic cancer patients and their potential implications in oncologic treatment decisions.
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Affiliation(s)
- Sergio Carrera
- Hereditary Cancer Genetic Counseling Unit- Medical Oncology Department, Cruces University Hospital, Plaza de Cruces s/n. 48903, Baracaldo, Bizkaia Spain
| | - Aintzane Sancho
- Medical Oncology Department, Cruces University Hospital, Baracaldo, Spain
| | - Eider Azkona
- Medical Oncology Department, Cruces University Hospital, Baracaldo, Spain
| | - Josune Azkuna
- Medical Oncology Department, Cruces University Hospital, Baracaldo, Spain
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Abstract
Hereditary pancreatitis (HP) is a rare cause of acute, recurrent acute, and chronic pancreatitis. It may present similarly to other causes of acute and chronic pancreatitis, and often there has been a protracted evaluation prior to the diagnosis of HP. Since it was first described in 1952, multiple genetic defects that affect the action of digestive enzymes in the pancreas have been implicated. The most common mutations involve the PRSS1, CFTR, SPINK1, and CTRC genes. New mutations in these genes and previously unrecognized mutations in other genes are being discovered due to the increasing use of next-generation genomic sequencing. While the inheritance pathways of these genetic mutations may be variable and complex, sometimes involving coinheritance of other mutations, the clinical presentation of patients tends to be similar. Interactions with environmental triggers often play a role. Patients tend to present at an early age (prior to the second decade of life) and have a significantly increased risk for the development of pancreatic adenocarcinoma. Patients with HP may develop sequelae of chronic pancreatitis such as strictures and fluid collections as well as exocrine and endocrine insufficiency. Management of patients with HP involves avoidance of environmental triggers, surveillance for pancreatic adenocarcinoma, medical therapy for endocrine and exocrine insufficiency, pain management, and endoscopic or surgical treatment for complications. Care for affected patients should be individualized, with an emphasis on early diagnosis and multidisciplinary involvement to develop a comprehensive treatment strategy.
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Affiliation(s)
- Kara L Raphael
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - Field F Willingham
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA
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Becker AE, Hernandez YG, Frucht H, Lucas AL. Pancreatic ductal adenocarcinoma: Risk factors, screening, and early detection. World J Gastroenterol 2014; 20:11182-11198. [PMID: 25170203 PMCID: PMC4145757 DOI: 10.3748/wjg.v20.i32.11182] [Citation(s) in RCA: 225] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 01/15/2014] [Accepted: 04/16/2014] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer is the fourth most common cause of cancer-related deaths in the United States, with over 38000 deaths in 2013. The opportunity to detect pancreatic cancer while it is still curable is dependent on our ability to identify and screen high-risk populations before their symptoms arise. Risk factors for developing pancreatic cancer include multiple genetic syndromes as well as modifiable risk factors. Genetic conditions include hereditary breast and ovarian cancer syndrome, Lynch Syndrome, familial adenomatous polyposis, Peutz-Jeghers Syndrome, familial atypical multiple mole melanoma syndrome, hereditary pancreatitis, cystic fibrosis, and ataxia-telangiectasia; having a genetic predisposition can raise the risk of developing pancreatic cancer up to 132-fold over the general population. Modifiable risk factors, which include tobacco exposure, alcohol use, chronic pancreatitis, diet, obesity, diabetes mellitus, as well as certain abdominal surgeries and infections, have also been shown to increase the risk of pancreatic cancer development. Several large-volume centers have initiated such screening protocols, and consensus-based guidelines for screening high-risk groups have recently been published. The focus of this review will be both the genetic and modifiable risk factors implicated in pancreatic cancer, as well as a review of screening strategies and their diagnostic yields.
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9
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LaRusch J, Jung J, General IJ, Lewis MD, Park HW, Brand RE, Gelrud A, Anderson MA, Banks PA, Conwell D, Lawrence C, Romagnuolo J, Baillie J, Alkaade S, Cote G, Gardner TB, Amann ST, Slivka A, Sandhu B, Aloe A, Kienholz ML, Yadav D, Barmada MM, Bahar I, Lee MG, Whitcomb DC, the North American Pancreatitis Study Group. Mechanisms of CFTR functional variants that impair regulated bicarbonate permeation and increase risk for pancreatitis but not for cystic fibrosis. PLoS Genet 2014; 10:e1004376. [PMID: 25033378 PMCID: PMC4102440 DOI: 10.1371/journal.pgen.1004376] [Citation(s) in RCA: 130] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2013] [Accepted: 03/10/2014] [Indexed: 02/07/2023] Open
Abstract
CFTR is a dynamically regulated anion channel. Intracellular WNK1-SPAK activation causes CFTR to change permeability and conductance characteristics from a chloride-preferring to bicarbonate-preferring channel through unknown mechanisms. Two severe CFTR mutations (CFTRsev) cause complete loss of CFTR function and result in cystic fibrosis (CF), a severe genetic disorder affecting sweat glands, nasal sinuses, lungs, pancreas, liver, intestines, and male reproductive system. We hypothesize that those CFTR mutations that disrupt the WNK1-SPAK activation mechanisms cause a selective, bicarbonate defect in channel function (CFTRBD) affecting organs that utilize CFTR for bicarbonate secretion (e.g. the pancreas, nasal sinus, vas deferens) but do not cause typical CF. To understand the structural and functional requirements of the CFTR bicarbonate-preferring channel, we (a) screened 984 well-phenotyped pancreatitis cases for candidate CFTRBD mutations from among 81 previously described CFTR variants; (b) conducted electrophysiology studies on clones of variants found in pancreatitis but not CF; (c) computationally constructed a new, complete structural model of CFTR for molecular dynamics simulation of wild-type and mutant variants; and (d) tested the newly defined CFTRBD variants for disease in non-pancreas organs utilizing CFTR for bicarbonate secretion. Nine variants (CFTR R74Q, R75Q, R117H, R170H, L967S, L997F, D1152H, S1235R, and D1270N) not associated with typical CF were associated with pancreatitis (OR 1.5, p = 0.002). Clones expressed in HEK 293T cells had normal chloride but not bicarbonate permeability and conductance with WNK1-SPAK activation. Molecular dynamics simulations suggest physical restriction of the CFTR channel and altered dynamic channel regulation. Comparing pancreatitis patients and controls, CFTRBD increased risk for rhinosinusitis (OR 2.3, p<0.005) and male infertility (OR 395, p<<0.0001). WNK1-SPAK pathway-activated increases in CFTR bicarbonate permeability are altered by CFTRBD variants through multiple mechanisms. CFTRBD variants are associated with clinically significant disorders of the pancreas, sinuses, and male reproductive system.
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Affiliation(s)
- Jessica LaRusch
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Jinsei Jung
- Department of Pharmacology and Brain Korea 21 Plus Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Ignacio J. General
- Department of Computational & Systems Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Michele D. Lewis
- Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, Florida, United States of America
| | - Hyun Woo Park
- Department of Pharmacology and Brain Korea 21 Plus Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Randall E. Brand
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Andres Gelrud
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Michelle A. Anderson
- Department of Medicine, University of Michigan, Ann Arbor, Michigan, United States of America
| | - Peter A. Banks
- Division of Gastroenterology, Brigham and Women's Hospital, Boston, Massachusetts, United States of America
| | - Darwin Conwell
- Division of Gastroenterology, Brigham and Women's Hospital, Boston, Massachusetts, United States of America
| | - Christopher Lawrence
- Digestive Disease Center, Medical University of South Carolina, Charleston, South Carolina, United States of America
| | - Joseph Romagnuolo
- Digestive Disease Center, Medical University of South Carolina, Charleston, South Carolina, United States of America
| | - John Baillie
- Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States of America
| | - Samer Alkaade
- Department of Internal Medicine, St. Louis University School of Medicine, St Louis, Missouri, United States of America
| | - Gregory Cote
- Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, United States of America
| | - Timothy B. Gardner
- Dartmouth-Hitchcock Medical Center, Hanover, New Hampshire, United States of America
| | - Stephen T. Amann
- North Mississippi Medical Center, Tupelo, Mississippi, United States of America
| | - Adam Slivka
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Bimaljit Sandhu
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University Medical Center, Richmond, Virginia, United States of America
| | - Amy Aloe
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Michelle L. Kienholz
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Dhiraj Yadav
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - M. Michael Barmada
- Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Ivet Bahar
- Department of Computational & Systems Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Min Goo Lee
- Department of Pharmacology and Brain Korea 21 Plus Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - David C. Whitcomb
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
- Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
- Department of Cell Biology and Molecular Physiology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
- * E-mail:
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Graziani R, Frulloni L, Cicero C, Manfredi R, Ambrosetti MC, Mautone S, Pozzi Mucelli R. Bull's-eye pattern of pancreatic-duct stones on multidetector computed tomography and gene-mutation-associated pancreatitis (GMAP). Radiol Med 2012; 117:1275-86. [PMID: 23090249 DOI: 10.1007/s11547-012-0888-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2011] [Accepted: 01/13/2012] [Indexed: 01/28/2023]
Abstract
PURPOSE This study prospectively assessed whether the presence of a bull's-eye pattern of pancreatic-duct stones on multidetector computed tomography (MDCT) correlated with gene-mutation-associated pancreatitis (GMAP) and whether other signs suggestive of GMAP can be detected with MDCT. MATERIALS AND METHODS Forty-seven patients with chronic calcific pancreatitis underwent genetic testing for CFTR, SPINK1 and PRSS1 mutations and an MDCT scan of the abdomen. Qualitative analysis assessed the presence or absence of pancreatic-duct stones with bull's-eye appearance. Quantitative analysis included the number and maximum diameter of stones and the diameter of the main pancreatic duct. RESULTS Fifteen of 47 patients (32%) were positive for gene mutations (GMAP patients). The bull's-eye pattern was found in 10/15 patients (67%) with GMAP and in 4/32 (12%) patients with chronic pancreatitis not associated with GMAP (NGMAP; p<0.0001). The mean diameter of duct stones was 15 mm in patients with GMAP and 10 mm in patients with NGMAP (p<0.04). CONCLUSIONS The presence of duct stones with a bull's-eye pattern correlates with GMAP. Duct stones with diameter ≥15 mm are another sign suggestive of GMAP.
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Affiliation(s)
- R Graziani
- Istituto di Radiologia, Università di Verona, P.le L.A. Scuro 10, 37134, Verona, Italy.
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A novel exon duplication of the cystic fibrosis transmembrane conductance regulator in a patient presenting with adult-onset recurrent pancreatitis. Pancreas 2011; 40:773-7. [PMID: 21673536 DOI: 10.1097/mpa.0b013e3182156e47] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Pancreatitis is a rare occurrence in patients with cystic fibrosis (CF) affecting 1.2% of all patients, but it can be the first presenting sign in approximately 15% of adults with pancreatic sufficiency and a milder CF phenotype. We report a case of a woman with recurrent pancreatitis who has one cystic fibrosis-causing mutation (G551D) and the first known description of a pathologic duplication of exon 19 of the CF transmembrane conductance regulator (CFTR). A 30-year-old white woman with 30 attacks of pancreatitis over a 5-year period starting at age 25 presented to the genetics department. She was found to have a mutation in the SPINK1 gene, IVS3+184T>A, and one cystic fibrosis-causing mutation (G551D) prompting full gene sequencing of the CFTR, revealing an additional duplication of exon 19. Sweat chloride testing was elevated at 97 and 106 mmol/L. Despite normal growth parameters and lung function, it is important to be aware of recurrent pancreatitis as a presenting sign of CF. Comprehensive CF gene analysis is necessary to detect a second CF-causing mutation that may put patients at risk for more severe symptoms of pancreatitis. There is a significant difference in the prevalence of heterozygote mutations between available testing methods.
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Abstract
OBJECTIVE We have assessed whether CFTR gene has a major impact on chronic pancreatitis (CP) pathogenesis than that provided by the CFTR mutations. For this aim, we have evaluated clinical parameters, CFTR mutations, and 3 potential regulatory CFTR variants (coding single-nucleotide polymorphisms): c.1540A>G, c.2694T>G, and c.4521G>A. METHODS CFTR gene analysis was performed in a cohort of 136 CP patients and 93 controls from Spanish population using current scanning techniques (single-strand conformation polymorphism/heteroduplex, denaturing gradient gel electrophoresis, and denaturing high-performance liquid chromatography) and direct sequencing. RESULTS A higher frequency of CFTR mutations were observed in patients (39%) than in controls (15%; P < or = 0.001), differences being mostly attributable to the prevalence of the cystic fibrosis (CF)-causing mutations (P = 0.009). The analysis of variants has shown statistically significant differences between patients and controls for c.4521G>A (Pcorrected = 0.036). Furthermore, the multi-marker analysis revealed that the 1540A;2694G;4521A (AGA) haplotype was more prevalent in CP than controls (Pcorrected = 0.042). Remarkably, this association was unrelated to CF-causing mutations (P = 0.006). CONCLUSIONS Our results corroborate the higher susceptibility of CF carriers to CP and, furthermore, suggest that the AGA haplotype could contribute to an increased risk in the development of CP irrespective of other CF-causing mutations.
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LaFemina J, Roberts PA, Hung YP, Gusella JF, Sahani D, Fernández-del Castillo C, Warshaw AL, Thayer SP. Identification of a novel kindred with familial pancreatitis and pancreatic cancer. Pancreatology 2009; 9:273-9. [PMID: 19407482 PMCID: PMC3713708 DOI: 10.1159/000201553] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2008] [Accepted: 01/31/2009] [Indexed: 12/11/2022]
Abstract
BACKGROUND/AIMS Hereditary pancreatic cancer comprises about 10% of pancreatic cancer cases. Multiple causative mutations have been identified. Here we describe a pancreatitis/pancreatic cancer (P/PC) family, which demonstrates pancreatitis and pancreatic cancer resulting from an uncharacterized mutation. METHODS Family members completed evaluations to determine signs of mutation status. Select patients were screened for mutations associated with hereditary pancreatic diseases. RESULTS In generation II, 12 siblings exhibit 6 cases of pancreatitis, 3 pancreatic cancer, and 2 obligate carrier status. The average age at pancreatitis diagnosis of enrolled members is 32.5 years; average age at pancreatic cancer diagnosis is 59 years. There is no association with known cancer syndromes. Those affected generally present with mild epigastric pain, and CT scans demonstrate characteristic fatty infiltration of the pancreatic body and tail with sparing of the head and neck. Full sequence analysis of genes associated with hereditary pancreatic disease failed to demonstrate known mutations or polymorphisms. CONCLUSION Based upon pedigree evaluation and preliminary DNA analysis, we believe that the family members with P/PC carry a novel genetic mutation resulting in hereditary pancreatitis. This mutation is autosomal dominant, expressed with high penetrance, and is part of a unique hereditary syndrome that significantly increases pancreatic cancer risk.
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Affiliation(s)
- Jennifer LaFemina
- Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Mass., USA
| | - Penelope A. Roberts
- Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, Mass., USA
| | - Yin P. Hung
- Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Mass., USA
| | - James F. Gusella
- Harvard Partners Center for Genetics and Genomics, Harvard Medical School, Boston, Mass., USA
| | - Dushyant Sahani
- Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Mass., USA
| | | | - Andrew L. Warshaw
- Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Mass., USA
| | - Sarah P. Thayer
- Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Mass., USA
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Clinical and radiological outcome of patients suffering from chronic pancreatitis associated with gene mutations. Pancreas 2008; 37:371-6. [PMID: 18953248 DOI: 10.1097/mpa.0b013e31817f52a1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVES Cystic fibrosis transmembrane conductance regulator (CFTR), cationic trypsinogen gene (PRSS1), and serine protease inhibitor kazal type 1 (SPINK1) gene mutations have been associated with chronic pancreatitis (CP). The aim of this study was to compare clinical and radiological findings in sporadic CP with (CPgm) and without (CPwt) gene mutations. METHODS Data from patients observed between 2001 and 2006 were collected. All patients were tested for 25 CFTR gene mutations, for R122H and N29I on the PRSS1 gene, and for N34S mutation on the SPINK1 gene. RESULTS We found 34 (17.2%) of 198 patients with CPgm, 23 (11.6%) of them on the CFTR gene, 11 (5.6%) on the SPINK1, and none on the PRSS1 gene. The age at clinical onset was younger in CPgm (36.2 +/- 17.2 years) than in CPwt (44 +/- 12.6 years; P = 0.005). There were more heavy drinkers among CPwt (33%) than among CPgm (9%; P = 0.003), and the same applied to smokers (69% vs 33%, respectively; P < 0.0001). In CPgm group, the onset of pancreatic calcifications was observed more frequently in drinkers and/or smokers. Exocrine and endocrine insufficiency occurred less frequently and later in CPgm than in CPwt patients. CONCLUSIONS Clinical and radiological outcome differ in CPgm compared with CPwt. Alcohol, even in small quantities, and cigarette smoking influence the onset of pancreatic calcifications.
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Abstract
Acute pancreatitis is a relatively common disease that affects about 300,000 patients per annum in America with a mortality of about 7%. About 75% of pancreatitis is caused by gallstones or alcohol. Other important causes include hypertriglyceridemia, medication toxicity, trauma from endoscopic retrograde cholangiopancreatography, hypercalcemia, abdominal trauma, various infections, autoimmune, ischemia, and hereditary causes. In about 15% of cases the cause remains unknown after thorough investigation. This article discusses the causes, diagnosis, imaging findings, therapy, and complications of acute pancreatitis.
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Affiliation(s)
- Mitchell S Cappell
- Division of Gastroenterology, Department of Medicine, William Beaumont Hospital, MOB 233, 3535 West Thirteen Mile Road, Royal Oak, MI 48073, USA.
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16
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Fink EN, Kant JA, Whitcomb DC. Genetic counseling for nonsyndromic pancreatitis. Gastroenterol Clin North Am 2007; 36:325-33, ix. [PMID: 17533082 DOI: 10.1016/j.gtc.2007.03.007] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
An appreciation for the background of disease, not to mention the medical management of individuals, may be significantly affected by testing for mutations and genetic variants associated with pancreatitis. Pretest and posttest counseling are essential for patients and families to benefit fully from genetic testing for a susceptibility to develop pancreatitis. The clinician, often working directly with a qualified genetic counselor, must ensure that patients and families appreciate the benefits and limitations of genetic tests, that results are interpreted accurately, and that patients understand implications of information for both their medical care and personal decisions. This article focuses on the approach to genetic counseling for pancreatitis and implications of recent advances.
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Affiliation(s)
- Erin N Fink
- Department of Medicine, University of Pittsburgh, 1218 Scaife Hall, 3550 Terrace Street, Pittsburgh, PA 15213, USA
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17
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Liddle RA. Pathophysiology of SPINK mutations in pancreatic development and disease. Endocrinol Metab Clin North Am 2006; 35:345-56, x. [PMID: 16632097 DOI: 10.1016/j.ecl.2006.02.012] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The endogenous pancreatic trypsin inhibitor, SPINK, is believed to limit enzyme activity in the pancreas and reduce the risk of pancreatitis. Recently, mutations in the SPINK1 gene have been associated with development of both acute and chronic pancreatitis. In most patients with SPINK1 mutations, the genetic variants do not cause the disease independently, but may act in concert with other genetic or environmental factors. Recent studies, using mice in which the trypsin inhibitor gene has been deleted or overexpressed, provide novel insights into the role of SPINK in pancreatic development and pancreatitis.
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Affiliation(s)
- Rodger A Liddle
- Department of Medicine, Duke University and Durham VA Medical Centers, Box 3913, Durham, NC 27710, USA.
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18
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Ahmed SA, Wray C, Rilo HLR, Choe KA, Gelrud A, Howington JA, Lowy AM, Matthews JB. Chronic pancreatitis: recent advances and ongoing challenges. Curr Probl Surg 2006; 43:127-238. [PMID: 16530053 DOI: 10.1067/j.cpsurg.2005.12.005] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Affiliation(s)
- Syed A Ahmed
- University of Cincinnati Medical Center, Ohio, USA
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