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Shah PD, Armanios M. Viewpoint: Pre- and post-lung transplant considerations for patients with ultra-short telomere length. Eur Respir J 2025; 65:2401545. [PMID: 39884762 PMCID: PMC11883148 DOI: 10.1183/13993003.01545-2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2024] [Accepted: 01/09/2025] [Indexed: 02/01/2025]
Abstract
Lung transplantation remains the only life-extending procedure for patients with idiopathic pulmonary fibrosis (IPF) and related progressive interstitial lung disease (ILD). Discoveries from recent decades have shown that mutations in telomerase and other telomere maintenance genes are their most common inherited risk factor, identifiable in up to 30–35% of families with pulmonary fibrosis [1]. Mutations in nine telomerase and telomere maintenance genes are confirmed to predispose to adult-onset pulmonary fibrosis by co-segregation in large families and functional studies (table 1) [2–13]. They compromise telomerase abundance, recruitment and function [1, 14]. Patients with ultra-short telomere length develop recurrent complications after lung transplantation; therefore, pre-transplant assessment and individualised post-transplant management may improve outcome in carefully defined high risk patient subsets https://bit.ly/3WvfLC1
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Affiliation(s)
- Pali D Shah
- Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Mary Armanios
- Departments of Oncology, Genetic Medicine and Pathology, Telomere Center at Johns Hopkins, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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2
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Yu G, Xin G, Liu X, Li W, Shao C, Gao R. TERT de novo mutation-associated dyskeratosis congenita and porto-sinusoidal vascular disease: a case report. J Med Case Rep 2025; 19:32. [PMID: 39849589 PMCID: PMC11759448 DOI: 10.1186/s13256-025-05031-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Accepted: 01/06/2025] [Indexed: 01/25/2025] Open
Abstract
BACKGROUND Dyskeratosis congenita is a rare genetic disease due to telomere biology disorder and characterized by heterogeneous clinical manifestations and severe complications. "Porto-sinusoidal vascular disease" has been recently proposed, according to new diagnostic criteria, to replace the term "idiopathic non-cirrhotic portal hypertension." TERT plays an important role in telomeric DNA repair and replication. A TERT c.2286 + 1G/A mutation in a splicing consensus site was identified in a patient with pulmonary fibrosis. Recently, a pathogenic de novo TERT c.280A > T variant was associated with diffuse lung disease in an infant. CASE PRESENTATION A 16-year-old Han male patient experienced unexplained black stool for 7 days, accompanied by dizziness and fatigue. On examination, there were mesh pigmentations on the exposed areas of the skin on both hands and feet. Laboratory testing revealed moderate hemorrhagic anemia and mild elevation of alanine aminotransferase. A computed tomography scan showed portal hypertension, esophageal and gastric varices, and splenomegaly. The liver stiffness measurement by FibroScan was 6.0 kPa. Liver biopsy revealed typical features of porto-sinusoidal vascular disease. Whole exome sequencing identified a heterozygous TERT c.2286 + 1G > A de novo mutation and quantitative polymerase chain reaction revealed very short telomeres (less than the first percentile for his age). The patient was diagnosed as TERT de novo mutation-related dyskeratosis congenita and porto-sinusoidal vascular disease. He underwent esophageal and gastric variceal ligation treatment and received a carvedilol tablet (12.5 mg) every morning. After 6 months, he has moderate iron deficiency anemia and has started receiving polysaccharide iron complex therapy. CONCLUSION When discovering reticular rash and unknown portal hypertension, it is necessary to perform whole exome sequencing and chromosome length testing to clarify the possibility of dyskeratosis congenita/telomere biology disorder with porto-sinusoidal vascular disease.
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Affiliation(s)
- Ge Yu
- Department of Hepatic Biliary Pancreatic Medicine, First Hospital of Jilin University, 1 Xinmin Avenue, Changchun, 130021, China
| | - Guijie Xin
- Department of Hepatic Biliary Pancreatic Medicine, First Hospital of Jilin University, 1 Xinmin Avenue, Changchun, 130021, China
| | - Xu Liu
- Department of Hepatic Biliary Pancreatic Medicine, First Hospital of Jilin University, 1 Xinmin Avenue, Changchun, 130021, China
| | - Wanyu Li
- Department of Hepatic Biliary Pancreatic Medicine, First Hospital of Jilin University, 1 Xinmin Avenue, Changchun, 130021, China
| | - Chen Shao
- Department of Pathology, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Runping Gao
- Department of Hepatic Biliary Pancreatic Medicine, First Hospital of Jilin University, 1 Xinmin Avenue, Changchun, 130021, China.
- Department of Infectious Diseases, First Hospital of Jilin University, Changchun, China.
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3
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Zhu N, Wang X, Zhu H, Zheng Y. Exploring the role of alternative lengthening of telomere-related genes in diagnostic modeling for non-alcoholic fatty liver disease. Sci Rep 2024; 14:30309. [PMID: 39638831 PMCID: PMC11621558 DOI: 10.1038/s41598-024-81129-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Accepted: 11/25/2024] [Indexed: 12/07/2024] Open
Abstract
Previous studies have reported an association between telomere length and non-alcoholic fatty liver disease (NAFLD). This study aimed to explore the involvement of alternative lengthening of telomere-related genes (ALTRGs) in the pathology of NAFLD, construct a risk signature, and evaluate both treatment and prognosis. Three NAFLD datasets (GSE48452, GSE89632, and GSE63067) were collected from the GEO database and merged into combined GEO datasets. ALTRGs were collected from GeneCards and PubMed databases. Differentially expressed genes (DEGs) were identified, and functional enrichment analysis was performed. This study employed a support vector machine algorithm and least absolute shrinkage and selection operator regression analysis to identify key genes for constructing a diagnostic model. High- and low-risk groups were identified from the combined GEO datasets using the diagnostic model. Gene set enrichment analysis, regulatory network analysis, and intergroup immune infiltration analysis were performed. This study identified the key genes using receiver operating characteristic and Friends analysis. Expression of these genes was validated in a mouse model of NAFLD. Twenty-five genes were differentially expressed, with a positive correlation between FOS and EGR1 and a negative correlation between MYC and CEBPA. A diagnostic model was constructed using 12 genes, and high- and low-risk groups were identified. CAMK2G, ERBB2, FOSB, WT1, and CEBPA showed certain accuracy, and their expression levels were significantly different in the model. Immune infiltration analysis between the risk groups revealed that six immune cells were statistically significant. This includes a strong negative interaction between type 2 T helper cells and SPHK2 in the high-risk group. These findings suggest that ALTRDEGs are potential therapeutic targets and prognostic indicators for NAFLD. However, further investigations are required to elucidate the specific underlying mechanisms.
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Affiliation(s)
- Nan Zhu
- Department of Internal Medicine, Hebei Medical University, Shijiazhuang, 050017, Hebei Province, China
- Department of Internal Medicine, The First Hospital of Qinhuangdao, Qinhuangdao, 066000, Hebei Province, China
| | - Xiaoliang Wang
- Department of Cardiology, The First Hospital of Qinhuangdao, Qinhuangdao, 066000, Hebei Province, China
| | - Huiting Zhu
- Department of Internal Medicine, The First Hospital of Qinhuangdao, Qinhuangdao, 066000, Hebei Province, China
| | - Yue Zheng
- Department of Internal Medicine, Hebei Medical University, Shijiazhuang, 050017, Hebei Province, China.
- Department of Gastroenterology, The First Hospital of Qinhuangdao, Qinhuangdao, 066000, Hebei Province, China.
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Shukla A, Rockey DC, Kamath PS, Kleiner DE, Singh A, Vaidya A, Koshy A, Goel A, Dökmeci AK, Meena B, Philips CA, Sharma CB, Payawal DA, Kim DJ, Lo GH, Han G, Qureshi H, Wanless IR, Jia J, Sollano JD, Al Mahtab M, Muthiah MD, Sonderup MW, Nahum MS, Merican MIB, Ormeci N, Kawada N, Reddy R, Dhiman RK, Gani R, Hameed SS, Harindranath S, Jafri W, Qi X, Chawla YK, Furuichi Y, Zheng MH, Sarin SK. Non-cirrhotic portal fibrosis/idiopathic portal hypertension: APASL recommendations for diagnosis and management. Hepatol Int 2024; 18:1684-1711. [PMID: 39546143 DOI: 10.1007/s12072-024-10739-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Accepted: 09/28/2024] [Indexed: 11/17/2024]
Abstract
Since the Asian Pacific Association for the Study of the Liver (APASL) published guidelines on non-cirrhotic portal fibrosis/idiopathic portal hypertension in 2007, there has been a surge in new information, especially with the introduction of the term porto-sinusoidal vascular disorder (PSVD). Non-cirrhotic intra-hepatic causes of portal hypertension include disorders with a clearly identifiable etiology, such as schistosomiasis, as well as disorders with an unclear etiology such as non-cirrhotic portal fibrosis (NCPF), also termed idiopathic portal hypertension (IPH). This entity is being increasingly recognized as being associated with systemic disease and drug therapy, especially cancer therapy. An international working group with extensive expertise in portal hypertension was assigned with formulating consensus guidelines to clarify the definition, diagnosis, histological features, natural history, and management of NCPF/IPH, especially in the context of PSVD. The guidelines were prepared based on evidence from existing published literature. Whenever there was paucity of evidence, expert opinion was included after detailed deliberation. The goal of this manuscript, therefore, is to enhance the current understanding and help create global consensus on the issues surrounding NCPF/IPH.
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Affiliation(s)
- Akash Shukla
- Department of Gastroenterology, King Edward Memorial Hospital and Seth Gordhandas Sunderdas Medical College, Mumbai, India
| | - Don C Rockey
- Digestive Disease Research Center, Medical University of South Carolina, 96 Jonathan Lucas Street, Suite 803, MSC 623, Charleston, SC, 29425, USA
| | | | | | - Ankita Singh
- Department of Gastroenterology, King Edward Memorial Hospital and Seth Gordhandas Sunderdas Medical College, Mumbai, India
| | - Arun Vaidya
- Department of Gastroenterology, King Edward Memorial Hospital and Seth Gordhandas Sunderdas Medical College, Mumbai, India
| | - Abraham Koshy
- Department of Gastroenterology, VPS Lakeshore Hospital, Kochi, Kerala, India
| | - Ashish Goel
- Department of Hepatology, CMC, Vellore, India
| | - A Kadir Dökmeci
- Department of Medicine, Ankara University School of Medicine, Ankara, Turkey
| | - Babulal Meena
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Cyriac Abby Philips
- Department of Clinical and Translational Hepatology, The Liver Institute, Rajagiri Hospital, Aluva, Kerala, India
| | - Chhagan Bihari Sharma
- Department of Pathology, Institute of Liver and Biliary Sciences, New Delhi, Delhi, India
| | - Diana A Payawal
- Fatima University Medical Center Manila, Manila, Philippines
| | - Dong Joon Kim
- Department of Internal Medicine, Hallym University College of Medicine, Seoul, South Korea
| | - Gin-Ho Lo
- Department of Medical Research, E-Da Hospital, Kaohsiung, School of Medicine for International Students, I-Shou University, 1, Yi-Da Road, Kaohsiung, 824, Taiwan
| | - Guohong Han
- Department of Liver Disease and Digestive Interventional Radiology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | | | - Ian R Wanless
- Department of Pathology, Dalhousie University, Halifax, Canada
| | - Jidong Jia
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, 95 Yongan Road, Beijing, Mainland, China
| | - Jose D Sollano
- Department of Medicine, University of Santo Tomas, Manila, Philippines
| | - Mamun Al Mahtab
- Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | - Mark Dhinesh Muthiah
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore, Singapore
- National University Centre for Organ Transplantation, National University Health System, Singapore, Singapore
| | - Mark W Sonderup
- Division of Hepatology, Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Mendez Sanchez Nahum
- Faculty of Medicine, National Autonomous University of Mexico, Mexico City, Mexico
| | | | - Necati Ormeci
- İstanbul Health and Technology University, Istanbul, Turkey
| | - Norifumi Kawada
- Department of Hepatology, Graduate School of Medicine, Osaka City University, 1-4-3 Asahimachi, Abeno-Ku, Osaka, 545-8585, Japan
| | - Rajender Reddy
- Division of Gastroenterology and Hepatology, 2 Dulles, Liver Transplant Office, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA, 19104, USA
| | - R K Dhiman
- Department of Hepatology, PGIMER, Chandigarh, India
| | - Rino Gani
- Division of Hepatobiliary, Department of Internal Medicine, Faculty of Medicine, Cipto Mangunkusumo Hospital, Universitas Indonesia, Jakarta, Indonesia
| | - Saeed S Hameed
- Department of Medicine, Aga Khan University and Hospital, Stadium Road, Karachi, 74800, Pakistan
| | - Sidharth Harindranath
- Department of Gastroenterology, King Edward Memorial Hospital and Seth Gordhandas Sunderdas Medical College, Mumbai, India
| | - Wasim Jafri
- Department of Medicine, Aga Khan University and Hospital, Stadium Road, Karachi, 74800, Pakistan
| | - Xiaolong Qi
- Center of Portal Hypertension, Department of Radiology, Zhongda Hospital, Medical School, Southeast University, Nurturing Center of Jiangsu Province for State Laboratory of AI Imaging & Interventional Radiology (Southeast University), Nanjing, China
| | - Yogesh Kumar Chawla
- Department of Hepatology and Gastroenterology, Kalinga Institute of MedicalSciences, KIIT University, Bhubaneshwar, India
| | - Yoshihiro Furuichi
- Department of Clinical Laboratory and Endoscopy, Tokyo Women's Medical University, Adachi Medical Center, Tokyo, Japan
| | - Ming-Hua Zheng
- MAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
- Key Laboratory of Diagnosis and Treatment for The Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, 325000, China
| | - Shiv Kumar Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India.
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Almalki WH, Almujri SS. Aging, ROS, and cellular senescence: a trilogy in the progression of liver fibrosis. Biogerontology 2024; 26:10. [PMID: 39546058 DOI: 10.1007/s10522-024-10153-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2024] [Accepted: 10/30/2024] [Indexed: 11/17/2024]
Abstract
Ageing is an inevitable and multifaceted biological process that impacts a wide range of cellular and molecular mechanisms, leading to the development of various diseases, such as liver fibrosis. Liver fibrosis progresses to cirrhosis, which is an advanced form due to high amounts of extracellular matrix and restoration of normal liver structure with failure to repair damaged tissue and cells, marking the end of liver function and total liver failure, ultimately death. The most important factors are reactive oxygen species (ROS) and cellular senescence. Oxidative stress is defined as an impairment by ROS, which are by-products of the mitochondrial electron transport chain and other key molecular pathways that induce cell damage and can activate cellular senescence pathways. Cellular senescence is characterized by pro-inflammatory cytokines, growth factors, and proteases secreted by senescent cells, collectively known as the senescence-associated secretory phenotype (SASP). The presence of senescent cells, which disrupt tissue architecture and function and increase senescent cell production in liver tissues, contributes to fibrogenesis. Hepatic stellate cells (HSCs) are activated in response to chronic liver injury, oxidative stress, and senescence signals that drive excessive production and deposition of extracellular matrix. This review article aims to provide a comprehensive overview of the pathogenic role of ROS and cellular senescence in the aging liver and their contribution to fibrosis.
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Affiliation(s)
- Waleed Hassan Almalki
- Department of Pharmacology, College of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Salem Salman Almujri
- Department of Pharmacology, College of Pharmacy, King Khalid University, 61421, Abha, Aseer, Saudi Arabia.
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Czaja AJ. Cellular senescence and its pathogenic and therapeutic implications in autoimmune hepatitis. Expert Rev Gastroenterol Hepatol 2024; 18:725-743. [PMID: 39575891 DOI: 10.1080/17474124.2024.2432480] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Accepted: 11/18/2024] [Indexed: 12/28/2024]
Abstract
INTRODUCTION Senescent cells are characterized by replicative arrest and phenotypes that produce diverse pro-inflammatory and pro-oxidant mediators. The senescence of diverse hepatic cell types could constitute an unrecognized pathogenic mechanism and prognostic determinant in autoimmune hepatitis. The impact of cellular senescence in autoimmune hepatitis is unknown, and it may suggest adjunctive management strategies. AREAS COVERED This review describes the molecular mechanisms of cellular senescence, indicates its diagnostic features, suggests its consequences, presents possible therapeutic interventions, and encourages investigations of its pathogenic role and management in autoimmune hepatitis. Treatment prospects include elimination or reversal of senescent cells, generation of ectopic telomerase, reactivation of dormant telomerase, neutralization of specific pro-inflammatory secretory products, and mitigation of the effects of mitochondrial dysfunction. EXPERT OPINION The occurrence, nature, and consequences of cellular senescence in autoimmune hepatitis must be determined. The senescence of diverse hepatic cell types could affect the outcome of autoimmune hepatitis by impairing hepatic regeneration, intensifying liver inflammation, and worsening hepatic fibrosis. Cellular senescence could contribute to suboptimal responses during conventional glucocorticoid-based therapy. Interventions that target specific pro-inflammatory products of the senescent phenotype or selectively promote apoptosis of senescent cells may be preferred adjunctive treatments for autoimmune hepatitis depending on the cancer risk.
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Affiliation(s)
- Albert J Czaja
- Mayo Clinic, Department of Medicine, Division of Gastroenterology and Hepatology, Rochester, MN, USA
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Kandemir I, Sahin AY, Oyaci Y, Khudiyeva S, Sahin M, Aksakal MT, Pehlivan M, Bas F, Pehlivan S. Effect of obesity and NAFLD on leukocyte telomere length and hTERT gene MNS16A VNTR variant. Sci Rep 2024; 14:25055. [PMID: 39443618 PMCID: PMC11499813 DOI: 10.1038/s41598-024-77091-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Accepted: 10/18/2024] [Indexed: 10/25/2024] Open
Abstract
It is known that telomere length (TL) (evaluated with T/S ratio) is shortened in the presence of obesity. In this study, we aimed to investigate how obesity in adolescents and non-alcoholic liver disease (NAFLD) within the obese group affect TL and the clinical significance of the human telomerase reverse transcriptase (hTERT) gene MNS16A VNTR variant in terms of NAFLD. Adolescents with exogenous obesity and healthy controls (aged 10-19 years) who applied to our adolescent outpatient clinic between May-October 2023 were included in this study. We performed upper abdominal ultrasonography to investigate the presence of NAFLD in adolescents with obesity and divided into two groups: those without hepatosteatosis (obese NAFLD (-)) and those with hepatosteatosis (obese NAFLD (+)). We recorded body weight, height, waist circumference, and blood pressure measurements and measured the T/S ratio (telomere sequence copy number/gene single copy number) by the Quantitative Polymerase Chain Reaction method. The groups were compared using frequentist and Bayesian methods. Eighty-three obese adolescents [63 NAFLD(+) 20 NAFLD(-)] and 69 lean controls were included in the study. Pairwise comparisons revealed that T/S ratio was significantly lower in the obese NAFLD (-) group than the obese NAFLD (+) and the control group (p = 0.025, p = 0.007, respectively). T/S ratio was lower in the LL allele group than in the other alleles (p = 0.022) and slightly higher in the obese group with metabolic syndrome compared to the obese group without metabolic syndrome (p = 0.072). hTERT-MNS16A-VNTR gene variant LL allele had a negative correlation with T/S ratio among the obese adolescent group. Patients with LL alleles had higher ALT, GGT, HOMA-IR, and ALT/AST. Diastolic blood pressure had a significant correlation with the T/S ratio. The T/S ratio was shorter in the obese adolescent group compared to healthy ones but was higher in the NAFLD (+) obese compared to the NAFLD (-) obese. ALT level and ALT/AST ratio were higher, T/S ratio was lower in the hTERT MNS16A VNTR variant LL allele group among obese adolescents. In addition, there was a significant correlation between the T/S ratio and diastolic blood pressure in obese adolescents.
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Affiliation(s)
- Ibrahim Kandemir
- Department of Pediatrics, Istanbul Health and Technology University Faculty of Medicine, Istanbul, Turkey.
| | - Aylin Yetim Sahin
- Adolescent Health PhD Program, Institute of Graduate Studies in Health Sciences, Istanbul University, Istanbul, Turkey
| | - Yasemin Oyaci
- Istanbul Faculty of Medicine, Department of Medical Biology, Istanbul University, Istanbul, Turkey
| | - Shahri Khudiyeva
- Department of Pediatrics, Istanbul University Istanbul Faculty of Medicine, Istanbul, Turkey
| | - Memduh Sahin
- Department of Gastroenterology, University of Health Sciences, Başakşehir Çam and Sakura City Hospital, Istanbul, Turkey
| | - Melike Tuğrul Aksakal
- Adolescent Health PhD Program, Institute of Graduate Studies in Health Sciences, Istanbul University, Istanbul, Turkey
| | - Mustafa Pehlivan
- Department of Hematology, University of Health Sciences, Başakşehir Çam and Sakura City Hospital, Istanbul, Turkey
| | - Firdevs Bas
- Department of Pediatric Endocrinology, Istanbul University Istanbul Faculty of Medicine, Istanbul, Turkey
| | - Sacide Pehlivan
- Istanbul Faculty of Medicine, Department of Medical Biology, Istanbul University, Istanbul, Turkey
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Moretti V, Romeo S, Valenti L. The contribution of genetics and epigenetics to MAFLD susceptibility. Hepatol Int 2024; 18:848-860. [PMID: 38662298 PMCID: PMC11450136 DOI: 10.1007/s12072-024-10667-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Accepted: 02/25/2024] [Indexed: 04/26/2024]
Abstract
Metabolic dysfunction-associated fatty liver disease (MAFLD) is the most common liver disease worldwide. The risk of developing MAFLD varies among individuals, due to a combination of environmental inherited and acquired genetic factors. Genome-wide association and next-generation sequencing studies are leading to the discovery of the common and rare genetic determinants of MAFLD. Thanks to the great advances in genomic technologies and bioinformatics analysis, genetic and epigenetic factors involved in the disease can be used to develop genetic risk scores specific for liver-related complications, which can improve risk stratification. Genetic and epigenetic factors lead to the identification of specific sub-phenotypes of MAFLD, and predict the individual response to a pharmacological therapy. Moreover, the variant transcripts and protein themselves represent new therapeutic targets. This review will discuss the current status of research into genetic as well as epigenetic modifiers of MAFLD development and progression.
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Affiliation(s)
- Vittoria Moretti
- Precision Medicine Lab, Biological Resource Center and Department of Transfusion Medicine, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Via F Sforza 35, 20122, Milan, Italy
| | - Stefano Romeo
- Department of Molecular and Clinical Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Luca Valenti
- Precision Medicine Lab, Biological Resource Center and Department of Transfusion Medicine, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Via F Sforza 35, 20122, Milan, Italy.
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy.
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Borie R, Ba I, Debray MP, Kannengiesser C, Crestani B. Syndromic genetic causes of pulmonary fibrosis. Curr Opin Pulm Med 2024; 30:473-483. [PMID: 38896087 DOI: 10.1097/mcp.0000000000001088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/21/2024]
Abstract
PURPOSE OF REVIEW The identification of extra-pulmonary symptoms plays a crucial role in diagnosing interstitial lung disease (ILD). These symptoms not only indicate autoimmune diseases but also hint at potential genetic disorders, suggesting a potential overlap between genetic and autoimmune origins. RECENT FINDINGS Genetic factors contributing to ILD are predominantly associated with telomere (TRG) and surfactant-related genes. While surfactant-related gene mutations typically manifest with pulmonary involvement alone, TRG mutations were initially linked to syndromic forms of pulmonary fibrosis, known as telomeropathies, which may involve hematological and hepatic manifestations with variable penetrance. Recognizing extra-pulmonary signs indicative of telomeropathy should prompt the analysis of TRG mutations, the most common genetic cause of familial pulmonary fibrosis. Additionally, various genetic diseases causing ILD, such as alveolar proteinosis, alveolar hemorrhage, or unclassifiable pulmonary fibrosis, often present as part of syndromes that include hepatic, hematological, or skin disorders. SUMMARY This review explores the main genetic conditions identified over the past two decades.
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Affiliation(s)
- Raphaël Borie
- Service de Pneumologie A Hôpital Bichat, APHP, Paris, France, Université Paris Cité, Inserm, PHERE, Université Paris Cité
| | | | | | | | - Bruno Crestani
- Service de Pneumologie A Hôpital Bichat, APHP, Paris, France, Université Paris Cité, Inserm, PHERE, Université Paris Cité
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Sanfeliu-Redondo D, Gibert-Ramos A, Gracia-Sancho J. Cell senescence in liver diseases: pathological mechanism and theranostic opportunity. Nat Rev Gastroenterol Hepatol 2024; 21:477-492. [PMID: 38485755 DOI: 10.1038/s41575-024-00913-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/12/2024] [Indexed: 06/30/2024]
Abstract
The liver is not oblivious to the passage of time, as ageing is a major risk factor for the development of acute and chronic liver diseases. Ageing produces alterations in all hepatic cells, affecting their phenotype and function and worsening the prognosis of liver disease. The ageing process also implies the accumulation of a cellular state characterized by a persistent proliferation arrest and a specific secretory phenotype named cellular senescence. Indeed, senescent cells have key roles in many physiological processes; however, their accumulation owing to ageing or pathological conditions contributes to the damage occurring in chronic diseases. The aim of this Review is to provide an updated description of the pathophysiological events in which hepatic senescent cells are involved and their role in liver disease progression. Finally, we discuss novel geroscience therapies that could be applied to prevent or improve liver diseases and age-mediated hepatic deregulations.
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Affiliation(s)
- David Sanfeliu-Redondo
- Liver Vascular Biology Laboratory, IDIBAPS Biomedical Research Institute - Hospital Clínic de Barcelona & CIBEREHD, Barcelona, Spain
| | - Albert Gibert-Ramos
- Liver Vascular Biology Laboratory, IDIBAPS Biomedical Research Institute - Hospital Clínic de Barcelona & CIBEREHD, Barcelona, Spain
| | - Jordi Gracia-Sancho
- Liver Vascular Biology Laboratory, IDIBAPS Biomedical Research Institute - Hospital Clínic de Barcelona & CIBEREHD, Barcelona, Spain.
- Department of Visceral Surgery and Medicine, Inselspital - University of Bern, Bern, Switzerland.
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Perrotta F, Sanduzzi Zamparelli S, D’Agnano V, Montella A, Fomez R, Pagliaro R, Schiattarella A, Cazzola M, Bianco A, Mariniello DF. Genomic Profiling for Predictive Treatment Strategies in Fibrotic Interstitial Lung Disease. Biomedicines 2024; 12:1384. [PMID: 39061958 PMCID: PMC11274143 DOI: 10.3390/biomedicines12071384] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Revised: 06/01/2024] [Accepted: 06/18/2024] [Indexed: 07/28/2024] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) has traditionally been considered the archetype of progressive fibrotic interstitial lung diseases (f-ILDs), but several other f-ILDs can also manifest a progressive phenotype. Integrating genomic signatures into clinical practice for f-ILD patients may help to identify patients predisposed to a progressive phenotype. In addition to the risk of progressive pulmonary fibrosis, there is a growing body of literature examining how pharmacogenomics influences treatment response, particularly regarding the efficacy and safety profiles of antifibrotic and immunomodulatory agents. In this narrative review, we discuss current studies in IPF and other forms of pulmonary fibrosis, including systemic autoimmune disorders associated ILDs, sarcoidosis and hypersensitivity pneumonitis. We also provide insights into the future direction of research in this complex field.
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Affiliation(s)
- Fabio Perrotta
- Department of Translational Medical Sciences, University of Campania “L. Vanvitelli”, 80131 Naples, Italy; (V.D.); (A.M.); (R.F.); (R.P.); (A.S.); (A.B.)
- Unit of Respiratory Medicine “L. Vanvitelli”, A.O. dei Colli, Monaldi Hospital, 80131 Naples, Italy
| | | | - Vito D’Agnano
- Department of Translational Medical Sciences, University of Campania “L. Vanvitelli”, 80131 Naples, Italy; (V.D.); (A.M.); (R.F.); (R.P.); (A.S.); (A.B.)
- Unit of Respiratory Medicine “L. Vanvitelli”, A.O. dei Colli, Monaldi Hospital, 80131 Naples, Italy
| | - Antonia Montella
- Department of Translational Medical Sciences, University of Campania “L. Vanvitelli”, 80131 Naples, Italy; (V.D.); (A.M.); (R.F.); (R.P.); (A.S.); (A.B.)
- Unit of Respiratory Medicine “L. Vanvitelli”, A.O. dei Colli, Monaldi Hospital, 80131 Naples, Italy
| | - Ramona Fomez
- Department of Translational Medical Sciences, University of Campania “L. Vanvitelli”, 80131 Naples, Italy; (V.D.); (A.M.); (R.F.); (R.P.); (A.S.); (A.B.)
- Unit of Respiratory Medicine “L. Vanvitelli”, A.O. dei Colli, Monaldi Hospital, 80131 Naples, Italy
| | - Raffaella Pagliaro
- Department of Translational Medical Sciences, University of Campania “L. Vanvitelli”, 80131 Naples, Italy; (V.D.); (A.M.); (R.F.); (R.P.); (A.S.); (A.B.)
- Unit of Respiratory Medicine “L. Vanvitelli”, A.O. dei Colli, Monaldi Hospital, 80131 Naples, Italy
| | - Angela Schiattarella
- Department of Translational Medical Sciences, University of Campania “L. Vanvitelli”, 80131 Naples, Italy; (V.D.); (A.M.); (R.F.); (R.P.); (A.S.); (A.B.)
- Unit of Respiratory Medicine “L. Vanvitelli”, A.O. dei Colli, Monaldi Hospital, 80131 Naples, Italy
| | - Mario Cazzola
- Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy;
| | - Andrea Bianco
- Department of Translational Medical Sciences, University of Campania “L. Vanvitelli”, 80131 Naples, Italy; (V.D.); (A.M.); (R.F.); (R.P.); (A.S.); (A.B.)
- Unit of Respiratory Medicine “L. Vanvitelli”, A.O. dei Colli, Monaldi Hospital, 80131 Naples, Italy
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12
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Téllez L, Donate J, Albillos A. [Portosinusoidal vascular disorder: A paradigm shift]. Med Clin (Barc) 2024; 162:439-447. [PMID: 38302397 DOI: 10.1016/j.medcli.2023.11.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2023] [Revised: 11/11/2023] [Accepted: 11/13/2023] [Indexed: 02/03/2024]
Abstract
The term portosinusoidal vascular disorder (PSVD) refers to a clinical-pathological entity that encompasses those patients with intrahepatic vascular damage without cirrhosis at risk of developing severe complications of portal hypertension. Numerous systemic diseases, genetic disorders, and toxic agents have been associated with this pathology, making its diagnosis an important clinical challenge. The recent description of uniform diagnostic criteria and a better understanding of its pathophysiology will allow for better identification of patients, even in early stages of the disease. Although there is currently no effective etiological treatment available, early diagnosis allows for the development of preventive strategies for some severe complications of portal hypertension.
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Affiliation(s)
- Luis Téllez
- Servicio de Gastroenterología y Hepatología. Hospital Universitario Ramón y Cajal, Madrid, España; Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, España; Centro de Investigación en Red Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, España; Universidad de Alcalá, Madrid, España.
| | - Jesús Donate
- Servicio de Gastroenterología y Hepatología. Hospital Universitario Ramón y Cajal, Madrid, España
| | - Agustín Albillos
- Servicio de Gastroenterología y Hepatología. Hospital Universitario Ramón y Cajal, Madrid, España; Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, España; Centro de Investigación en Red Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, España; Universidad de Alcalá, Madrid, España
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13
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Gellert-Kristensen H, Bojesen SE, Tybjærg Hansen A, Stender S. Telomere length and risk of cirrhosis, hepatocellular carcinoma, and cholangiocarcinoma in 63,272 individuals from the general population. Hepatology 2024; 79:857-868. [PMID: 37732945 DOI: 10.1097/hep.0000000000000608] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Accepted: 09/12/2023] [Indexed: 09/22/2023]
Abstract
BACKGROUND AND AIMS Inherited short telomeres are associated with a risk of liver disease, whereas longer telomeres predispose to cancer. The association between telomere length and risk of HCC and cholangiocarcinoma remains unknown. APPROACH AND RESULTS We measured leukocyte telomere length using multiplex PCR in 63,272 individuals from the Danish general population. Telomere length and plasma ALT concentration were not associated (β = 4 ×10 -6 , p -value = 0.06) in a linear regression model, without any signs of a nonlinear relationship. We tested the association between telomere length and risk of cirrhosis, HCC, and cholangiocarcinoma using Cox regression. During a median follow-up of 11 years, 241, 76, and 112 individuals developed cirrhosis, HCC, and cholangiocarcinoma, respectively. Telomere length and risk of cirrhosis were inversely and linearly associated ( p -value = 0.004, p for nonlinearity = 0.27). Individuals with telomeres in the shortest vs. longest quartile had a 2.25-fold higher risk of cirrhosis. Telomere length and risk of HCC were nonlinearly associated ( p -value = 0.009, p -value for nonlinearity = 0.01). This relationship resembled an inverted J-shape, with the highest risk observed in individuals with short telomeres. Individuals with telomeres in the shortest versus longest quartile had a 2.29-fold higher risk of HCC. Telomere length was inversely and linearly associated with the risk of cholangiocarcinoma. Individuals with telomeres in the shortest versus longest quartile had a 1.86-fold higher risk of cholangiocarcinoma. CONCLUSIONS Shorter telomere length is associated with a higher risk of cirrhosis, HCC, and cholangiocarcinoma.
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Affiliation(s)
- Helene Gellert-Kristensen
- Department of Clinical Biochemistry, Rigshospitalet, Denmark
- Copenhagen University Hospitals and Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
| | - Stig E Bojesen
- Copenhagen University Hospitals and Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
- Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Denmark
| | - Anne Tybjærg Hansen
- Department of Clinical Biochemistry, Rigshospitalet, Denmark
- Copenhagen University Hospitals and Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
| | - Stefan Stender
- Department of Clinical Biochemistry, Rigshospitalet, Denmark
- Copenhagen University Hospitals and Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
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14
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Kapse B, Budev MM, Singer JP, Greenland JR. Immune aging: biological mechanisms, clinical symptoms, and management in lung transplant recipients. FRONTIERS IN TRANSPLANTATION 2024; 3:1356948. [PMID: 38993782 PMCID: PMC11235310 DOI: 10.3389/frtra.2024.1356948] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/16/2023] [Accepted: 01/23/2024] [Indexed: 07/13/2024]
Abstract
While chronologic age can be precisely defined, clinical manifestations of advanced age occur in different ways and at different rates across individuals. The observed phenotype of advanced age likely reflects a superposition of several biological aging mechanisms which have gained increasing attention as the world contends with an aging population. Even within the immune system, there are multiple age-associated biological mechanisms at play, including telomere dysfunction, epigenetic dysregulation, immune senescence programs, and mitochondrial dysfunction. These biological mechanisms have associated clinical syndromes, such as telomere dysfunction leading to short telomere syndrome (STS), and optimal patient management may require recognition of biologically based aging syndromes. Within the clinical context of lung transplantation, select immune aging mechanisms are particularly pronounced. Indeed, STS is increasingly recognized as an indication for lung transplantation. At the same time, common aging phenotypes may be evoked by the stress of transplantation because lung allografts face a potent immune response, necessitating higher levels of immune suppression and associated toxicities, relative to other solid organs. Age-associated conditions exacerbated by lung transplant include bone marrow suppression, herpes viral infections, liver cirrhosis, hypogammaglobulinemia, frailty, and cancer risk. This review aims to dissect the molecular mechanisms of immune aging and describe their clinical manifestations in the context of lung transplantation. While these mechanisms are more likely to manifest in the context of lung transplantation, this mechanism-based approach to clinical syndromes of immune aging has broad relevance to geriatric medicine.
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Affiliation(s)
- Bhavya Kapse
- Department of Medicine, University of California, San Francisco, San Francisco, CA, United States
| | - Marie M. Budev
- Department of Pulmonary Medicine, Respiratory Institute, Cleveland Clinic, Cleveland, OH, United States
| | - Jonathan P. Singer
- Department of Medicine, University of California, San Francisco, San Francisco, CA, United States
| | - John R. Greenland
- Department of Medicine, University of California, San Francisco, San Francisco, CA, United States
- San Francisco VA Health Care System, Medicine, San Francisco, CA, United States
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15
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Campreciós G, Bartrolí B, Montironi C, Belmonte E, García-Pagán JC, Hernández-Gea V. Porto-sinusoidal vascular disorder. SINUSOIDAL CELLS IN LIVER DISEASES 2024:445-464. [DOI: 10.1016/b978-0-323-95262-0.00022-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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16
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Vittal A, Niewisch MR, Bhala S, Kudaravalli P, Rahman F, Hercun J, Kleiner DE, Savage SA, Koh C, Heller T, Giri N. Progression of liver disease and portal hypertension in dyskeratosis congenita and related telomere biology disorders. Hepatology 2023; 78:1777-1787. [PMID: 37184208 PMCID: PMC10733788 DOI: 10.1097/hep.0000000000000461] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Accepted: 04/28/2023] [Indexed: 05/16/2023]
Abstract
BACKGROUND AND AIMS Dyskeratosis congenita (DC) and related telomere biology disorders (TBD) are characterized by very short telomeres and multisystem organ involvement including liver disease. Our study aimed to characterize baseline hepatic abnormalities in patients with DC/TBD and determine risk factors associated with liver disease progression. APPROACH AND RESULTS A retrospective review was performed on a cohort of 58 patients (39 males) with DC/TBD who were prospectively evaluated at a single institute from 2002 to 2019. The median age at initial assessment was 18 (1.4-67.6) years, and median follow-up duration was 6 (1.4-8.2) years. Patients with autosomal or X-linked recessive inheritance and those with heterozygous TINF2 DC were significantly younger, predominantly male, and more likely to have DC-associated mucocutaneous triad features and severe bone marrow failure compared with autosomal dominant-non- TINF2 DC/TBD patients. Liver abnormality (defined at baseline assessment by laboratory and/or radiological findings) was present in 72.4% of patients with predominantly cholestatic pattern of liver enzyme elevation. Clinically significant liver disease and portal hypertension developed in 17.2% of patients during the 6-year follow-up; this progression was mainly seen in patients with recessive or TINF2 -associated DC. Significant risk factors associated with progression included the presence of pulmonary or vascular disease. CONCLUSIONS Our experience shows a high prevalence of cholestatic pattern of liver abnormality with progression to portal hypertension in patients with DC/TBD. Presence of pulmonary and/or vascular disease in patients with recessive or TINF2 DC was an important predictor of liver disease progression, suggesting the need for increased vigilance and monitoring for complications in these patients.
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Affiliation(s)
- Anusha Vittal
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Marena R Niewisch
- Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Sonia Bhala
- Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Pujitha Kudaravalli
- Department of Internal Medicine, SUNY Upstate Medical University, Syracuse, New York, USA
| | - Farial Rahman
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Julian Hercun
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - David E Kleiner
- Laboratory of Pathology, National Cancer Institute, Bethesda, Maryland, USA
| | - Sharon A Savage
- Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Christopher Koh
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Theo Heller
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Neelam Giri
- Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
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Banaszak LG, Smith-Simmer K, Shoger K, Lovrien L, Malik A, Sandbo N, Sultan S, Guzy R, Lowery EM, Churpek JE. Implementation of a prospective screening strategy to identify adults with a telomere biology disorder among those undergoing lung transplant evaluation for interstitial lung disease. Respir Med 2023; 220:107464. [PMID: 37951311 DOI: 10.1016/j.rmed.2023.107464] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Revised: 11/04/2023] [Accepted: 11/06/2023] [Indexed: 11/13/2023]
Abstract
INTRODUCTION Patients with interstitial lung disease (ILD) secondary to telomere biology disorders (TBD) experience increased morbidity after lung transplantation. Identifying patients with TBD may allow for personalized management to facilitate better outcomes. However, establishing a TBD diagnosis in adults is challenging. METHODS A TBD screening questionnaire was introduced prospectively into the lung transplant evaluation. Patients with ILD screening positive were referred for comprehensive TBD phenotyping and concurrent telomere length measurement and germline genetic testing. RESULTS Of 98 patients, 32 (33%) screened positive. Eight patients (8% of total; 25% of patients with a positive screen) met strict TBD diagnostic criteria, requiring either critically short lymphocyte telomeres (<1st percentile) (n = 4), a pathogenic variant in a TBD-associated gene (n = 1), or both (n = 3) along with a TBD clinical phenotype. Additional patients not meeting strict diagnostic criteria had histories consistent with TBD along with telomere lengths <10th percentile and/or rare variants in TBD-associated genes, highlighting a critical need to refine TBD diagnostic criteria for this patient population. CONCLUSION A TBD phenotype screening questionnaire in patients with ILD undergoing lung transplant evaluation has a diagnostic yield of 25%. Additional gene discovery, rare variant functional testing, and refined TBD diagnostic criteria are needed to realize the maximum benefit of testing for TBD in patients undergoing lung transplantation.
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Affiliation(s)
- Lauren G Banaszak
- Department of Medicine, University of Wisconsin-Madison, Madison, WI, 53705, USA.
| | - Kelcy Smith-Simmer
- Oncology Genetics, University of Wisconsin Carbone Cancer Center, UW Health, Madison, WI, 53705, USA
| | - Kyle Shoger
- Department of Medicine, University of Wisconsin-Madison, Madison, WI, 53705, USA
| | - Lauren Lovrien
- Department of Medicine, University of Wisconsin-Madison, Madison, WI, 53705, USA
| | - Amy Malik
- Department of Medicine, University of Wisconsin-Madison, Madison, WI, 53705, USA
| | - Nathan Sandbo
- Department of Medicine, University of Wisconsin-Madison, Madison, WI, 53705, USA
| | - Samir Sultan
- Department of Medicine, University of Wisconsin-Madison, Madison, WI, 53705, USA
| | - Robert Guzy
- Department of Medicine, University of Wisconsin-Madison, Madison, WI, 53705, USA
| | - Erin M Lowery
- Department of Medicine, University of Wisconsin-Madison, Madison, WI, 53705, USA
| | - Jane E Churpek
- Department of Medicine, University of Wisconsin-Madison, Madison, WI, 53705, USA.
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Liao P, Yan B, Wang C, Lei P. Telomeres: Dysfunction, Maintenance, Aging and Cancer. Aging Dis 2023; 15:2595-2631. [PMID: 38270117 PMCID: PMC11567242 DOI: 10.14336/ad.2023.1128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Accepted: 11/28/2023] [Indexed: 01/26/2024] Open
Abstract
Aging has emerged at the forefront of scientific research due to the growing social and economic costs associated with the growing aging global population. The defining features of aging involve a variety of molecular processes and cellular systems, which are interconnected and collaboratively contribute to the aging process. Herein, we analyze how telomere dysfunction potentially amplifies or accelerates the molecular and biochemical mechanisms underpinning each feature of aging and contributes to the emergence of age-associated illnesses, including cancer and neurodegeneration, via the perspective of telomere biology. Furthermore, the recently identified novel mechanistic actions for telomere maintenance offer a fresh viewpoint and approach to the management of telomeres and associated disorders. Telomeres and the defining features of aging are intimately related, which has implications for therapeutic and preventive approaches to slow aging and reduce the prevalence of age-related disorders.
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Affiliation(s)
- Pan Liao
- The School of Medicine, Nankai University, Tianjin, China.
- Haihe Laboratory of Cell Ecosystem, Department of Geriatrics, Tianjin Medical University General Hospital, Tianjin, China.
- Tianjin Geriatrics Institute, Tianjin Medical University General Hospital, Tianjin, China.
| | - Bo Yan
- Haihe Laboratory of Cell Ecosystem, Department of Geriatrics, Tianjin Medical University General Hospital, Tianjin, China.
- Tianjin Geriatrics Institute, Tianjin Medical University General Hospital, Tianjin, China.
| | - Conglin Wang
- Haihe Laboratory of Cell Ecosystem, Department of Geriatrics, Tianjin Medical University General Hospital, Tianjin, China.
- Tianjin Geriatrics Institute, Tianjin Medical University General Hospital, Tianjin, China.
| | - Ping Lei
- The School of Medicine, Nankai University, Tianjin, China.
- Haihe Laboratory of Cell Ecosystem, Department of Geriatrics, Tianjin Medical University General Hospital, Tianjin, China.
- Tianjin Geriatrics Institute, Tianjin Medical University General Hospital, Tianjin, China.
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Kagihara JE, Goyes D, Rabiee A. Diagnosis and Management of Noncirrhotic Portal Hypertension. CURRENT HEPATOLOGY REPORTS 2023; 22:252-262. [DOI: 10.1007/s11901-023-00619-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 10/10/2023] [Indexed: 01/04/2025]
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Fiordaliso M, Marincola G, Pala B, Muraro R, Mazzone M, Di Marcantonio MC, Mincione G. A Narrative Review on Non-Cirrohotic Portal Hypertension: Not All Portal Hypertensions Mean Cirrhosis. Diagnostics (Basel) 2023; 13:3263. [PMID: 37892084 PMCID: PMC10606323 DOI: 10.3390/diagnostics13203263] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Revised: 10/17/2023] [Accepted: 10/18/2023] [Indexed: 10/29/2023] Open
Abstract
Non-cirrhotic portal hypertension (NCPH), also known as idiopathic non-cirrhotic portal hypertension (INCPH) and porto-sinusoidal vascular disorder (PSVD), is a rare disease characterized by intrahepatic portal hypertension (IPH) in the absence of cirrhosis. The precise etiopathogenesis of IPH is an area of ongoing research. NCPH diagnosis is challenging, as there are no specific tests available to confirm the disease, and a high-quality liver biopsy, detailed clinical information, and an expert pathologist are necessary for diagnosis. Currently, the treatment of NCPH relies on the prevention of complications related to portal hypertension, following current guidelines of cirrhotic portal hypertension. No treatment has been studied that aimed to modify the natural history of the disease; however, transjugular intrahepatic porto-systemic shunt (TIPS) placement, shunt and liver transplantation are considerable symptomatic options. In this review, we discuss the heterogeneity of NCPH as well as its etiopathogenesis, clinical presentation and management issues. Starting from the assumption that portal hypertension does not always mean cirrhosis, cooperative studies are probably needed to clarify the issues of etiology and the possible genetic background of this rare disease. This knowledge might lead to better treatment and perhaps better prevention.
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Affiliation(s)
- Michele Fiordaliso
- Department of Medicine and Ageing Sciences, University “G. D’Annunzio” of Chieti–Pescara, Via dei Vestini 29, 66100 Chieti, Italy;
| | - Giuseppe Marincola
- Bariatric and Metabolic Surgery Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Largo Agostino Gemelli 8, 00168 Rome, Italy;
| | - Barbara Pala
- Division of Cardiology, Department of Clinical and Molecular Medicine, Sant’Andrea Hospital, Sapienza University of Rome, Via di Grottarossa, 1035/1039, 00189 Rome, Italy;
| | - Raffaella Muraro
- Department of Innovative Technologies in Medicine & Dentistry, University “G. D’Annunzio” of Chieti–Pescara, Via dei Vestini 29, 66100 Chieti, Italy; (R.M.); (M.M.); (M.C.D.M.)
| | - Mariangela Mazzone
- Department of Innovative Technologies in Medicine & Dentistry, University “G. D’Annunzio” of Chieti–Pescara, Via dei Vestini 29, 66100 Chieti, Italy; (R.M.); (M.M.); (M.C.D.M.)
| | - Maria Carmela Di Marcantonio
- Department of Innovative Technologies in Medicine & Dentistry, University “G. D’Annunzio” of Chieti–Pescara, Via dei Vestini 29, 66100 Chieti, Italy; (R.M.); (M.M.); (M.C.D.M.)
| | - Gabriella Mincione
- Department of Innovative Technologies in Medicine & Dentistry, University “G. D’Annunzio” of Chieti–Pescara, Via dei Vestini 29, 66100 Chieti, Italy; (R.M.); (M.M.); (M.C.D.M.)
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Moreno E, Martínez-Sanz J, Martín-Mateos R, Díaz-Álvarez J, Serrano-Villar S, Burgos-Santamaría D, Luna L, Vivancos MJ, Moreno-Zamora A, Pérez-Elías MJ, Moreno S, Dronda F, Montes ML, Sánchez-Conde M. Global DNA methylation and telomere length as markers of accelerated aging in people living with HIV and non-alcoholic fatty liver disease. BMC Genomics 2023; 24:567. [PMID: 37741970 PMCID: PMC10517540 DOI: 10.1186/s12864-023-09653-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Accepted: 09/05/2023] [Indexed: 09/25/2023] Open
Abstract
Metabolic-dysfunction-associated fatty liver disease (MAFLD) is a comorbidity that generally increases in people living with HIV (PLWH). This condition is usually accompanied by persistent inflammation and premature immune system aging. In this prospective cohort study, we describe a straightforward methodology for quantifying biomarkers of aging, such as DNA methylation and telomere length, in PLWH and in the context of another relevant condition, such as MAFLD. Fifty-seven samples in total, thirty-eight from PLWH and nineteen from non-PLWH participants with or without MAFLD, were obtained and subjected to DNA extraction from peripheral blood mononuclear cells (PBMCs). Global DNA methylation and telomere length quantification were performed using an adapted enzyme-linked immunosorbent assay (ELISA) and qPCR, respectively. The quantification results were analysed and corrected by clinically relevant variables in this context, such as age, sex, and metabolic syndrome. Our results show an increased association of these biomarkers in PLWH regardless of their MAFLD status. Thus, we propose including the quantification of these age-related factors in studies of comorbidities. This will allow a better understanding of the effect of comorbidities of HIV infection and MAFLD and prevent their effects in these populations in the future.
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Affiliation(s)
- Elena Moreno
- Department of Infectious Diseases, Hospital Universitario Ramón Y Cajal, Instituto Ramón Y Cajal de Investigación Sanitaria (IRYCIS), 28034, Madrid, Spain.
- CIBER de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, 28029, Madrid, Spain.
| | - Javier Martínez-Sanz
- Department of Infectious Diseases, Hospital Universitario Ramón Y Cajal, Instituto Ramón Y Cajal de Investigación Sanitaria (IRYCIS), 28034, Madrid, Spain
- CIBER de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, 28029, Madrid, Spain
| | - Rosa Martín-Mateos
- Department of Gastroenterology and Hepatology, Metabolic Liver Disease Clinic, Hospital Universitario Ramón Y Cajal, Instituto Ramón Y Cajal de Investigación Sanitaria (IRYCIS), 28034, Madrid, Spain
- Universidad de Alcalá, 28871, Madrid, Spain
| | - Jorge Díaz-Álvarez
- Department of Infectious Diseases, Hospital Universitario Ramón Y Cajal, Instituto Ramón Y Cajal de Investigación Sanitaria (IRYCIS), 28034, Madrid, Spain
- CIBER de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, 28029, Madrid, Spain
| | - Sergio Serrano-Villar
- Department of Infectious Diseases, Hospital Universitario Ramón Y Cajal, Instituto Ramón Y Cajal de Investigación Sanitaria (IRYCIS), 28034, Madrid, Spain
- CIBER de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, 28029, Madrid, Spain
| | - Diego Burgos-Santamaría
- Department of Gastroenterology and Hepatology, Metabolic Liver Disease Clinic, Hospital Universitario Ramón Y Cajal, Instituto Ramón Y Cajal de Investigación Sanitaria (IRYCIS), 28034, Madrid, Spain
| | - Laura Luna
- Department of Infectious Diseases, Hospital Universitario Ramón Y Cajal, Instituto Ramón Y Cajal de Investigación Sanitaria (IRYCIS), 28034, Madrid, Spain
- CIBER de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, 28029, Madrid, Spain
| | - María Jesús Vivancos
- Department of Infectious Diseases, Hospital Universitario Ramón Y Cajal, Instituto Ramón Y Cajal de Investigación Sanitaria (IRYCIS), 28034, Madrid, Spain
- CIBER de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, 28029, Madrid, Spain
| | - Ana Moreno-Zamora
- Department of Infectious Diseases, Hospital Universitario Ramón Y Cajal, Instituto Ramón Y Cajal de Investigación Sanitaria (IRYCIS), 28034, Madrid, Spain
- CIBER de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, 28029, Madrid, Spain
| | - María Jesús Pérez-Elías
- Department of Infectious Diseases, Hospital Universitario Ramón Y Cajal, Instituto Ramón Y Cajal de Investigación Sanitaria (IRYCIS), 28034, Madrid, Spain
- CIBER de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, 28029, Madrid, Spain
| | - Santiago Moreno
- Department of Infectious Diseases, Hospital Universitario Ramón Y Cajal, Instituto Ramón Y Cajal de Investigación Sanitaria (IRYCIS), 28034, Madrid, Spain
- CIBER de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, 28029, Madrid, Spain
- Universidad de Alcalá, 28871, Madrid, Spain
| | - Fernando Dronda
- Department of Infectious Diseases, Hospital Universitario Ramón Y Cajal, Instituto Ramón Y Cajal de Investigación Sanitaria (IRYCIS), 28034, Madrid, Spain
- CIBER de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, 28029, Madrid, Spain
| | - María Luisa Montes
- CIBER de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, 28029, Madrid, Spain
- Internal Medicine Service, Hospital Universitario La Paz. IdiPAZ, 28046, Madrid, Spain
| | - Matilde Sánchez-Conde
- Department of Infectious Diseases, Hospital Universitario Ramón Y Cajal, Instituto Ramón Y Cajal de Investigación Sanitaria (IRYCIS), 28034, Madrid, Spain.
- CIBER de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, 28029, Madrid, Spain.
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22
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Giuli L, Pallozzi M, Venturini G, Gasbarrini A, Ponziani FR, Santopaolo F. Molecular Mechanisms Underlying Vascular Liver Diseases: Focus on Thrombosis. Int J Mol Sci 2023; 24:12754. [PMID: 37628933 PMCID: PMC10454315 DOI: 10.3390/ijms241612754] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2023] [Revised: 08/07/2023] [Accepted: 08/11/2023] [Indexed: 08/27/2023] Open
Abstract
Vascular liver disorders (VLDs) comprise a wide spectrum of clinical-pathological entities that primarily affect the hepatic vascular system of both cirrhotic and non-cirrhotic patients. VLDs more frequently involve the portal and the hepatic veins, as well as liver sinusoids, resulting in an imbalance of liver homeostasis with serious consequences, such as the development of portal hypertension and liver fibrosis. Surprisingly, many VLDs are characterized by a prothrombotic phenotype. The molecular mechanisms that cause thrombosis in VLD are only partially explained by the alteration in the Virchow's triad (hypercoagulability, blood stasis, and endothelial damage) and nowadays their pathogenesis is incompletely described and understood. Studies about this topic have been hampered by the low incidence of VLDs in the general population and by the absence of suitable animal models. Recently, the role of coagulation imbalance in liver disease has been postulated as one of the main mechanisms linked to fibrogenesis, so a novel interest in vascular alterations of the liver has been renewed. This review provides a detailed analysis of the current knowledge of molecular mechanisms of VLD. We also focus on the promising role of anticoagulation as a strategy to prevent liver complications and to improve the outcome of these patients.
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Affiliation(s)
- Lucia Giuli
- Hepatology Unit, CEMAD Centro Malattie Dell’Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, 00168 Rome, Italy; (L.G.); (M.P.); (G.V.); (F.R.P.); (F.S.)
| | - Maria Pallozzi
- Hepatology Unit, CEMAD Centro Malattie Dell’Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, 00168 Rome, Italy; (L.G.); (M.P.); (G.V.); (F.R.P.); (F.S.)
| | - Giulia Venturini
- Hepatology Unit, CEMAD Centro Malattie Dell’Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, 00168 Rome, Italy; (L.G.); (M.P.); (G.V.); (F.R.P.); (F.S.)
| | - Antonio Gasbarrini
- Hepatology Unit, CEMAD Centro Malattie Dell’Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, 00168 Rome, Italy; (L.G.); (M.P.); (G.V.); (F.R.P.); (F.S.)
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Francesca Romana Ponziani
- Hepatology Unit, CEMAD Centro Malattie Dell’Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, 00168 Rome, Italy; (L.G.); (M.P.); (G.V.); (F.R.P.); (F.S.)
| | - Francesco Santopaolo
- Hepatology Unit, CEMAD Centro Malattie Dell’Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, 00168 Rome, Italy; (L.G.); (M.P.); (G.V.); (F.R.P.); (F.S.)
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23
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Putra J, Agarwal S, Al-Ibraheemi A, Alomari AI, Perez-Atayde AR. Spectrum of Liver Pathology in Dyskeratosis Congenita. Am J Surg Pathol 2023; 47:869-877. [PMID: 37246821 PMCID: PMC10524011 DOI: 10.1097/pas.0000000000002060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/30/2023]
Abstract
Dyskeratosis congenita (DC) is a rare multisystemic disorder associated with defective telomere maintenance. Frequent clinical manifestations of DC include reticular skin pigmentation, dystrophic nails, oral leukoplakia, and bone marrow failure. Hepatic disturbances are reported to occur in 7% of DC patients. This study aimed to evaluate the histopathologic spectrum of hepatic involvement in this disorder. DC patients with liver tissue in the pathology database at Boston Children's Hospital from 1995 to 2022 were identified. Clinical and pathologic information was documented. Thirteen specimens from 11 DC patients were included (M:F = 7:4; median age at the time of liver tissue evaluation: 18 y). DC-associated gene mutations were identified in 9 patients; TERF1-interacting nuclear factor 2 ( TINF2) was the most frequently represented gene mutation, seen in 4 patients. All patients had bone marrow failure, whereas dystrophic nails, cutaneous abnormal pigmentation, and oral leukoplakia were noted in 73%, 64%, and 55% of patients, respectively. Seven patients underwent bone marrow transplants before biopsy/autopsy (median interval of 45 mo). Histologically, 3 of 4 patients who presented with portal hypertension showed noncirrhotic changes (nodular regenerative hyperplasia and/or obliterative portal venopathy), whereas prominent central and sinusoidal fibrosis was noted in patients with intrahepatic shunting and those showing features of chronic passive congestion. All cases showed hepatocyte anisonucleosis. One patient developed hepatic angiosarcoma, and another 1 had colorectal adenocarcinoma metastatic to the liver. DC patients show heterogeneous histologic findings in their liver. The findings of noncirrhotic portal hypertension, intrahepatic shunting, and angiosarcoma suggest vascular functional/structural pathology as a possible unifying etiology of hepatic manifestations of DC.
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Affiliation(s)
| | | | | | - Ahmad I Alomari
- Division of Vascular and Interventional Radiology, Boston Children's Hospital and Harvard Medical School, Boston, MA
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24
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Choi YJ, Kim MS, Rhoades JH, Johnson NM, Berry CT, Root S, Chen Q, Tian Y, Fernandez RJ, Cramer Z, Adams-Tzivelekidis S, Li N, Johnson FB, Lengner CJ. Patient-Induced Pluripotent Stem Cell-Derived Hepatostellate Organoids Establish a Basis for Liver Pathologies in Telomeropathies. Cell Mol Gastroenterol Hepatol 2023; 16:451-472. [PMID: 37302654 PMCID: PMC10404563 DOI: 10.1016/j.jcmgh.2023.06.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 06/02/2023] [Accepted: 06/05/2023] [Indexed: 06/13/2023]
Abstract
BACKGROUND & AIMS Dyskeratosis congenita (DC) is a telomere biology disorder caused primarily by mutations in the DKC1 gene. Patients with DC and related telomeropathies resulting from premature telomere dysfunction experience multiorgan failure. In the liver, DC patients present with nodular hyperplasia, steatosis, inflammation, and cirrhosis. However, the mechanism responsible for telomere dysfunction-induced liver disease remains unclear. METHODS We used isogenic human induced pluripotent stem cells (iPSCs) harboring a causal DC mutation in DKC1 or a CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/Cas9)-corrected control allele to model DC liver pathologies. We differentiated these iPSCs into hepatocytes (HEPs) or hepatic stellate cells (HSCs) followed by generation of genotype-admixed hepatostellate organoids. Single-cell transcriptomics were applied to hepatostellate organoids to understand cell type-specific genotype-phenotype relationships. RESULTS Directed differentiation of iPSCs into HEPs and stellate cells and subsequent hepatostellate organoid formation revealed a dominant phenotype in the parenchyma, with DC HEPs becoming hyperplastic and also eliciting a pathogenic hyperplastic, proinflammatory response in stellate cells independent of stellate cell genotype. Pathogenic phenotypes in DKC1-mutant HEPs and hepatostellate organoids could be rescued via suppression of serine/threonine kinase AKT (protein kinase B) activity, a central regulator of MYC-driven hyperplasia downstream of DKC1 mutation. CONCLUSIONS Isogenic iPSC-derived admixed hepatostellate organoids offer insight into the liver pathologies in telomeropathies and provide a framework for evaluating emerging therapies.
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Affiliation(s)
- Young-Jun Choi
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Melissa S Kim
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Joshua H Rhoades
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Nicolette M Johnson
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Corbett T Berry
- Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Sarah Root
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Qijun Chen
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Yuhua Tian
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Rafael J Fernandez
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Zvi Cramer
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Stephanie Adams-Tzivelekidis
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Ning Li
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - F Brad Johnson
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
| | - Christopher J Lengner
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
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25
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Tometten M, Kirschner M, Meyer R, Begemann M, Halfmeyer I, Vieri M, Kricheldorf K, Maurer A, Platzbecker U, Radsak M, Schafhausen P, Corbacioglu S, Höchsmann B, Matthias Wilk C, Hinze C, Chromik J, Heuser M, Kreuter M, Koschmieder S, Panse J, Isfort S, Kurth I, Brümmendorf TH, Beier F. Identification of Adult Patients With Classical Dyskeratosis Congenita or Cryptic Telomere Biology Disorder by Telomere Length Screening Using Age-modified Criteria. Hemasphere 2023; 7:e874. [PMID: 37096215 PMCID: PMC10121438 DOI: 10.1097/hs9.0000000000000874] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Accepted: 03/08/2023] [Indexed: 04/26/2023] Open
Abstract
Telomere biology disorders (TBD) result from premature telomere shortening due to pathogenic germline variants in telomere maintenance-associated genes. In adults, TBD are characterized by mono/oligosymptomatic clinical manifestations (cryptic TBD) contributing to severe underdiagnosis. We present a prospective multi-institutional cohort study where telomere length (TL) screening was performed in either newly diagnosed patients with aplastic anemia (AA) or if TBD was clinically suspected by the treating physician. TL of 262 samples was measured via flow-fluorescence in situ hybridization (FISH). TL was considered suspicious once below the 10th percentile of normal individuals (standard screening) or if below 6.5 kb in patients >40 years (extended screening). In cases with shortened TL, next generation sequencing (NGS) for TBD-associated genes was performed. The patients referred fell into 6 different screening categories: (1) AA/paroxysmal nocturnal hemoglobinuria, (2) unexplained cytopenia, (3) dyskeratosis congenita, (4) myelodysplastic syndrome/acute myeloid leukemia, (5) interstitial lung disease, and (6) others. Overall, TL was found to be shortened in 120 patients (n = 86 standard and n = 34 extended screening). In 17 of the 76 (22.4%) standard patients with sufficient material for NGS, a pathogenic/likely pathogenic TBD-associated gene variant was identified. Variants of uncertain significance were detected in 17 of 76 (22.4%) standard and 6 of 29 (20.7%) extended screened patients. Expectedly, mutations were mainly found in TERT and TERC. In conclusion, TL measured by flow-FISH represents a powerful functional in vivo screening for an underlying TBD and should be performed in every newly diagnosed patient with AA as well as other patients with clinical suspicion for an underlying TBD in both children and adults.
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Affiliation(s)
- Mareike Tometten
- Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Medical Faculty, RWTH Aachen University, Aachen, Germany
- Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Germany
| | - Martin Kirschner
- Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Medical Faculty, RWTH Aachen University, Aachen, Germany
- Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Germany
| | - Robert Meyer
- Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Germany
- Institute for Human Genetics and Genomic Medicine, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Matthias Begemann
- Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Germany
- Institute for Human Genetics and Genomic Medicine, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Insa Halfmeyer
- Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Medical Faculty, RWTH Aachen University, Aachen, Germany
- Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Germany
| | - Margherita Vieri
- Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Medical Faculty, RWTH Aachen University, Aachen, Germany
- Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Germany
| | - Kim Kricheldorf
- Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Medical Faculty, RWTH Aachen University, Aachen, Germany
- Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Germany
| | - Angela Maurer
- Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Medical Faculty, RWTH Aachen University, Aachen, Germany
- Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Germany
| | - Uwe Platzbecker
- Clinic for Hematology, Cellular Therapy, and Hemostaseology, University Hospital Leipzig, Germany
| | - Markus Radsak
- Department of Hematology, Medical Oncology, and Pneumology, University Medical Center of the Johannes Gutenberg University, Mainz, Germany
| | - Philippe Schafhausen
- Department of Oncology, Hematology, and Bone Marrow Transplantation with Section of Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Selim Corbacioglu
- Department of Pediatric Hematology, Oncology and Stem Cell Transplantation, University of Hospital Regensburg, Germany
| | - Britta Höchsmann
- Institute of Transfusion Medicine and Immunogenetics, University of Ulm, Germany
- Institute of Clinical Transfusion Medicine and Immunogenetics, German Red Cross Blood Transfusion Service Baden-Württemberg-Hessen and University Hospital Ulm, Germany
| | - C. Matthias Wilk
- Department of Medical Oncology and Hematology, University Hospital Zurich, University of Zurich, Switzerland
| | - Claas Hinze
- Department of Pediatric Rheumatology and Immunology, University Hospital Muenster, Germany
| | - Jörg Chromik
- Department of Medicine, Hematology and Oncology, Goethe-University, Frankfurt, Germany
| | - Michael Heuser
- Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany
| | - Michael Kreuter
- Center for Interstitial and Rare Lung Diseases, Thoraxklinik, University of Heidelberg, German Center for Lung Research (DZL), Heidelberg, Germany
- Academic Center for Pulmonary Medicine, Departments of Pneumology, Mainz University Medical Center, and of Pulmonary, Critical Care & Sleep Medicine, Marienhaus Clinic Mainz, Germany
| | - Steffen Koschmieder
- Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Medical Faculty, RWTH Aachen University, Aachen, Germany
- Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Germany
| | - Jens Panse
- Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Medical Faculty, RWTH Aachen University, Aachen, Germany
- Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Germany
| | - Susanne Isfort
- Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Medical Faculty, RWTH Aachen University, Aachen, Germany
- Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Germany
| | - Ingo Kurth
- Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Germany
- Institute for Human Genetics and Genomic Medicine, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Tim H. Brümmendorf
- Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Medical Faculty, RWTH Aachen University, Aachen, Germany
- Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Germany
| | - Fabian Beier
- Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Medical Faculty, RWTH Aachen University, Aachen, Germany
- Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Germany
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26
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Revy P, Kannengiesser C, Bertuch AA. Genetics of human telomere biology disorders. Nat Rev Genet 2023; 24:86-108. [PMID: 36151328 DOI: 10.1038/s41576-022-00527-z] [Citation(s) in RCA: 68] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/11/2022] [Indexed: 01/24/2023]
Abstract
Telomeres are specialized nucleoprotein structures at the ends of linear chromosomes that prevent the activation of DNA damage response and repair pathways. Numerous factors localize at telomeres to regulate their length, structure and function, to avert replicative senescence or genome instability and cell death. In humans, Mendelian defects in several of these factors can result in abnormally short or dysfunctional telomeres, causing a group of rare heterogeneous premature-ageing diseases, termed telomeropathies, short-telomere syndromes or telomere biology disorders (TBDs). Here, we review the TBD-causing genes identified so far and describe their main functions associated with telomere biology. We present molecular aspects of TBDs, including genetic anticipation, phenocopy, incomplete penetrance and somatic genetic rescue, which underlie the complexity of these diseases. We also discuss the implications of phenotypic and genetic features of TBDs on fundamental aspects related to human telomere biology, ageing and cancer, as well as on diagnostic, therapeutic and clinical approaches.
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Affiliation(s)
- Patrick Revy
- INSERM UMR 1163, Laboratory of Genome Dynamics in the Immune System, Equipe Labellisée Ligue Nationale contre le Cancer, Paris, France.
- Université Paris Cité, Imagine Institute, Paris, France.
| | - Caroline Kannengiesser
- APHP Service de Génétique, Hôpital Bichat, Paris, France
- Inserm U1152, Université Paris Cité, Paris, France
| | - Alison A Bertuch
- Departments of Paediatrics and Molecular & Human Genetics, Baylor College of Medicine, Houston, TX, USA
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27
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Optimizing Screening for Early Disease Detection in Familial Pulmonary Fibrosis (FLORIS): A Prospective Cohort Study Design. J Clin Med 2023; 12:jcm12020674. [PMID: 36675603 PMCID: PMC9862447 DOI: 10.3390/jcm12020674] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 12/22/2022] [Accepted: 01/04/2023] [Indexed: 01/19/2023] Open
Abstract
Background: Familial pulmonary fibrosis (FPF) can be defined as pulmonary fibrosis in two or more first-degree family members. The first-degree family members of FPF patients are at high risk of developing FPF and are eligible for screening. Reproducible studies investigating risk factors for disease are much needed. Methods: Description of the screening study protocol for a single-center, prospective cohort study; the study will include 200 asymptomatic, first-degree family members of patients with FPF who will undergo three study visits in two years. The primary objective is determining the diagnostic value of parameters for detection of early FPF; the secondary objectives are determining the optimal timing of the screening interval and gaining insight into the natural history of early FPF. The presence of interstitial lung disease (ILD) changes on high-resolution computed tomography of the chest is indicative of preclinical ILD; the changes are determined at baseline. The comparison between the group with and without ILD changes is made for clinical parameters (pulmonary function, presence of digital clubbing, presence of Velcro-like crackles, blood count, liver- and kidney-function testing, patient-reported cough and dyspnea score) and exploratory parameters. Discussion: This study will be the first large-size, prospective, longitudinal cohort study for yearly screening of asymptomatic family members of FPF patients investigating the diagnostic value of parameters, including lung function, to detect early FPF. More effective screening strategies could advance early disease detection.
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28
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Papiris SA, Kannengiesser C, Borie R, Kolilekas L, Kallieri M, Apollonatou V, Ba I, Nathan N, Bush A, Griese M, Dieude P, Crestani B, Manali ED. Genetics in Idiopathic Pulmonary Fibrosis: A Clinical Perspective. Diagnostics (Basel) 2022; 12:2928. [PMID: 36552935 PMCID: PMC9777433 DOI: 10.3390/diagnostics12122928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 11/17/2022] [Accepted: 11/18/2022] [Indexed: 11/25/2022] Open
Abstract
BACKGROUND Unraveling the genetic background in a significant proportion of patients with both sporadic and familial IPF provided new insights into the pathogenic pathways of pulmonary fibrosis. AIM The aim of the present study is to overview the clinical significance of genetics in IPF. PERSPECTIVE It is fascinating to realize the so-far underestimated but dynamically increasing impact that genetics has on aspects related to the pathophysiology, accurate and early diagnosis, and treatment and prevention of this devastating disease. Genetics in IPF have contributed as no other in unchaining the disease from the dogma of a "a sporadic entity of the elderly, limited to the lungs" and allowed all scientists, but mostly clinicians, all over the world to consider its many aspects and "faces" in all age groups, including its co-existence with several extra pulmonary conditions from cutaneous albinism to bone-marrow and liver failure. CONCLUSION By providing additional evidence for unsuspected characteristics such as immunodeficiency, impaired mucus, and surfactant and telomere maintenance that very often co-exist through the interaction of common and rare genetic variants in the same patient, genetics have created a generous and pluralistic yet unifying platform that could lead to the understanding of the injurious and pro-fibrotic effects of many seemingly unrelated extrinsic and intrinsic offending factors. The same platform constantly instructs us about our limitations as well as about the heritability, the knowledge and the wisdom that is still missing.
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Affiliation(s)
- Spyros A. Papiris
- 2nd Pulmonary Medicine Department, General University Hospital “Attikon”, Medical School, National and Kapodistrian University of Athens, 12462 Athens, Greece
| | - Caroline Kannengiesser
- Département de Génétique, APHP Hôpital Bichat, Université de Paris, 75018 Paris, France
- INSERM UMR 1152, Université de Paris, 75018 Paris, France
| | - Raphael Borie
- Service de Pneumologie A, INSERM UMR_1152, Centre de Référence des Maladies Pulmonaires Rares, FHU APOLLO, APHP Hôpital Bichat, Sorbonne Université, 75018 Paris, France
| | - Lykourgos Kolilekas
- 7th Pulmonary Department, Athens Chest Hospital “Sotiria”, 11527 Athens, Greece
| | - Maria Kallieri
- 2nd Pulmonary Medicine Department, General University Hospital “Attikon”, Medical School, National and Kapodistrian University of Athens, 12462 Athens, Greece
| | - Vasiliki Apollonatou
- 2nd Pulmonary Medicine Department, General University Hospital “Attikon”, Medical School, National and Kapodistrian University of Athens, 12462 Athens, Greece
| | - Ibrahima Ba
- Département de Génétique, APHP Hôpital Bichat, Université de Paris, 75018 Paris, France
| | - Nadia Nathan
- Peditric Pulmonology Department and Reference Centre for Rare Lung Diseases RespiRare, INSERM UMR_S933 Laboratory of Childhood Genetic Diseases, Armand Trousseau Hospital, Sorbonne University and APHP, 75012 Paris, France
| | - Andrew Bush
- Paediatrics and Paediatric Respirology, Imperial College, Imperial Centre for Paediatrics and Child Health, Royal Brompton Harefield NHS Foundation Trust, London SW3 6NP, UK
| | - Matthias Griese
- Department of Pediatric Pneumology, Dr von Hauner Children’s Hospital, Ludwig-Maximilians-University, German Center for Lung Research, 80337 Munich, Germany
| | - Philippe Dieude
- Department of Rheumatology, INSERM U1152, APHP Hôpital Bichat-Claude Bernard, Université de Paris, 75018 Paris, France
| | - Bruno Crestani
- Service de Pneumologie A, INSERM UMR_1152, Centre de Référence des Maladies Pulmonaires Rares, FHU APOLLO, APHP Hôpital Bichat, Sorbonne Université, 75018 Paris, France
| | - Effrosyni D. Manali
- 2nd Pulmonary Medicine Department, General University Hospital “Attikon”, Medical School, National and Kapodistrian University of Athens, 12462 Athens, Greece
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29
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Faingelernt Y, Nassar R, Ling G, Kodman Y, Feuerstein T, Yerushalmi B. Early life liver cirrhosis and variable clinical presentation in telomere disease. Acta Paediatr 2022; 111:2416-2421. [PMID: 36070080 DOI: 10.1111/apa.16539] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2022] [Revised: 08/25/2022] [Accepted: 09/06/2022] [Indexed: 11/28/2022]
Abstract
AIM Telomeres are DNA sequences of tandem TTAGGG repeats that protect chromosome ends from degradation and instability. Constitutional loss-of-function telomerase mutations result in rapid telomere shortening, premature senescence, and cell death. Liver cirrhosis is rare and has only been reported in adults. We present five family members of Bedouin-Muslim origin, all of which carry the same mutation, and yet demonstrate an extremely variable phenotypical presentation, including liver cirrhosis during early childhood. METHODS A multidisciplinary long-term follow-up of two healthy and three affected patients was analysed. The mutation (r.95G>C) was identified in all patients using Sanger sequencing. Telomere length samples were obtained and analysed. RESULTS Clinical phenotypes were extremely variable, including age at first symptoms, organ involvement, disease severity, and patient prognosis. The most prominent clinical phenotype is liver involvement, including end-stage liver disease early in life, which affects three members of the family. Affected patients had markedly shorter telomeres. CONCLUSION We describe an unusual presentation of early liver failure in telomere disease patients. Little, if any, is known about the association between the genotype and phenotype among children with telomere disease and whether the mutation we have described (r.95G>C) is predisposed to early severe hepatic involvement.
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Affiliation(s)
- Yaniv Faingelernt
- Paediatric Gastroenterology Unit, Soroka University Medical Centre, Beer-Sheva, Israel.,Faculty of Health Sciences, Ben-Gurion University, Beer-Sheva, Israel
| | - Raouf Nassar
- Paediatric Gastroenterology Unit, Soroka University Medical Centre, Beer-Sheva, Israel.,Faculty of Health Sciences, Ben-Gurion University, Beer-Sheva, Israel
| | - Galina Ling
- Paediatric Gastroenterology Unit, Soroka University Medical Centre, Beer-Sheva, Israel.,Faculty of Health Sciences, Ben-Gurion University, Beer-Sheva, Israel
| | - Yona Kodman
- Immune Phenotype Laboratory, Department of Haematology-Oncology, Schneider Children's Medical Centre of Israel, Israel
| | - Tamar Feuerstein
- Immune Phenotype Laboratory, Department of Haematology-Oncology, Schneider Children's Medical Centre of Israel, Israel
| | - Baruch Yerushalmi
- Paediatric Gastroenterology Unit, Soroka University Medical Centre, Beer-Sheva, Israel.,Faculty of Health Sciences, Ben-Gurion University, Beer-Sheva, Israel
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30
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Abstract
Telomere biology was first studied in maize, ciliates, yeast, and mice, and in recent decades, it has informed understanding of common disease mechanisms with broad implications for patient care. Short telomere syndromes are the most prevalent premature aging disorders, with prominent phenotypes affecting the lung and hematopoietic system. Less understood are a newly recognized group of cancer-prone syndromes that are associated with mutations that lengthen telomeres. A large body of new data from Mendelian genetics and epidemiology now provides an opportunity to reconsider paradigms related to the role of telomeres in human aging and cancer, and in some cases, the findings diverge from what was interpreted from model systems. For example, short telomeres have been considered potent drivers of genome instability, but age-associated solid tumors are rare in individuals with short telomere syndromes, and T cell immunodeficiency explains their spectrum. More commonly, short telomeres promote clonal hematopoiesis, including somatic reversion, providing a new leukemogenesis paradigm that is independent of genome instability. Long telomeres, on the other hand, which extend the cellular life span in vitro, are now appreciated to be the most common shared germline risk factor for cancer in population studies. Through this contemporary lens, I revisit here the role of telomeres in human aging, focusing on how short and long telomeres drive cancer evolution but through distinct mechanisms.
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Affiliation(s)
- Mary Armanios
- Departments of Oncology, Genetic Medicine, Pathology, and Molecular Biology and Genetics; Telomere Center at Johns Hopkins; and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA;
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31
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Fiesco-Roa MÓ, García-de Teresa B, Leal-Anaya P, van ‘t Hek R, Wegman-Ostrosky T, Frías S, Rodríguez A. Fanconi anemia and dyskeratosis congenita/telomere biology disorders: Two inherited bone marrow failure syndromes with genomic instability. Front Oncol 2022; 12:949435. [PMID: 36091172 PMCID: PMC9453478 DOI: 10.3389/fonc.2022.949435] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Accepted: 08/01/2022] [Indexed: 11/13/2022] Open
Abstract
Inherited bone marrow failure syndromes (IBMFS) are a complex and heterogeneous group of genetic diseases. To date, at least 13 IBMFS have been characterized. Their pathophysiology is associated with germline pathogenic variants in genes that affect hematopoiesis. A couple of these diseases also have genomic instability, Fanconi anemia due to DNA damage repair deficiency and dyskeratosis congenita/telomere biology disorders as a result of an alteration in telomere maintenance. Patients can have extramedullary manifestations, including cancer and functional or structural physical abnormalities. Furthermore, the phenotypic spectrum varies from cryptic features to patients with significantly evident manifestations. These diseases require a high index of suspicion and should be considered in any patient with abnormal hematopoiesis, even if extramedullary manifestations are not evident. This review describes the disrupted cellular processes that lead to the affected maintenance of the genome structure, contrasting the dysmorphological and oncological phenotypes of Fanconi anemia and dyskeratosis congenita/telomere biology disorders. Through a dysmorphological analysis, we describe the phenotypic features that allow to make the differential diagnosis and the early identification of patients, even before the onset of hematological or oncological manifestations. From the oncological perspective, we analyzed the spectrum and risks of cancers in patients and carriers.
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Affiliation(s)
- Moisés Ó. Fiesco-Roa
- Laboratorio de Citogenética, Instituto Nacional de Pediatría, Ciudad de México, Mexico
- Maestría y Doctorado en Ciencias Médicas, Universidad Nacional Autónoma de México (UNAM), Ciudad Universitaria, Ciudad de México, Mexico
| | | | - Paula Leal-Anaya
- Departamento de Genética Humana, Instituto Nacional de Pediatría, Ciudad de México, Mexico
| | - Renée van ‘t Hek
- Facultad de Medicina, Universidad Nacional Autoínoma de Meíxico (UNAM), Ciudad Universitaria, Ciudad de México, Mexico
| | - Talia Wegman-Ostrosky
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Ciudad de México, Mexico
| | - Sara Frías
- Laboratorio de Citogenética, Instituto Nacional de Pediatría, Ciudad de México, Mexico
- Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México (UNAM), Ciudad de México, Mexico
- *Correspondence: Alfredo Rodríguez, ; Sara Frías,
| | - Alfredo Rodríguez
- Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México (UNAM), Ciudad de México, Mexico
- Unidad de Genética de la Nutrición, Instituto Nacional de Pediatría, Ciudad de México, Mexico
- *Correspondence: Alfredo Rodríguez, ; Sara Frías,
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32
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Dokal I, Tummala H, Vulliamy T. Inherited bone marrow failure in the pediatric patient. Blood 2022; 140:556-570. [PMID: 35605178 PMCID: PMC9373017 DOI: 10.1182/blood.2020006481] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Accepted: 12/17/2020] [Indexed: 12/05/2022] Open
Abstract
Inherited bone marrow (BM) failure syndromes are a diverse group of disorders characterized by BM failure, usually in association with ≥1 extrahematopoietic abnormalities. BM failure, which can involve ≥1 cell lineages, often presents in the pediatric age group. Furthermore, some children initially labeled as having idiopathic aplastic anemia or myelodysplasia represent cryptic cases of inherited BM failure. Significant advances in the genetics of these syndromes have been made, identifying more than 100 disease genes, giving insights into normal hematopoiesis and how it is disrupted in patients with BM failure. They have also provided important information on fundamental biological pathways, including DNA repair: Fanconi anemia (FA) genes; telomere maintenance: dyskeratosis congenita (DC) genes; and ribosome biogenesis: Shwachman-Diamond syndrome and Diamond-Blackfan anemia genes. In addition, because these disorders are usually associated with extrahematopoietic abnormalities and increased risk of cancer, they have provided insights into human development and cancer. In the clinic, genetic tests stemming from the recent advances facilitate diagnosis, especially when clinical features are insufficient to accurately classify a disorder. Hematopoietic stem cell transplantation using fludarabine-based protocols has significantly improved outcomes, particularly in patients with FA or DC. Management of some other complications, such as cancer, remains a challenge. Recent studies have suggested the possibility of new and potentially more efficacious therapies, including a renewed focus on hematopoietic gene therapy and drugs [transforming growth factor-β inhibitors for FA and PAPD5, a human poly(A) polymerase, inhibitors for DC] that target disease-specific defects.
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Affiliation(s)
- Inderjeet Dokal
- Centre for Genomics and Child Health, Blizard Institute, London, United Kingdom; and
- Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Barts Health National Health Service (NHS) Trust, London, United Kingdom
| | - Hemanth Tummala
- Centre for Genomics and Child Health, Blizard Institute, London, United Kingdom; and
- Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Barts Health National Health Service (NHS) Trust, London, United Kingdom
| | - Tom Vulliamy
- Centre for Genomics and Child Health, Blizard Institute, London, United Kingdom; and
- Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Barts Health National Health Service (NHS) Trust, London, United Kingdom
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33
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Tummala H, Walne A, Dokal I. The biology and management of dyskeratosis congenita and related disorders of telomeres. Expert Rev Hematol 2022; 15:685-696. [PMID: 35929966 DOI: 10.1080/17474086.2022.2108784] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Accepted: 07/29/2022] [Indexed: 11/04/2022]
Abstract
BACKGROUND Dyskeratosis congenita (DC) is a multisystem syndrome characterized by mucocutaneous abnormalities, bone marrow failure, and predisposition to cancer. Studies over the last 25 years have led to the identification of 18 disease genes. These have a principal role in telomere maintenance, and patients usually have very short/abnormal telomeres. The advances have also led to the unification of DC with a number of other diseases, now collectively referred to as the telomeropathies or telomere biology disorders. WHAT IS COVERED Clinical features, genetics, and biology of the different subtypes. Expert view on diagnosis, treatment of the hematological complications and future. EXPERT VIEW As these are very pleotropic disorders affecting multiple organs, a high index of suspicion is necessary to make the diagnosis. Telomere length measurement and genetic analysis of the disease genes have become useful diagnostic tools. Although hematological defects can respond to danazol/oxymetholone, the only current curative treatment for these is hematopoietic stem cell transplantation (HSCT) using fludarabine-based conditioning protocols. New therapies are needed where danazol/oxymetholone is ineffective and HSCT is not feasible.
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Affiliation(s)
- Hemanth Tummala
- Centre for Genomics and Child Health, Blizard Institute, Barts and The London Faculty of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Amanda Walne
- Centre for Genomics and Child Health, Blizard Institute, Barts and The London Faculty of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Inderjeet Dokal
- Centre for Genomics and Child Health, Blizard Institute, Barts and The London Faculty of Medicine and Dentistry, Queen Mary University of London, London, UK
- Department of Haematology, Barts Health, London, UK
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34
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Guérin C, Crestani B, Dupin C, Kawano-Dourado L, Ba I, Kannengiesser C, Borie R. [Telomeres and lung]. Rev Mal Respir 2022; 39:595-606. [PMID: 35715316 DOI: 10.1016/j.rmr.2022.03.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Accepted: 02/26/2022] [Indexed: 10/18/2022]
Abstract
Genetic studies of familial forms of interstitial lung disease (ILD) have led to the discovery of telomere-related gene (TRG) mutations (TERT, TERC, RTEL1, PARN, DKC1, TINF2, NAF1, NOP10, NHP2, ACD, ZCCH8) in approximately 30% of familial ILD forms. ILD patients with TRG mutation are also subject to extra-pulmonary (immune-hematological, hepatic and/or mucosal-cutaneous) manifestations. TRG mutations may be associated not only with idiopathic pulmonary fibrosis (IPF), but also with non-IPF ILDs, including idiopathic and secondary ILDs, such as hypersensitivity pneumonitis (HP). The presence of TRG mutation may also be associated with an accelerated decline of forced vital capacity (FVC) or poorer prognosis after lung transplantation, notwithstanding which, usual ILD treatments may be proposed. Lastly, patients and their relatives are called upon to reduce their exposure to environmental lung toxicity, and are likely to derive benefit from specific genetic counseling and pre-symptomatic genetic testing.
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Affiliation(s)
- C Guérin
- Service de Pneumologie A, Centre de compétences maladies pulmonaires rares, AP-HP, Hôpital Bichat, Paris, France..
| | - B Crestani
- Service de Pneumologie A, Centre de compétences maladies pulmonaires rares, AP-HP, Hôpital Bichat, Paris, France.; INSERM, Unité 1152; Université Paris Diderot, Paris, France
| | - C Dupin
- Service de Pneumologie A, Centre de compétences maladies pulmonaires rares, AP-HP, Hôpital Bichat, Paris, France.; INSERM, Unité 1152; Université Paris Diderot, Paris, France
| | - L Kawano-Dourado
- INSERM, Unité 1152; Université Paris Diderot, Paris, France.; HCor Research Institute, Hôpital de Caracao, Sao Paulo, Brésil.; Département de Pneumologie, InCor, Université de Sao Paulo, Sao Paulo, Brésil
| | - I Ba
- INSERM, Unité 1152; Université Paris Diderot, Paris, France.; Département de Génétique, AP-HP, Hôpital Bichat, Paris, France
| | - C Kannengiesser
- INSERM, Unité 1152; Université Paris Diderot, Paris, France.; Département de Génétique, AP-HP, Hôpital Bichat, Paris, France
| | - R Borie
- Service de Pneumologie A, Centre de compétences maladies pulmonaires rares, AP-HP, Hôpital Bichat, Paris, France.; INSERM, Unité 1152; Université Paris Diderot, Paris, France
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35
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Abstract
Parenchymal lung disease is the fourth leading cause of death in the United States; among the top causes, it continues on the rise. Telomeres and telomerase have historically been linked to cellular processes related to aging and cancer, but surprisingly, in the recent decade genetic discoveries have linked the most apparent manifestations of telomere and telomerase dysfunction in humans to the etiology of lung disease: both idiopathic pulmonary fibrosis (IPF) and emphysema. The short telomere defect is pervasive in a subset of IPF patients, and human IPF is the phenotype most intimately tied to germline defects in telomere maintenance. One-third of families with pulmonary fibrosis carry germline mutations in telomerase or other telomere maintenance genes, and one-half of patients with apparently sporadic IPF have short telomere length. Beyond explaining genetic susceptibility, short telomere length uncovers clinically relevant syndromic extrapulmonary disease, including a T-cell immunodeficiency and a propensity to myeloid malignancies. Recognition of this subset of patients who share a unifying molecular defect has provided a precision medicine paradigm wherein the telomere-mediated lung disease diagnosis provides more prognostic value than histopathology or multidisciplinary evaluation. Here, we critically evaluate this progress, emphasizing how the genetic findings put forth a new pathogenesis paradigm of age-related lung disease that links telomere abnormalities to alveolar stem senescence, remodeling, and defective gas exchange.
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Affiliation(s)
- Jonathan K. Alder
- Division of Pulmonary and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh PA, United States
| | - Mary Armanios
- Departments of Oncology and Genetic Medicine, Telomere Center at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, MD, United States
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36
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Liver Steatosis: A Marker of Metabolic Risk in Children. Int J Mol Sci 2022; 23:ijms23094822. [PMID: 35563210 PMCID: PMC9100068 DOI: 10.3390/ijms23094822] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 04/24/2022] [Accepted: 04/24/2022] [Indexed: 11/16/2022] Open
Abstract
Obesity is one of the greatest health challenges affecting children of all ages and ethnicities. Almost 19% of children and adolescents worldwide are overweight or obese, with an upward trend in the last decades. These reports imply an increased risk of fat accumulation in hepatic cells leading to a series of histological hepatic damages gathered under the acronym NAFLD (Non-Alcoholic Fatty Liver Disease). Due to the complex dynamics underlying this condition, it has been recently renamed as 'Metabolic Dysfunction Associated Fatty Liver Disease (MAFLD)', supporting the hypothesis that hepatic steatosis is a key component of the large group of clinical and laboratory abnormalities of Metabolic Syndrome (MetS). This review aims to share the latest scientific knowledge on MAFLD in children in an attempt to offer novel insights into the complex dynamics underlying this condition, focusing on the novel molecular aspects. Although there is still no treatment with a proven efficacy for this condition, starting from the molecular basis of the disease, MAFLD's therapeutic landscape is rapidly expanding, and different medications seem to act as modifiers of liver steatosis, inflammation, and fibrosis.
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37
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Phillips-Houlbracq M, Mal H, Cottin V, Gauvain C, Beier F, Sicre de Fontbrune F, Sidali S, Mornex JF, Hirschi S, Roux A, Weisenburger G, Roussel A, Wémeau-Stervinou L, Le Pavec J, Pison C, Marchand Adam S, Froidure A, Lazor R, Naccache JM, Jouneau S, Nunes H, Reynaud-Gaubert M, Le Borgne A, Boutboul D, Ba I, Boileau C, Crestani B, Kannengiesser C, Borie R. Determinants of survival after lung transplantation in telomerase-related gene mutation carriers: A retrospective cohort. Am J Transplant 2022; 22:1236-1244. [PMID: 34854205 DOI: 10.1111/ajt.16893] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 10/01/2021] [Accepted: 10/20/2021] [Indexed: 01/25/2023]
Abstract
Carriers of germline telomerase-related gene (TRG) mutations can show poor prognosis, with an increase in common hematological complications after lung transplantation (LT) for pulmonary fibrosis. The aim of this study was to describe the outcomes after LT in recipients carrying a germline TRG mutation and to identify the predictors of survival. In a multicenter cohort of LT patients, we retrospectively reviewed those carrying pathogenic TRG variations (n = 38; TERT, n = 23, TERC, n = 9, RTEL1, n = 6) between 2009 and 2018. The median age at LT was 54 years (interquartile range [IQR] 46-59); 68% were male and 71% had idiopathic pulmonary fibrosis. During the diagnosis of pulmonary fibrosis, 28 (74%) had a hematological disease, including eight with myelodysplasia. After a median follow-up of 26 months (IQR 15-46), 38 patients received LT. The overall post-LT median survival was 3.75 years (IQR 1.8-NA). The risk of death after LT was increased for patients with myelodysplasia (HR 4.1 [95% CI 1.5-11.5]) or short telomere (HR 2.2 [1.0-5.0]) before LT. After LT, all patients had anemia, 66% had thrombocytopenia, and 39% had neutropenia. Chronic lung allograft dysfunction frequency was 29% at 4 years. The present findings support the use of LT in TRG mutation carriers without myelodysplasia. Hematological evaluation should be systematically performed before LT.
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Affiliation(s)
- Mathilde Phillips-Houlbracq
- Service de Pneumologie A, Centre de référence des maladies pulmonaires rares (site constitutif), APHP, Hôpital Bichat, Paris, France
| | - Hervé Mal
- Université de Paris and INSERM U1152, Paris, France.,Service de Pneumologie B, APHP, Hôpital Bichat, Paris, France
| | - Vincent Cottin
- Service de Pneumologie, Centre coordonnateur national de référence des maladies pulmonaires rares, Hôpital Louis Pradel, Université Claude Bernard Lyon 1, Université de Lyon, INRAE, ERN-LUNG, Lyon, France
| | - Clément Gauvain
- Service d'oncologie, Hôpital Calmette, CHU de Lille, Lille, France
| | - Fabian Beier
- Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, RWTH Aachen University, Aachen, Germany.,Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Aachen, Germany
| | | | - Sabrina Sidali
- Service d'hépatologie, Hôpital Beaujon, APHP, Clichy, France
| | - Jean François Mornex
- Service de Pneumologie, Centre coordonnateur national de référence des maladies pulmonaires rares, Hôpital Louis Pradel, Université Claude Bernard Lyon 1, Université de Lyon, INRAE, ERN-LUNG, Lyon, France
| | - Sandrine Hirschi
- Service de Pneumologie, Centre de compétence des maladies pulmonaires rares, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
| | - Antoine Roux
- Service de Pneumologie, Hôpital Foch, Suresnes, France
| | - Gaelle Weisenburger
- Université de Paris and INSERM U1152, Paris, France.,Service de Pneumologie B, APHP, Hôpital Bichat, Paris, France
| | - Arnaud Roussel
- Service de chirurgie vasculaire et thoracique, Hopital Bichat, Paris, France
| | - Lidwine Wémeau-Stervinou
- Service de Pneumologie, Centre de référence des maladies pulmonaires rares (site constitutif), CHU de Lille, Lille, France
| | - Jérôme Le Pavec
- Service de Chirurgie Thoracique, Vasculaire et Transplantation Cardio-pulmonaire, Groupe Hospitalier Saint Joseph/Marie-Lannelongue, Le Plessis-Robinson, France.,Faculté de Médecine, Université Paris-Sud, Université Paris-Saclay, Le Kremlin Bicêtre, France.,UMR_S 999, Université Paris-Sud, INSERM, Hôpital Marie Lannelongue, Le Plessis Robinson, France
| | - Christophe Pison
- Service Hospitalier Universitaire Pneumologie Physiologie, Pôle Thorax et Vaisseaux, CHU Grenoble Alpes, Université Grenoble Alpes, Grenoble, France
| | | | - Antoine Froidure
- Service de pneumologie, Cliniques universitaires Saint-Luc, Bruxelles, Belgique
| | - Romain Lazor
- Service de Pneumologie, Centre hospitalier universitaire vaudois, Lausanne, Suisse
| | - Jean-Marc Naccache
- Service de Pneumologie, Centre de référence des maladies pulmonaires rares (site constitutif), Hôpital Tenon, Paris, France
| | - Stéphane Jouneau
- Service de Pneumologie, Centre de compétences des maladies rares pulmonaires, Hôpital Pontchaillou, IRSET UMR 1085, Université de Rennes 1, Rennes, France
| | - Hilario Nunes
- Service de Pneumologie Centre de référence des maladies pulmonaires rares (site constitutif), Hôpital Avicenne, Bobigny, France
| | - Martine Reynaud-Gaubert
- Service de Pneumologie, Centre de compétences des maladies pulmonaires rares, CHU Nord, AP-HM, Marseille, France.,Aix-Marseille Université, IHU Méditerranée Infection, MEPHI, Marseille, France
| | - Aurélie Le Borgne
- Service de Pneumologie, Centre de compétence des maladies pulmonaires rares Hôpital Larrey CHU Toulouse, Toulouse, France
| | - David Boutboul
- Service d'Immunopathologie Clinique, Hôpital St Louis, APHP, Paris, France
| | - Ibrahima Ba
- Laboratoire de Génétique, APHP, Hôpital Bichat, Paris, France
| | | | - Bruno Crestani
- Service de Pneumologie A, Centre de référence des maladies pulmonaires rares (site constitutif), APHP, Hôpital Bichat, Paris, France
| | | | - Raphaël Borie
- Service de Pneumologie A, Centre de référence des maladies pulmonaires rares (site constitutif), APHP, Hôpital Bichat, Paris, France
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38
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Niewisch MR, Giri N, McReynolds LJ, Alsaggaf R, Bhala S, Alter BP, Savage SA. Disease progression and clinical outcomes in telomere biology disorders. Blood 2022; 139:1807-1819. [PMID: 34852175 PMCID: PMC8952184 DOI: 10.1182/blood.2021013523] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Accepted: 11/11/2021] [Indexed: 11/20/2022] Open
Abstract
Dyskeratosis congenita related telomere biology disorders (DC/TBDs) are characterized by very short telomeres caused by germline pathogenic variants in telomere biology genes. Clinical presentations can affect all organs, and inheritance patterns include autosomal dominant (AD), autosomal recessive (AR), X-linked (XLR), or de novo. This study examined the associations between mode of inheritance with phenotypes and long-term clinical outcomes. Two hundred thirty-one individuals with DC/TBDs (144 male, 86.6% known genotype, median age at diagnosis 19.4 years [range 0 to 71.6]), enrolled in the National Cancer Institute's Inherited Bone Marrow Failure Syndrome Study, underwent detailed clinical assessments and longitudinal follow-up (median follow-up 5.2 years [range 0 to 36.7]). Patients were grouped by inheritance pattern, considering AD-nonTINF2, AR/XLR, and TINF2 variants separately. Severe bone marrow failure (BMF), severe liver disease, and gastrointestinal telangiectasias were more prevalent in AR/XLR or TINF2 disease, whereas pulmonary fibrosis developed predominantly in adults with AD disease. After adjusting for age at DC/TBD diagnosis, we observed the highest cancer risk in AR/XLR individuals. At last follow-up, 42% of patients were deceased with a median overall survival (OS) of 52.8 years (95% confidence interval [CI] 45.5-57.6), and the hematopoietic cell or solid organ transplant-free median survival was 45.3 years (95% CI 37.4-52.1). Significantly better OS was present in AD vs AR/XLR/TINF2 disease (P < .01), while patients with AR/XLR and TINF2 disease had similar survival probabilities. This long-term study of the clinical manifestations of DC/TBDs creates a foundation for incorporating the mode of inheritance into evidence-based clinical care guidelines and risk stratification in patients with DC/TBDs. This trial was registered at www.clinicaltrials.gov as #NCT00027274.
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Affiliation(s)
- Marena R Niewisch
- Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Neelam Giri
- Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Lisa J McReynolds
- Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Rotana Alsaggaf
- Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Sonia Bhala
- Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Blanche P Alter
- Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Sharon A Savage
- Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD
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Multisystemic Manifestations in Rare Diseases: The Experience of Dyskeratosis Congenita. Genes (Basel) 2022; 13:genes13030496. [PMID: 35328050 PMCID: PMC8953471 DOI: 10.3390/genes13030496] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 03/07/2022] [Accepted: 03/08/2022] [Indexed: 01/27/2023] Open
Abstract
Dyskeratosis congenital (DC) is the first genetic syndrome described among telomeropathies. Its classical phenotype is characterized by the mucocutaneous triad of reticulated pigmentation of skin lace, nail dystrophy and oral leukoplakia. The clinical presentation, however, is heterogeneous and serious clinical complications include bone marrow failure, hematological and solid tumors. It may also involve immunodeficiencies, dental, pulmonary and liver disorders, and other minor complication. Dyskeratosis congenita shows marked genetic heterogeneity, as at least 14 genes are responsible for the shortening of telomeres characteristic of this disease. This review discusses clinical characteristics, molecular genetics, disease evolution, available therapeutic options and differential diagnosis of dyskeratosis congenita to provide an interdisciplinary and personalized medical assessment that includes family genetic counseling.
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Groarke EM, Calado RT, Liu JM. Cell senescence and malignant transformation in the inherited bone marrow failure syndromes: Overlapping pathophysiology with therapeutic implications. Semin Hematol 2022; 59:30-37. [PMID: 35491056 PMCID: PMC9062194 DOI: 10.1053/j.seminhematol.2022.01.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 01/19/2022] [Accepted: 01/26/2022] [Indexed: 02/02/2023]
Abstract
Fanconi anemia, telomeropathies and ribosomopathies are members of the inherited bone marrow failure syndromes, rare genetic disorders that lead to failure of hematopoiesis, developmental abnormalities, and cancer predisposition. While each disorder is caused by different genetic defects in seemingly disparate processes of DNA repair, telomere maintenance, or ribosome biogenesis, they appear to lead to a common pathway characterized by premature senescence of hematopoietic stem cells. Here we review the experimental data on senescence and inflammation underlying marrow failure and malignant transformation. We conclude with a critical assessment of current and future therapies targeting these pathways in inherited bone marrow failure syndromes patients.
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Affiliation(s)
- Emma M Groarke
- Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD.
| | - Rodrigo T Calado
- Department of Medical Imaging, Hematology, and Oncology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Johnson M Liu
- Division of Hematology, Maine Medical Center, Portland, ME
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Bai L, Rohrer C, Liu Y. Liver Histology in Short Telomere Syndrome: A Case Report and Review of the Literature. Int J Surg Pathol 2021; 30:350-355. [PMID: 34714693 DOI: 10.1177/10668969211054102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Short telomere syndrome (STS) encompasses a broad family of genetically inherited conditions caused by various mutations in telomerase and other telomere maintenance genes, resulting in premature telomere shortening. STS involves a variety of clinical manifestations, including dyskeratosis congenita, premature achromotrichia, bone marrow failure, immunodeficiency, pulmonary fibrosis and liver disease. Liver histopathologic features in STS patients have not been well characterized. We report a 46-year-old male patient who presented for dyspnea. The patient had a complicated medical history significant for immune thrombocytopenic purpura and splenectomy, recurrent respiratory tract infections, pneumonia, primary immunodeficiency, and severe hepatopulmonary syndrome. He and his brother both developed gray hair by their late 20s. He had a long history of intermittently elevated liver enzymes starting at age 33. These clinical manifestations prompted an evaluation for a possible telomere biology disorder, which revealed the telomere length was critically short and fell at or below the first percentile for age, supporting the diagnosis. The liver biopsy showed marked portal inflammation with interface hepatitis, ductular reaction and frequent foci of lobular inflammation with focal hepatocyte dropout. Hepatocytes around the portal tracts demonstrated ballooning degeneration and occasional Mallory-Denk bodies. A trichrome stain highlighted bridging fibrosis. A literature review shows liver histology is available in only a small number of STS patients, demonstrating a variety of morphologic features. Our case and others suggest liver disease associated with STS exhibits a spectrum of histopathology. Being aware of these features is important for establishing the correct diagnosis of STS which is under recognized.
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Affiliation(s)
- Lixia Bai
- 5228University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA
| | - Charles Rohrer
- 5228University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA
| | - Yongjun Liu
- 5228University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA
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Mangaonkar AA, Ferrer A, Vairo FPE, Hammel CW, Prochnow C, Gangat N, Hogan WJ, Litzow MR, Peters SG, Scott JP, Utz JP, Baqir M, Carmona-Porquera EM, Kalra S, Sekiguchi H, Khan SP, Simonetto DA, Klee EW, Kamath PS, Roden AC, Joshi AY, Kennedy CC, Wylam ME, Patnaik MM. Clinical and molecular correlates from a predominantly adult cohort of patients with short telomere lengths. Blood Cancer J 2021; 11:170. [PMID: 34686653 PMCID: PMC8536738 DOI: 10.1038/s41408-021-00564-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 07/21/2021] [Accepted: 07/22/2021] [Indexed: 11/09/2022] Open
Affiliation(s)
| | - Alejandro Ferrer
- Center for Individualized Medicine, Department of Quantitative Health Science, Rochester, MN, USA
| | - Filippo Pinto E Vairo
- Center for Individualized Medicine, Department of Quantitative Health Science, Rochester, MN, USA.,Department of Clinical Genomics, Rochester, MN, USA
| | - Caleb W Hammel
- Center for Individualized Medicine, Department of Quantitative Health Science, Rochester, MN, USA
| | - Carri Prochnow
- Center for Individualized Medicine, Department of Quantitative Health Science, Rochester, MN, USA
| | - Naseema Gangat
- Division of Hematology, Department of Medicine, Rochester, MN, USA
| | - William J Hogan
- Division of Hematology, Department of Medicine, Rochester, MN, USA
| | - Mark R Litzow
- Division of Hematology, Department of Medicine, Rochester, MN, USA
| | - Steve G Peters
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Rochester, MN, USA
| | - J P Scott
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Rochester, MN, USA
| | - James P Utz
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Rochester, MN, USA
| | - Misbah Baqir
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Rochester, MN, USA
| | - Eva M Carmona-Porquera
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Rochester, MN, USA
| | - Sanjay Kalra
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Rochester, MN, USA
| | - Hiroshi Sekiguchi
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Rochester, MN, USA
| | - Shakila P Khan
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, Rochester, MN, USA
| | | | - Eric W Klee
- Center for Individualized Medicine, Department of Quantitative Health Science, Rochester, MN, USA
| | - Patrick S Kamath
- Division of Gastroenterology, Department of Medicine, Rochester, MN, USA
| | - Anja C Roden
- Department of Laboratory Medicine and Pathology, Rochester, MN, USA
| | - Avni Y Joshi
- Division of Pediatric Allergy and Immunology, Department of Pediatrics, Mayo Clinic, Rochester, MN, USA
| | - Cassie C Kennedy
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Rochester, MN, USA
| | - Mark E Wylam
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Rochester, MN, USA
| | - Mrinal M Patnaik
- Division of Hematology, Department of Medicine, Rochester, MN, USA.
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Udomsinprasert W, Sobhonslidsuk A, Jittikoon J, Honsawek S, Chaikledkaew U. Cellular senescence in liver fibrosis: Implications for age-related chronic liver diseases. Expert Opin Ther Targets 2021; 25:799-813. [PMID: 34632912 DOI: 10.1080/14728222.2021.1992385] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
INTRODUCTION New insights indicate a causative link between cellular senescence and liver fibrosis. Senescent hepatic stellate cells (HSCs) facilitate fibrosis resolution, while senescence in hepatocytes and cholangiocytes acts as a potent mechanism driving liver fibrogenesis. In many clinical studies, telomeres and mitochondrial DNA contents, which are both aging biomarkers, were reportedly associated with a degree of liver fibrosis in patients with chronic liver diseases (CLDs); this highlights their potential as biomarkers for liver fibrogenesis. A deeper understanding of mechanisms underlying multi-step progression of senescence may yield new therapeutic strategies for age-related chronic liver pathologies. AREAS COVERED This review examines the recent findings from preclinical and clinical studies on mechanisms of senescence in liver fibrogenesis and its involvement in liver fibrosis. A comprehensive literature search in electronic databases consisting of PubMed and Scopus from inception to 31 August 2021 was performed. EXPERT OPINION Cellular senescence has diagnostic, prognostic, and therapeutic potential in progressive liver complications, especially liver fibrosis. Stimulating or reinforcing the immune response against senescent cells may be a promising and forthright biotherapeutic strategy. This approach will need a deeper understanding of the immune system's ability to eliminate senescent cells and the molecular and cellular mechanisms underlying this process.
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Affiliation(s)
| | - Abhasnee Sobhonslidsuk
- Division of Gastroenterology and Hepatology, Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Jiraphun Jittikoon
- Department of Biochemistry, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand
| | - Sittisak Honsawek
- Department of Biochemistry, Osteoarthritis and Musculoskeleton Research Unit, Faculty of Medicine, Chulalongkorn University, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand
| | - Usa Chaikledkaew
- Social and Administrative Pharmacy Division, Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand.,Mahidol University Health Technology Assessment (MUHTA) Graduate Program, Mahidol University, Bangkok, Thailand
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Meroni M, Longo M, Tria G, Dongiovanni P. Genetics Is of the Essence to Face NAFLD. Biomedicines 2021; 9:1359. [PMID: 34680476 PMCID: PMC8533437 DOI: 10.3390/biomedicines9101359] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Accepted: 09/27/2021] [Indexed: 02/07/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the commonest cause of chronic liver disease worldwide. It is closely related to obesity, insulin resistance (IR) and dyslipidemia so much so it is considered the hepatic manifestation of the Metabolic Syndrome. The NAFLD spectrum extends from simple steatosis to nonalcoholic steatohepatitis (NASH), a clinical condition which may progress up to fibrosis, cirrhosis and hepatocellular carcinoma (HCC). NAFLD is a complex disease whose pathogenesis is shaped by both environmental and genetic factors. In the last two decades, several heritable modifications in genes influencing hepatic lipid remodeling, and mitochondrial oxidative status have been emerged as predictors of progressive hepatic damage. Among them, the patatin-like phospholipase domain-containing 3 (PNPLA3) p.I148M, the Transmembrane 6 superfamily member 2 (TM6SF2) p.E167K and the rs641738 membrane bound-o-acyltransferase domain-containing 7 (MBOAT7) polymorphisms are considered the most robust modifiers of NAFLD. However, a forefront frontier in the study of NAFLD heritability is to postulate score-based strategy, building polygenic risk scores (PRS), which aggregate the most relevant genetic determinants of NAFLD and biochemical parameters, with the purpose to foresee patients with greater risk of severe NAFLD, guaranteeing the most highly predictive value, the best diagnostic accuracy and the more precise individualized therapy.
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Affiliation(s)
- Marica Meroni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milan, Italy; (M.M.); (M.L.); (G.T.)
| | - Miriam Longo
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milan, Italy; (M.M.); (M.L.); (G.T.)
- Department of Clinical Sciences and Community Health, Università Degli Studi di Milano, 20122 Milano, Italy
| | - Giada Tria
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milan, Italy; (M.M.); (M.L.); (G.T.)
| | - Paola Dongiovanni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milan, Italy; (M.M.); (M.L.); (G.T.)
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van der Vis JJ, van der Smagt JJ, van Batenburg AA, Goldschmeding R, van Es HW, Grutters JC, van Moorsel CHM. Pulmonary fibrosis in non-mutation carriers of families with short telomere syndrome gene mutations. Respirology 2021; 26:1160-1170. [PMID: 34580961 DOI: 10.1111/resp.14145] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Revised: 07/16/2021] [Accepted: 08/23/2021] [Indexed: 11/29/2022]
Abstract
BACKGROUND AND OBJECTIVE Diagnostic and predictive genetic testing for disease cause and risk estimation is common in many countries. For genetic diseases, predictive test results are commonly straightforward: presence of the mutation involves increased risk for disease and absence of the mutation involves no inherit risk for disease. Germline mutations in telomere-related genes (TRGs) can lead to telomere shortening and are associated with short telomere syndrome (STS). Telomere length is heritable, and in families with STS due to a TRG mutation, progeny with and without the TRG mutation is known to have shorter than average telomeres. We hypothesize that progeny of TRG mutation carriers who did not inherit the TRG mutation may still develop pulmonary fibrosis. METHODS A genetic screen of 99 unrelated families with familial pulmonary fibrosis revealed five patients with features of pulmonary fibrosis but without carrying the familial disease-causing TRG mutation. RESULTS Features of STS were present in each family, including short telomeres in blood and tissue of the non-mutation carrying patients. Additional genetic, clinical or environmental risk factors for pulmonary fibrosis were present in each non-mutation carrying patient. CONCLUSION Our study shows that non-mutation carrying first-degree relatives in families with STS are at increased risk for pulmonary fibrosis. Disease development may be triggered by inherited short telomeres and additional risk factors for disease. This observation has profound consequences for genetic counselling. Unlike any other genetic syndrome, absence of the mutation does not imply absence of disease risk. Therefore, clinical follow-up is still urged for non-mutation carrying first-degree family members.
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Affiliation(s)
- Joanne J van der Vis
- ILD Center of Excellence, Department of Pulmonology, St Antonius Hospital, Nieuwegein, The Netherlands
| | - Jasper J van der Smagt
- ILD Center of Excellence, Department of Clinical Chemistry, St Antonius Hospital, Nieuwegein, The Netherlands
| | | | - Roel Goldschmeding
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - H Wouter van Es
- ILD Center of Excellence, Department of Radiology, St Antonius Hospital, Nieuwegein, The Netherlands
| | - Jan C Grutters
- Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Coline H M van Moorsel
- Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, The Netherlands
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Tometten M, Kirschner M, Isfort S, Berres ML, Brümmendorf TH, Beier F. Transient elastography in adult patients with cryptic dyskeratosis congenita reveals subclinical liver fibrosis: a retrospective analysis of the Aachen telomere biology disease registry. Orphanet J Rare Dis 2021; 16:395. [PMID: 34565437 PMCID: PMC8474920 DOI: 10.1186/s13023-021-02024-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Accepted: 09/19/2021] [Indexed: 11/10/2022] Open
Abstract
Background Telomere biology disorders (TBD) such as dyskeratosis congenita (DKC) lead to progressive multi-organ failure as impaired telomere maintenance disturbs cellular proliferative capacity. A wide range of hepatic manifestations from asymptomatic liver enzyme elevation to overt liver fibrosis/cirrhosis can be observed in TBD patients. However, the incidence of hepatic involvement remains unknown. Non-invasive transient elastography (TE) predicts early fibrosis by measuring liver stiffness and may uncover subclinical liver damage in TBD patients. Methods Liver screening procedures of nine TBD patients from the Aachen TBD Registry are being presented retrospectively. Following clinical suspicion, TBD was diagnosed using flow-FISH with telomere length (TL) below the 1% percentile and confirmed by next-generation sequencing (NGS) detecting pathogenic mutations in telomere maintenance genes TERC or TERT. Results In all patients, TBD was first diagnosed in adulthood. Patients showed normal to slightly elevated liver function test parameters. Hepatic ultrasound revealed inhomogeneous parenchyma in seven (77.7%) and increased liver echogenicity in four patients (44.4%). Median liver stiffness was 10.7 kilopascal (kPa) (interquartile range 8.4, 15.7 kPa). Using 7.1 kPa as cut-off, 88.8% of patients were classified as moderate fibrosis to cirrhosis. Conclusion Subclinical chronic liver involvement is frequent in patients with adult-onset TBD. TE could have a valuable role in the routine work-up of patients with telomere disorders including DKC for early detection of patients at risk for liver function impairment.
Supplementary Information The online version contains supplementary material available at 10.1186/s13023-021-02024-8.
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Affiliation(s)
- Mareike Tometten
- Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Medical Faculty, RWTH Aachen University, Aachen, Germany.,Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf (CIO ABCD), Aachen, Germany
| | - Martin Kirschner
- Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Medical Faculty, RWTH Aachen University, Aachen, Germany.,Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf (CIO ABCD), Aachen, Germany
| | - Susanne Isfort
- Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Medical Faculty, RWTH Aachen University, Aachen, Germany.,Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf (CIO ABCD), Aachen, Germany
| | - Marie-Luise Berres
- Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf (CIO ABCD), Aachen, Germany.,Department of Internal Medicine III, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Tim H Brümmendorf
- Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Medical Faculty, RWTH Aachen University, Aachen, Germany.,Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf (CIO ABCD), Aachen, Germany
| | - Fabian Beier
- Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Medical Faculty, RWTH Aachen University, Aachen, Germany. .,Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf (CIO ABCD), Aachen, Germany.
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Familial Melanoma and Susceptibility Genes: A Review of the Most Common Clinical and Dermoscopic Phenotypic Aspect, Associated Malignancies and Practical Tips for Management. J Clin Med 2021; 10:jcm10163760. [PMID: 34442055 PMCID: PMC8397216 DOI: 10.3390/jcm10163760] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Revised: 08/13/2021] [Accepted: 08/18/2021] [Indexed: 12/11/2022] Open
Abstract
A family history of melanoma greatly increases the risk of developing cutaneous melanoma, a highly aggressive skin cancer whose incidence has been steadily increasing worldwide. Familial melanomas account for about 10% of all malignant melanomas and display an inheritance pattern consistent with the presence of pathogenic germline mutations, among which those involving CDKN2A are the best characterized. In recent years, a growing number of genes, such as MC1R, MITF, CDK4, POT1, TERT, ACD, TERF2IP, and BAP1, have been implicated in familial melanoma. The fact that individuals harboring these germline mutations along with their close blood relatives have a higher risk of developing multiple primary melanomas as well as other internal organ malignancies, especially pancreatic cancer, makes cascade genetic testing and surveillance of these families of the utmost importance. Unfortunately, due to a polygenic inheritance mechanism involving multiple low-risk alleles, genetic modifiers, and environmental factors, it is still very difficult to predict the presence of these mutations. It is, however, known that germline mutation carriers can sometimes develop specific clinical traits, such as high atypical nevus counts and specific dermoscopic features, which could theoretically help clinicians predict the presence of these mutations in prone families. In this review, we provide a comprehensive overview of the high- and intermediate-penetrance genes primarily linked to familial melanoma, highlighting their most frequently associated non-cutaneous malignancies and clinical/dermoscopic phenotypes.
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Vieri M, Brümmendorf TH, Beier F. Treatment of telomeropathies. Best Pract Res Clin Haematol 2021; 34:101282. [PMID: 34404536 DOI: 10.1016/j.beha.2021.101282] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 06/22/2021] [Accepted: 06/25/2021] [Indexed: 10/21/2022]
Abstract
Telomeropathies or telomere biology disorders (TBDs) are a group of rare diseases characterised by altered telomere maintenance. Most patients with TBDs show pathogenic variants of genes that encode factors involved in the prevention of telomere shortening. Particularly in adults, TBDs mostly present themselves with heterogeneous clinical features that often include bone marrow failure, hepatopathies, interstitial lung disease and other organ sites. Different degrees of severity are also observed among patients with TBDs, ranging from very severe syndromes manifesting themselves in early childhood, such as Revesz syndrome, Hoyeraal-Hreidarsson syndrome, and Coats plus disease, to dyskeratosis congenita (DKC) and adult-onset "cryptic" forms of TBD, which often affect fewer organ systems. Overall, the most relevant clinical complications of TBD are bone marrow failure, lung fibrosis, and liver cirrhosis. In this review, we summarise recent advances in the management and treatment of TBD and provide a brief overview of the various treatment approaches.
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Affiliation(s)
- Margherita Vieri
- Department of Hematology, Oncology, Hemostaseology, Stem Cell Transplantation, Medical Faculty, RWTH Aachen University, Aachen, Germany; Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Germany.
| | - Tim H Brümmendorf
- Department of Hematology, Oncology, Hemostaseology, Stem Cell Transplantation, Medical Faculty, RWTH Aachen University, Aachen, Germany; Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Germany.
| | - Fabian Beier
- Department of Hematology, Oncology, Hemostaseology, Stem Cell Transplantation, Medical Faculty, RWTH Aachen University, Aachen, Germany; Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Germany.
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Boyraz B, Agarwal S, Pratt DS, Simoneau T, Bhan I, Markmann JF, Misdraji J. Hepatic Vascular Remodeling in a Patient with Dyskeratosis Congenita. Histopathology 2021; 80:450-453. [PMID: 34327718 DOI: 10.1111/his.14530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Telomere biology disorders (TBD), including dyskeratosis congenita (DC), are a group of accelerated aging diseases caused by mutations in genes encoding factors involved in telomere maintenance. Hepatic involvement affects 10-40% of TBD patients with nodular regenerative hyperplasia (NRH) and cirrhosis being the most common hepatic manifestations, both of which can result in portal hypertension (1-3). Lung involvement includes interstitial lung disease (ILD) such as idiopathic pulmonary fibrosis (IPF) and hepatopulmonary syndrome (HPS) which can be associated with portal hypertension. Vascular complications in TBD include pulmonary arteriovenous malformations, gastrointestinal telangiectasias and exudative vitreoretinopathy.
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Affiliation(s)
- Baris Boyraz
- Department of Pathology, Massachusetts General Hospital, Boston, MA, USA
| | - Suneet Agarwal
- Department of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA
| | - Daniel S Pratt
- Department of Medicine, Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA
| | - Tregony Simoneau
- Department of Pediatrics, Division of Pulmonary Medicine, Boston Children's Hospital, Boston, MA, USA
| | - Irun Bhan
- Department of Medicine, Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA
| | - James F Markmann
- Department of Surgery, Massachusetts General Hospital, Boston, MA, USA
| | - Joseph Misdraji
- Department of Pathology, Massachusetts General Hospital, Boston, MA, USA
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50
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Miner AE, Graves JS. What telomeres teach us about MS. Mult Scler Relat Disord 2021; 54:103084. [PMID: 34371369 DOI: 10.1016/j.msard.2021.103084] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 05/14/2021] [Accepted: 06/09/2021] [Indexed: 02/03/2023]
Abstract
While the precise mechanisms driving progressive forms of MS are not fully understood, patient age has clear impact on disease phenotype. The very young with MS have high relapse rates and virtually no progressive disease, whereas older patients tend to experience more rapid disability accumulation with few relapses. Defining a patient's biological age may offer more precision in determining the role of aging processes in MS phenotype and pathophysiology than just working with an individual's birthdate. The most well recognized measurement of an individual's "biological clock" is telomere length (TL). While TL may differ across tissue types in an individual, most cells TL correlate well with leukocyte TL (LTL), which is the most common biomarker used for aging. LTL has been associated with risk for aging related diseases and most recently with higher levels of disability and brain atrophy in people living with MS. LTL explains 15% of the overall association of chronological age with MS disability level. While LTL may be used just as a biomarker of overall somatic aging processes, triggering of the DNA damage response by telomere attrition leads to senescence pathways that are likely highly relevant to a chronic autoimmune disease. Considering reproductive aging factors, particularly ovarian aging in women, which correlates with LTL and oocyte telomere length, may complement measurements of somatic aging in understanding MS progression. The key to stopping non-relapse related progression in MS might lie in targeting pathways related to biological aging effects on the immune and nervous systems.
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Affiliation(s)
- Annalise E Miner
- Department of Neurosciences, University of California, San Diego, USA
| | - Jennifer S Graves
- Department of Neurosciences, University of California, San Diego, USA.
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