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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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2
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Liu YC, Eldomery MK, Maciaszek JL, Klco JM. Inherited Predispositions to Myeloid Neoplasms: Pathogenesis and Clinical Implications. ANNUAL REVIEW OF PATHOLOGY 2025; 20:87-114. [PMID: 39357070 PMCID: PMC12048009 DOI: 10.1146/annurev-pathmechdis-111523-023420] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/04/2024]
Abstract
Myeloid neoplasms with and without preexisting platelet disorders frequently develop in association with an underlying germline predisposition. Germline alterations affecting ANKRD26, CEBPA, DDX41, ETV6, and RUNX1 are associated with nonsyndromic predisposition to the development of myeloid neoplasms including acute myeloid leukemia and myelodysplastic syndrome. However, germline predisposition to myeloid neoplasms is also associated with a wide range of other syndromes, including SAMD9/9L associated predisposition, GATA2 deficiency, RASopathies, ribosomopathies, telomere biology disorders, Fanconi anemia, severe congenital neutropenia, Down syndrome, and others. In the fifth edition of the World Health Organization (WHO) series on the classification of tumors of hematopoietic and lymphoid tissues, myeloid neoplasms associated with germline predisposition have been recognized as a separate entity. Here, we review several disorders from this WHO entity as well as other related conditions with an emphasis on the molecular pathogenesis of disease and accompanying somatic alterations. Finally, we provide an overview of establishing the molecular diagnosis of these germline genetic conditions and general recommendations for screening and management of the associated hematologic conditions.
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Affiliation(s)
- Yen-Chun Liu
- Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA;
| | - Mohammad K Eldomery
- Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA;
| | - Jamie L Maciaszek
- Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA;
| | - Jeffery M Klco
- Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA;
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Roka K, Solomou E, Kattamis A, Stiakaki E. Telomere biology disorders: from dyskeratosis congenita and beyond. Postgrad Med J 2024; 100:879-889. [PMID: 39197110 DOI: 10.1093/postmj/qgae102] [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: 05/18/2024] [Revised: 07/05/2024] [Accepted: 07/31/2024] [Indexed: 08/30/2024]
Abstract
Defective telomerase function or telomere maintenance causes genomic instability. Alterations in telomere length and/or attrition are the primary features of rare diseases known as telomere biology disorders or telomeropathies. Recent advances in the molecular basis of these disorders and cutting-edge methods assessing telomere length have increased our understanding of this topic. Multiorgan manifestations and different phenotypes have been reported even in carriers within the same family. In this context, apart from dyskeratosis congenita, disorders formerly considered idiopathic (i.e. pulmonary fibrosis, liver cirrhosis) frequently correlate with underlying defective telomere maintenance mechanisms. Moreover, these patients are prone to developing specific cancer types and exhibit exceptional sensitivity and toxicity in standard chemotherapy regimens. The current review describes the diverse spectrum of clinical manifestations of telomere biology disorders in pediatric and adult patients, their correlation with pathogenic variants, and considerations during their management to increase awareness and improve a multidisciplinary approach.
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Affiliation(s)
- Kleoniki Roka
- Division of Pediatric Hematology-Oncology, First Department of Pediatrics, National and Kapodistrian University of Athens, Aghia Sophia Children's Hospital, Full Member of ERN GENTURIS and ERN EuroBloodnet, 8 Levadias Street, Goudi, Athens, 11527, Greece
| | - Elena Solomou
- Department of Internal Medicine, University of Patras Medical School, Rion, 26500, Greece
| | - Antonis Kattamis
- Division of Pediatric Hematology-Oncology, First Department of Pediatrics, National and Kapodistrian University of Athens, Aghia Sophia Children's Hospital, Full Member of ERN GENTURIS and ERN EuroBloodnet, 8 Levadias Street, Goudi, Athens, 11527, Greece
| | - Eftychia Stiakaki
- Department of Pediatric Hematology-Oncology & Autologous Hematopoietic Stem Cell Transplantation Unit, University Hospital of Heraklion & Laboratory of Blood Diseases and Childhood Cancer Biology, School of Medicine, University of Crete, Voutes, Heraklion, Crete, 71500, Greece
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4
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Hussein-Agha R, Kannengiesser C, Lainey E, Marcais A, Srour M, Sterin A, Buchbinder N, Borie R, Plessier A, Socié G, Peffault de Latour R, Sicre de Fontbrune F. Alemtuzumab-based conditioning regimen before hematopoietic stem cell transplantation in patients with short telomere syndromes: a retrospective study of the SFGM-TC. Bone Marrow Transplant 2024; 59:1428-1432. [PMID: 39080469 DOI: 10.1038/s41409-024-02381-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Revised: 07/17/2024] [Accepted: 07/24/2024] [Indexed: 10/06/2024]
Abstract
While HSCT is the only curative option for patients with short telomere syndromes (STSs) and severe bone marrow failure (BMF) or myeloid malignancies (MM), their increase sensitivity to conditioning regimen strongly affect outcomes. To minimize HSCT related mortality, alemtuzumab-based conditioning regimens have been proposed, but the number of patients transplanted with those regimens reported in the literature remains very low. We retrospectively analyzed outcome of adults and adolescents with STSs transplanted after an alemtuzumab, fludarabine and cyclophosphamide based regimen registered by the SFGM-TC. Seven patients were transplanted for a BMF and 5 for a MM (median age 34 years, (IQR [22-45])). The 2-year GRFS for patients with MM was 20% (95% CI [3;100]), and 57% (95% CI [30;100]) in others. In univariate (hazard ratio, HR = 6, 95% CI [1;31]) and multivariate analysis (HR = 26, 95% CI [2;414]) stem cell source was a predictive factor for GRFS. Three of the 5 patients with pre-transplant MM relapsed and 2 of them died at last follow up. The 2-year OS was 66% (95% CI [43;99]) in the whole cohort with a median follow up of 32 months (IQR [13-56]). In conclusion, Alemtuzumab-based conditioning regimen with bone marrow is an option for patients with STSs and BMF, but others modalities have to be explored for patients with MM.
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Affiliation(s)
- Rim Hussein-Agha
- Hospices Civils de Lyon, Hôpital Lyon Sud, Service d'Hématologie Adulte, Lyon, France
| | - Caroline Kannengiesser
- Assistance Publique des Hôpitaux de Paris, Hôpital Bichat, Laboratoire de Génétique, Paris, France
- Université Paris Cité, Paris, France
| | - Elodie Lainey
- Université Paris Cité, Paris, France
- Assistance Publique des Hôpitaux de Paris, Hôpital Robert-Debré, Laboratoire d'Hématologie, Paris, France
| | - Ambroise Marcais
- Assistance Publique des Hôpitaux de Paris, Service d'Hématologie Adulte, Hôpital Necker-Enfants Malades, Paris, France
| | - Micha Srour
- Centre Hospitalier Universitaire de Lille, Service d'Hématologie Transfusion, Lille, France
| | - Arthur Sterin
- Assistance Publique des Hôpitaux de Marseille, Hôpital de la Timone, Service d'Hématologie-Oncologie Pédiatrique, Marseille, France
| | - Nimrod Buchbinder
- Centre Hospitalier Universitaire de Rouen, Service d'Hématologie-Oncologie Pédiatrique, Rouen, France
| | - Raphael Borie
- Service de Pneumologie A Hôpital Bichat, APHP, Paris, France
- Université Paris Cité, Inserm, PHERE, Université Paris Cité, 75018, Paris, France
| | - Aurelie Plessier
- Assistance Publique des Hôpitaux de Paris, Hôpital Beaujon, Service d'Hépatologie, Paris, France
| | - Gerard Socié
- Université Paris Cité, Paris, France
- Assistance Publique des Hôpitaux de Paris, Hôpital Saint-Louis, Service d'Hématologie Greffe de Moelle & Centre de référence national des aplasies médullaires acquises et constitutionnelles, Paris, France
| | - Regis Peffault de Latour
- Université Paris Cité, Paris, France
- Assistance Publique des Hôpitaux de Paris, Hôpital Saint-Louis, Service d'Hématologie Greffe de Moelle & Centre de référence national des aplasies médullaires acquises et constitutionnelles, Paris, France
| | - Flore Sicre de Fontbrune
- Assistance Publique des Hôpitaux de Paris, Hôpital Saint-Louis, Service d'Hématologie Greffe de Moelle & Centre de référence national des aplasies médullaires acquises et constitutionnelles, Paris, France.
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Rolles B, Tometten M, Meyer R, Kirschner M, Beier F, Brümmendorf TH. Inherited Telomere Biology Disorders: Pathophysiology, Clinical Presentation, Diagnostics, and Treatment. Transfus Med Hemother 2024; 51:292-309. [PMID: 39371255 PMCID: PMC11452174 DOI: 10.1159/000540109] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Accepted: 06/25/2024] [Indexed: 10/08/2024] Open
Abstract
Background Telomeres are the end-capping structures of all eukaryotic chromosomes thereby protecting the genome from damage and degradation. During the aging process, telomeres shorten continuously with each cell division until critically short telomeres prevent further proliferation whereby cells undergo terminal differentiation, senescence, or apoptosis. Premature aging due to critically short telomere length (TL) can also result from pathogenic germline variants in the telomerase complex or related genes that typically counteract replicative telomere shortening in germline and certain somatic cell populations, e.g., hematopoetic stem cells. Inherited diseases that result in altered telomere maintenance are summarized under the term telomere biology disorder (TBD). Summary Since TL both reflects but more importantly restricts the replicative capacity of various human tissues, a sufficient telomere reserve is particularly important in cells with high proliferative activity (e.g., hematopoiesis, immune cells, intestinal cells, liver, lung, and skin). Consequently, altered telomere maintenance as observed in TBDs typically results in premature replicative cellular exhaustion in the respective organ systems eventually leading to life-threatening complications such as bone marrow failure (BMF), pulmonary fibrosis, and liver cirrhosis. Key Messages The recognition of a potential congenital origin in approximately 10% of adult patients with clinical BMF is of utmost importance for the proper diagnosis, appropriate patient and family counseling, to prevent the use of inefficient treatment and to avoid therapy-related toxicities including appropriate donor selection when patients have to undergo stem cell transplantation from related donors. This review summarizes the current state of knowledge about TBDs with particular focus on the clinical manifestation patterns in children (termed early onset TBD) compared to adults (late-onset TBD) including typical treatment- and disease course-related complications as well as their prognosis and adequate therapy. Thereby, it aims to raise awareness for a disease group that is currently still highly underdiagnosed particularly when it first manifests itself in adulthood.
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Affiliation(s)
- Benjamin Rolles
- Division of Hematology, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- 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), Cologne, Germany
| | - 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), Cologne, Germany
| | - Robert Meyer
- Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf (CIO ABCD), Cologne, Germany
- Institute for Human Genetics and Genomic Medicine, Medical Faculty, RWTH Aachen University, 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), Cologne, 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), Cologne, 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), Cologne, Germany
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Strauss JD, Brown DW, Zhou W, Dagnall C, Yuan JM, Im A, Savage SA, Wang Y, Rafati M, Spellman SR, Gadalla SM. Telomere length and clonal chromosomal alterations in peripheral blood of patients with severe aplastic anaemia. Br J Haematol 2024; 205:1180-1187. [PMID: 39103182 PMCID: PMC11499016 DOI: 10.1111/bjh.19681] [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: 03/06/2024] [Accepted: 07/21/2024] [Indexed: 08/07/2024]
Abstract
Severe aplastic anaemia (SAA) is a rare and life-threatening bone marrow failure disorder. We used data from the transplant outcomes in aplastic anaemia study to characterize mosaic chromosomal alterations (mCAs) in the peripheral blood of 738 patients with acquired SAA and evaluate their associations with telomere length (TL) and survival post-haematopoietic cell transplant (HCT). The median age at HCT was 20.4 years (range = 0.2-77.4). Patients with SAA had shorter TL than expected for their age (median TL percentile for age: 35.7th; range <1-99.99). mCAs were detected in 211 patients (28.6%), with chr6p copy-neutral loss of heterozygosity (6p-CNLOH) in 15.9% and chr7 loss in 3.0% of the patients; chrX loss was detected in 4.1% of female patients. Negative correlations between mCA cell fraction and measured TL (r = -0.14, p = 0.0002), and possibly genetically predicted TL (r = -0.07, p = 0.06) were noted. The post-HCT 3-year survival probability was low in patients with chr7 loss (39% vs. 72% in patients with chr6-CNLOH, 60% in patients with other mCAs and 70% in patients with no mCAs; p-log rank = 0.001). In multivariable analysis, short TL (p = 0.01), but not chr7 loss (p = 0.29), was associated with worse post-HCT survival. TL may guide clinical decisions in patients with SAA.
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Affiliation(s)
- Joshua D Strauss
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
- Department of Epidemiology, School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Derek W Brown
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
| | - Weiyin Zhou
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
- Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA
| | - Casey Dagnall
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
- Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA
| | - Jian-Min Yuan
- Department of Epidemiology, School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
- Cancer Epidemiology and Prevention Program, UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USA
| | - Annie Im
- Division of Hematology/Oncology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Sharon A Savage
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
| | - Youjin Wang
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
| | - Maryam Rafati
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
| | - Stephen R Spellman
- Center for International Blood and Marrow Transplant Research, NMDP, Minneapolis, Minnesota, USA
| | - Shahinaz M Gadalla
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
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Villa A, William WN, Hanna GJ. Cancer Precursor Syndromes and Their Detection in the Head and Neck. Hematol Oncol Clin North Am 2024; 38:813-830. [PMID: 38705773 DOI: 10.1016/j.hoc.2024.04.001] [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] [Indexed: 05/07/2024]
Abstract
This article explores the multifaceted landscape of oral cancer precursor syndromes. Hereditary disorders like dyskeratosis congenita and Fanconi anemia increase the risk of malignancy. Oral potentially malignant disorders, notably leukoplakia, are discussed as precursors influenced by genetic and immunologic facets. Molecular insights delve into genetic mutations, allelic imbalances, and immune modulation as key players in precancerous progression, suggesting potential therapeutic targets. The article navigates the controversial terrain of management strategies of leukoplakia, encompassing surgical resection, chemoprevention, and immune modulation, while emphasizing the ongoing challenges in developing effective, evidence-based preventive approaches.
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Affiliation(s)
- Alessandro Villa
- Oral Medicine, Oral Oncology and Dentistry, Miami Cancer Institute, Baptist Health South Florida, 8900 N. Kendall Drive. Miami, FL 33176, USA; Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA
| | - William N William
- Thoracic Oncology Program, Grupo Oncoclínicas Grupo Oncoclínicas, Av. Pres. Juscelino Kubitschek, 510, 2º andar, São Paulo, São Paulo 04543-906, Brazil
| | - Glenn J Hanna
- Department of Medical Oncology, Center for Head & Neck Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Dana Building, Room 2-140. Boston, MA 02215, USA.
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Coukos A, Saglietti C, Sempoux C, Haubitz M, Greuter T, Mittaz-Crettol L, Maurer F, Mdawar-Bailly E, Moradpour D, Alberio L, Good JM, Baerlocher GM, Fraga M. High prevalence of short telomeres in idiopathic porto-sinusoidal vascular disorder. Hepatol Commun 2024; 8:e0500. [PMID: 39037376 PMCID: PMC11265777 DOI: 10.1097/hc9.0000000000000500] [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: 04/22/2024] [Accepted: 06/01/2024] [Indexed: 07/23/2024] Open
Abstract
BACKGROUND Telomeres prevent damage to coding DNA as end-nucleotides are lost during mitosis. Mutations in telomere maintenance genes cause excessive telomere shortening, a condition known as short telomere syndrome (STS). One hepatic manifestation documented in STS is porto-sinusoidal vascular disorder (PSVD). METHODS As the etiology of many cases of PSVD remains unknown, this study explored the extent to which short telomeres are present in patients with idiopathic PSVD. RESULTS This monocentric cross-sectional study included patients with histologically defined idiopathic PSVD. Telomere length in 6 peripheral blood leukocyte subpopulations was assessed using fluorescent in situ hybridization and flow cytometry. Variants of telomere-related genes were identified using high-throughput exome sequencing. In total, 22 patients were included, of whom 16 (73%) had short (9/22) or very short (7/22) telomeres according to age-adjusted reference ranges. Fourteen patients (64%) had clinically significant portal hypertension. Shorter telomeres were more frequent in males (p = 0.005) and patients with concomitant interstitial lung disease (p < 0.001), chronic kidney disease (p < 0.001), and erythrocyte macrocytosis (p = 0.007). Portal hypertension (p = 0.021), low serum albumin level (p < 0.001), low platelet count (p = 0.007), and hyperbilirubinemia (p = 0.053) were also associated with shorter telomeres. Variants in known STS-related genes were identified in 4 patients with VSTel and 1 with STel. CONCLUSIONS Short and very short telomeres were highly prevalent in patients with idiopathic PSVD, with 31% presenting with variants in telomere-related genes. Telomere biology may play an important role in vascular liver disease development. Clinicians should consider measuring telomeres in any patient presenting with PSVD.
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Affiliation(s)
- Alexander Coukos
- Divisions of Gastroenterology and Hepatology, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Chiara Saglietti
- Institute of Pathology, Department of Laboratory Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Christine Sempoux
- Institute of Pathology, Department of Laboratory Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Monika Haubitz
- Department of Biomedical Research, Laboratory for Hematopoiesis and Molecular Genetics, University of Bern, Bern, Switzerland
| | - Thomas Greuter
- Divisions of Gastroenterology and Hepatology, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
- Division of Gastroenterology and Hepatology, Department of Medicine, GZO-Zurich Regional Health Center, Wetzikon, Switzerland
| | - Laureane Mittaz-Crettol
- Genetic Medicine, Department of Laboratory Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Fabienne Maurer
- Genetic Medicine, Department of Laboratory Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Elise Mdawar-Bailly
- Divisions of Gastroenterology and Hepatology, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Darius Moradpour
- Divisions of Gastroenterology and Hepatology, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Lorenzo Alberio
- Department of Oncology, Hematology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Jean-Marc Good
- Genetic Medicine, Department of Laboratory Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Gabriela M. Baerlocher
- Department of Biomedical Research, Laboratory for Hematopoiesis and Molecular Genetics, University of Bern, Bern, Switzerland
| | - Montserrat Fraga
- Divisions of Gastroenterology and Hepatology, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
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9
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Lin F, Cao K, Chang F, Oved JH, Luo M, Fan Z, Schubert J, Wu J, Zhong Y, Gallo DJ, Denenberg EH, Chen J, Fanning EA, Lambert MP, Paessler ME, Surrey LF, Zelley K, MacFarland S, Kurre P, Olson TS, Li MM. Uncovering the Genetic Etiology of Inherited Bone Marrow Failure Syndromes Using a Custom-Designed Next-Generation Sequencing Panel. J Mol Diagn 2024; 26:191-201. [PMID: 38103590 DOI: 10.1016/j.jmoldx.2023.11.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2023] [Revised: 09/13/2023] [Accepted: 11/20/2023] [Indexed: 12/19/2023] Open
Abstract
Inherited bone marrow failure syndromes (IBMFS) are a group of heterogeneous disorders that account for ∼30% of pediatric cases of bone marrow failure and are often associated with developmental abnormalities and cancer predisposition. This article reports the laboratory validation and clinical utility of a large-scale, custom-designed next-generation sequencing panel, Children's Hospital of Philadelphia (CHOP) IBMFS panel, for the diagnosis of IBMFS in a cohort of pediatric patients. This panel demonstrated excellent analytic accuracy, with 100% sensitivity, ≥99.99% specificity, and 100% reproducibility on validation samples. In 269 patients with suspected IBMFS, this next-generation sequencing panel was used for identifying single-nucleotide variants, small insertions/deletions, and copy number variations in mosaic or nonmosaic status. Sixty-one pathogenic/likely pathogenic variants (54 single-nucleotide variants/insertions/deletions and 7 copy number variations) and 24 hypomorphic variants were identified, resulting in the molecular diagnosis of IBMFS in 21 cases (7.8%) and exclusion of IBMFS with a diagnosis of a blood disorder in 10 cases (3.7%). Secondary findings, including evidence of early hematologic malignancies and other hereditary cancer-predisposition syndromes, were observed in 9 cases (3.3%). The CHOP IBMFS panel was highly sensitive and specific, with a significant increase in the diagnostic yield of IBMFS. These findings suggest that next-generation sequencing-based panel testing should be a part of routine diagnostics in patients with suspected IBMFS.
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Affiliation(s)
- Fumin Lin
- Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Kajia Cao
- Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Fengqi Chang
- Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Joseph H Oved
- Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Minjie Luo
- Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Zhiqian Fan
- Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Jeffrey Schubert
- Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Jinhua Wu
- Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Yiming Zhong
- Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Daniel J Gallo
- Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Elizabeth H Denenberg
- Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Jiani Chen
- Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Elizabeth A Fanning
- Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Michele P Lambert
- Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Pediatric Comprehensive Bone Marrow Failure Center, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Michele E Paessler
- Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Lea F Surrey
- Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Kristin Zelley
- Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Suzanne MacFarland
- Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Peter Kurre
- Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Pediatric Comprehensive Bone Marrow Failure Center, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Timothy S Olson
- Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Pediatric Comprehensive Bone Marrow Failure Center, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
| | - Marilyn M Li
- Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
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10
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Ongie L, Raj HA, Stevens KB. Genetic Counseling and Family Screening Recommendations in Patients with Telomere Biology Disorders. Curr Hematol Malig Rep 2023; 18:273-283. [PMID: 37787873 DOI: 10.1007/s11899-023-00713-8] [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] [Accepted: 09/11/2023] [Indexed: 10/04/2023]
Abstract
PURPOSE OF REVIEW Telomere biology disorders (TBDs) encompass a spectrum of genetic diseases with a common pathogenesis of defects in telomerase function and telomere maintenance causing extremely short telomere lengths. Here, we review the current literature surrounding genetic testing strategies, cascade testing, reproductive implications, and the role of genetic counseling. RECENT FINDINGS The understanding of the genetic causes and clinical symptoms of TBDs continues to expand while genetic testing and telomere length testing are nuanced tools utilized in the diagnosis of this condition. Access to genetic counseling is becoming more abundant and is valuable in supporting patients and their families in making informed decisions. Patient resources and support groups are valuable to this community. Defining which populations should be offered genetic counseling and testing is imperative to provide proper diagnoses and medical management for not only the primary patient, but also their biological relatives.
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Affiliation(s)
| | - Hannah A Raj
- Team Telomere, Inc., New York, NY, USA
- College of Medicine, University of Illinois, Chicago, IL, USA
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11
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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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12
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Li J, Bledsoe JR. Inherited bone marrow failure syndromes and germline predisposition to myeloid neoplasia: A practical approach for the pathologist. Semin Diagn Pathol 2023; 40:429-442. [PMID: 37507252 DOI: 10.1053/j.semdp.2023.06.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Accepted: 06/27/2023] [Indexed: 07/30/2023]
Abstract
The diagnostic work up and surveillance of germline disorders of bone marrow failure and predisposition to myeloid malignancy is complex and involves correlation between clinical findings, laboratory and genetic studies, and bone marrow histopathology. The rarity of these disorders and the overlap of clinical and pathologic features between primary and secondary causes of bone marrow failure, acquired aplastic anemia, and myelodysplastic syndrome may result in diagnostic uncertainty. With an emphasis on the pathologist's perspective, we review diagnostically useful features of germline disorders including Fanconi anemia, Shwachman-Diamond syndrome, telomere biology disorders, severe congenital neutropenia, GATA2 deficiency, SAMD9/SAMD9L diseases, Diamond-Blackfan anemia, and acquired aplastic anemia. We discuss the distinction between baseline morphologic and genetic findings of these disorders and features that raise concern for the development of myelodysplastic syndrome.
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Affiliation(s)
- Jingwei Li
- Department of Pathology, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115, United States
| | - Jacob R Bledsoe
- Department of Pathology, Boston Children's Hospital, 300 Longwood Ave, Boston, MA 02115, United States.
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13
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Gener-Ricos G, Gerstein YS, Hammond D, DiNardo CD. Germline Predisposition to Myelodysplastic Syndromes. Cancer J 2023; 29:143-151. [PMID: 37195770 DOI: 10.1097/ppo.0000000000000660] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/18/2023]
Abstract
ABSTRACT While germline predisposition to myelodysplastic syndromes is well-established, knowledge has advanced rapidly resulting in more cases of inherited hematologic malignancies being identified. Understanding the biological features and main clinical manifestations of hereditary hematologic malignancies is essential to recognizing and referring patients with myelodysplastic syndrome, who may underlie inherited predisposition, for appropriate genetic evaluation. Importance lies in individualized genetic counseling along with informed treatment decisions, especially with regard to hematopoietic stem cell transplant-related donor selection. Future studies will improve comprehension of these disorders, enabling better management of affected patients and their families.
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Affiliation(s)
| | - Yoheved S Gerstein
- Clinical Cancer Genetics Program, The University of Texas MD Anderson Cancer Center, Houston, TX
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14
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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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15
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Dyskeratosis congenita and telomere biology disorders. HEMATOLOGY. AMERICAN SOCIETY OF HEMATOLOGY. EDUCATION PROGRAM 2022; 2022:637-648. [PMID: 36485133 PMCID: PMC9821046 DOI: 10.1182/hematology.2022000394] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Numerous genetic discoveries and the advent of clinical telomere length testing have led to the recognition of a spectrum of telomere biology disorders (TBDs) beyond the classic dyskeratosis congenita (DC) triad of nail dysplasia, abnormal skin pigmentation, and oral leukoplakia occurring with pediatric bone marrow failure. Patients with DC/TBDs have very short telomeres for their age and are at high risk of bone marrow failure, cancer, pulmonary fibrosis (PF), pulmonary arteriovenous malformations, liver disease, stenosis of the urethra, esophagus, and/or lacrimal ducts, avascular necrosis of the hips and/or shoulders, and other medical problems. However, many patients with TBDs do not develop classic DC features; they may present in middle age and/or with just 1 feature, such as PF or aplastic anemia. TBD-associated clinical manifestations are progressive and attributed to aberrant telomere biology caused by the X-linked recessive, autosomal dominant, autosomal recessive, or de novo occurrence of pathogenic germline variants in at least 18 different genes. This review describes the genetics and clinical manifestations of TBDs and highlights areas in need of additional clinical and basic science research.
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16
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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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17
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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: 38] [Impact Index Per Article: 12.7] [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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18
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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: 46] [Impact Index Per Article: 15.3] [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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19
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Park M. Overview of inherited bone marrow failure syndromes. Blood Res 2022; 57:49-54. [PMID: 35483926 PMCID: PMC9057667 DOI: 10.5045/br.2022.2022012] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 02/27/2022] [Accepted: 03/14/2022] [Indexed: 01/02/2023] Open
Abstract
Patients with inherited bone marrow failure syndrome (IBMFS) can develop peripheral blood cytopenia, which can ultimately progress to myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Although some cases of IBMFS are diagnosed based on their typical presentation, variable disease penetrance and expressivity may result in diagnostic dilemmas. With recent advances in genomic evaluation including next-generation sequencing, many suspected cases of IBMFS with atypical presentations can be identified. Identification of the genetic causes of IBMFS has led to important advances in understanding DNA repair, telomere biology, ribosome biogenesis, and hematopoietic stem cell regulation. An overview of this syndromes is summarized in this paper.
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Affiliation(s)
- Meerim Park
- Department of Pediatrics, Center for Pediatric Cancer, National Cancer Center, Goyang, Korea
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20
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Vagher J, Gammon A, Kohlmann W, Jeter J. Non-Melanoma Skin Cancers and Other Cutaneous Manifestations in Bone Marrow Failure Syndromes and Rare DNA Repair Disorders. Front Oncol 2022; 12:837059. [PMID: 35359366 PMCID: PMC8960432 DOI: 10.3389/fonc.2022.837059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 02/17/2022] [Indexed: 11/17/2022] Open
Abstract
Although most non-melanoma skin cancers are felt to be sporadic in origin, these tumors do play a role in several cancer predisposition syndromes. The manifestations of skin cancers in these hereditary populations can include diagnosis at extremely early ages and/or multiple primary cancers, as well as tumors at less common sites. Awareness of baseline skin cancer risks for these individuals is important, particularly in the setting of treatments that may compromise the immune system and further increase risk of cutaneous malignancies. Additionally, diagnosis of these disorders and management of non-cutaneous manifestations of these diseases have profound implications for both the patient and their family. This review highlights the current literature on the diagnosis, features, and non-melanoma skin cancer risks associated with lesser-known cancer predisposition syndromes, including bone marrow failure disorders, genomic instability disorders, and base excision repair disorders.
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Affiliation(s)
- Jennie Vagher
- Family Cancer Assessment Clinic, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, United States
| | - Amanda Gammon
- Family Cancer Assessment Clinic, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, United States
| | - Wendy Kohlmann
- Family Cancer Assessment Clinic, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, United States
| | - Joanne Jeter
- Family Cancer Assessment Clinic, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, United States
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21
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Are Dyskeratosis Congenita Patients at Higher Risk of Symptomatic COVID-19? Med Hypotheses 2022; 163:110843. [PMID: 35464998 PMCID: PMC9011900 DOI: 10.1016/j.mehy.2022.110843] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 02/19/2022] [Accepted: 03/04/2022] [Indexed: 11/25/2022]
Abstract
Dyskeratosis Congenita (DC) is a rare and heterogeneous disease. This disorder is resulted from a defect in the telomere maintenance in stem cells. Telomerase RNA component, shelterin complex, and telomerase reverse transcriptase are mutated in this disease. Many studies have previously confirmed shorter leukocyte telomere length in DC. On the other hand, the association between telomere length and Coronavirus disease 2019 (COVID-19) indicated that people with a short telomere background mostly show more severe symptoms related to COVID-19, and the mortality rate among them increases as well. Because patients with DC have an abnormally short telomere length, in the current study, we hypothesized that they are at higher risk of developing symptomatic COVID-19 that requires further clinical care.
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22
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Telomere biology disorders: ends and (genetic) means. Blood 2022; 139:1776-1777. [PMID: 35323880 DOI: 10.1182/blood.2021014855] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Accepted: 11/26/2021] [Indexed: 11/20/2022] Open
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23
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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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Григорян ОР, Фролова ТМ, Михеев РК, Шереметьева ЕВ, Абсатарова ЮС, Ужегова ЖА, Андреева ЕН, Мокрышева НГ. [The dual role of the menopausal hormonal therapy as the enhancer of pleiotropic telomere rejuvenation and the silencer of cellular aging (literature review)]. PROBLEMY ENDOKRINOLOGII 2022; 68:105-112. [PMID: 35841174 PMCID: PMC9762536 DOI: 10.14341/probl12895] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Accepted: 03/21/2022] [Indexed: 06/15/2023]
Abstract
Present worldwide healthcare researches prove that female patients are more sensitive to the population aging. Menopause or climacteria (climax) - is not as ageing itself, but a physiological unstoppable process. The main task for a physician is to improve life quality for female despite of ageing problems. Menopausal hormone therapy (MHT) due to the estrogen component has an anti-inflammatory, antioxidant effect and promotes the expression of telomerase, which together changes the homeostasis and integrity of telomeres. The use of MHT for five years or more can not only significantly change the quality of life, but also increase its duration. Literature search was carried out in national (eLibrary, CyberLeninka.ru) and international (PubMed, Cochrane Library) databases in Russian and English. The priority was free access to the full text of articles. The choice of sources was prioritized for the period from 2019 to 2021. However, taking into account the insufficient knowledge of the chosen topic, the choice of sources dates back to 1989.
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Affiliation(s)
- О. Р. Григорян
- Национальный медицинский исследовательский центр эндокринологии
| | - Т. М. Фролова
- Национальный медицинский исследовательский центр эндокринологии
| | - Р. К. Михеев
- Национальный медицинский исследовательский центр эндокринологии
| | | | | | - Ж. А. Ужегова
- Национальный медицинский исследовательский центр эндокринологии
| | - Е. Н. Андреева
- Национальный медицинский исследовательский центр эндокринологии; Московский государственный медико-стоматологический университет им. А.И. Евдокимова
| | - Н. Г. Мокрышева
- Национальный медицинский исследовательский центр эндокринологии
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25
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Keel S. The clinical and laboratory evaluation of patients with suspected hypocellular marrow failure. HEMATOLOGY. AMERICAN SOCIETY OF HEMATOLOGY. EDUCATION PROGRAM 2021; 2021:134-142. [PMID: 34889426 PMCID: PMC8791137 DOI: 10.1182/hematology.2021000244] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/07/2023]
Abstract
The overlap in clinical presentation and bone marrow features of acquired and inherited causes of hypocellular marrow failure poses a significant diagnostic challenge in real case scenarios, particularly in nonsevere disease. The distinction between acquired aplastic anemia (aAA), hypocellular myelodysplastic syndrome (MDS), and inherited bone marrow failure syndromes presenting with marrow hypocellularity is critical to inform appropriate care. Here, we review the workup of hypocellular marrow failure in adolescents through adults. Given the limitations of relying on clinical stigmata or family history to identify patients with inherited etiologies, we outline a diagnostic approach incorporating comprehensive genetic testing in patients with hypocellular marrow failure that does not require immediate therapy and thus allows time to complete the evaluation. We also review the clinical utility of marrow array to detect acquired 6p copy number-neutral loss of heterozygosity to support a diagnosis of aAA, the complexities of telomere length testing in patients with aAA, short telomere syndromes, and other inherited bone marrow failure syndromes, as well as the limitations of somatic mutation testing for mutations in myeloid malignancy genes for discriminating between the various diagnostic possibilities.
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Affiliation(s)
- Siobán Keel
- University of Washington, Seattle, WA
- Correspondence Siobán Keel, University of Washington, Division of Hematology, Seattle, WA 98105; e-mail:
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26
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Tacheva T, Zienolddiny S, Dimov D, Vlaykova D, Vlaykova T. The leukocyte telomere length, single nucleotide polymorphisms near TERC gene and risk of COPD. PeerJ 2021; 9:e12190. [PMID: 34824901 PMCID: PMC8590800 DOI: 10.7717/peerj.12190] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Accepted: 08/30/2021] [Indexed: 12/12/2022] Open
Abstract
Chronic obstructive pulmonary disease (COPD) is characterized by irreversible airflow obstruction and is associated with chronic local and systemic inflammation and oxidative stress. The enhanced oxidative stress and inflammation have been reported to affect telomere length (TL). Furthermore, a number of SNPs at loci encoding the main components of the telomerase genes, TERT and TERC have been shown to correlate with TL. We aimed to explore the leukocyte TL and genotypes for single nucleotide polymorphisms, rs12696304 (C > G) and rs10936599 (C > T) near TERC in COPD cases and matched healthy controls using q-PCR technologies. Successful assessment of TL was performed for 91 patients and 88 controls. The patients had shorter TL (17919.36 ± 1203.01 bp) compared to controls (21 271.48 ± 1891.36 bp) although not significant (p = 0.137). The TL did not associate with the gender, age, spirometric indexes, smoking habits but tended to correlate negatively with BMI (Rho = − 0.215, p = 0.076) in the controls, but not in COPD patients. The genotype frequencies of the SNPs rs12696304 and rs10936599 were compared between patients and controls and the odds ratios (OR) for developing COPD were calculated. The carriers of the common homozygous (CC) genotypes of the SNPs had higher risk for COPD, compared to carriers of the variants alleles (rs12696304 CG+GG vs. CC; OR: 0.615, 95% CI [0.424–0.894], p = 0.011 and for rs10936599 CT+TT vs. CC OR = 0.668, 95% CI [0.457–0.976], p = 0.044). Analysis on the combined effects of the TERCrs12696304 (C > G) and rs10936599 (C > T) genotypes, CC/CC genotype combination was associated with higher risk for COPD (p < 0.0001) and marginally lower FEV1% pr. in patients with GOLD II (p = 0.052). There was no association between the SNP genotypes and TL. In summary, our results suggest that COPD patients may have shorter TL, and rs12696304 and rs10936599 near TERC may affect the risk of COPD independently of TL.
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Affiliation(s)
- Tanya Tacheva
- Department of Medical Chemistry and Biochemistry, Medical Faculty, Trakia University, Stara Zagora, Bulgaria
| | - Shanbeh Zienolddiny
- Section for Toxicology and Biological Work Environment, National Institute of Occupational Health, Oslo, Norway
| | - Dimo Dimov
- Department of Medical Chemistry and Biochemistry, Medical Faculty, Trakia University, Stara Zagora, Bulgaria
| | - Denitsa Vlaykova
- Department of Medical Chemistry and Biochemistry, Medical Faculty, Trakia University, Stara Zagora, Bulgaria
| | - Tatyana Vlaykova
- Department of Medical Chemistry and Biochemistry, Medical Faculty, Trakia University, Stara Zagora, Bulgaria.,Department of Medical Biochemistry, Medical University - Plovdiv, Plovdiv, Bulgaria
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27
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Shimano KA, Narla A, Rose MJ, Gloude NJ, Allen SW, Bergstrom K, Broglie L, Carella BA, Castillo P, Jong JLO, Dror Y, Geddis AE, Huang JN, Lau BW, McGuinn C, Nakano TA, Overholt K, Rothman JA, Sharathkumar A, Shereck E, Vlachos A, Olson TS, Bertuch AA, Wlodarski MW, Shimamura A, Boklan J. Diagnostic work-up for severe aplastic anemia in children: Consensus of the North American Pediatric Aplastic Anemia Consortium. Am J Hematol 2021; 96:1491-1504. [PMID: 34342889 DOI: 10.1002/ajh.26310] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 07/26/2021] [Accepted: 07/27/2021] [Indexed: 12/19/2022]
Abstract
The North American Pediatric Aplastic Anemia Consortium (NAPAAC) is a group of pediatric hematologist-oncologists, hematopathologists, and bone marrow transplant physicians from 46 institutions in North America with interest and expertise in aplastic anemia, inherited bone marrow failure syndromes, and myelodysplastic syndromes. The NAPAAC Bone Marrow Failure Diagnosis and Care Guidelines Working Group was established with the charge of harmonizing the approach to the diagnostic workup of aplastic anemia in an effort to standardize best practices in the field. This document outlines the rationale for initial evaluations in pediatric patients presenting with signs and symptoms concerning for severe aplastic anemia.
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Affiliation(s)
- Kristin A. Shimano
- Department of Pediatrics University of California San Francisco Benioff Children's Hospital San Francisco California USA
| | - Anupama Narla
- Department of Pediatrics Stanford University School of Medicine Stanford California USA
| | - Melissa J. Rose
- Division of Hematology, Oncology, and Bone Marrow Transplant Nationwide Children's Hospital, The Ohio State University College of Medicine Columbus Ohio USA
| | - Nicholas J. Gloude
- Department of Pediatrics University of California San Diego, Rady Children's Hospital San Diego California USA
| | - Steven W. Allen
- Pediatric Hematology/Oncology University of Pittsburgh School of Medicine, UPMC Children's Hospital of Pittsburgh Pittsburgh Pennsylvania USA
| | - Katie Bergstrom
- Cancer and Blood Disorders Center Seattle Children's Hospital Seattle Washington USA
| | - Larisa Broglie
- Department of Pediatric Hematology, Oncology, Blood and Marrow Transplantation Medical College of Wisconsin Milwaukee Wisconsin USA
| | - Beth A. Carella
- Department of Pediatrics Kaiser Permanente Washington District of Columbia USA
| | - Paul Castillo
- Division of Pediatric Hematology Oncology UF Health Shands Children's Hospital Gainesville Florida USA
| | - Jill L. O. Jong
- Section of Hematology‐Oncology, Department of Pediatrics University of Chicago Chicago Illinois USA
| | - Yigal Dror
- Marrow Failure and Myelodysplasia Program, Division of Hematology and Oncology, Department of Paediatrics The Hospital for Sick Children Toronto Ontario Canada
| | - Amy E. Geddis
- Cancer and Blood Disorders Center Seattle Children's Hospital Seattle Washington USA
| | - James N. Huang
- Department of Pediatrics University of California San Francisco Benioff Children's Hospital San Francisco California USA
| | - Bonnie W. Lau
- Pediatric Hematology‐Oncology Dartmouth‐Hitchcock Lebanon New Hampshire USA
| | - Catherine McGuinn
- Department of Pediatrics Weill Cornell Medicine New York New York USA
| | - Taizo A. Nakano
- Center for Cancer and Blood Disorders Children's Hospital Colorado Aurora Colorado USA
| | - Kathleen Overholt
- Pediatric Hematology and Oncology Riley Hospital for Children at Indiana University Indianapolis Indiana USA
| | - Jennifer A. Rothman
- Division of Pediatric Hematology and Oncology Duke University Medical Center Durham North Carolina USA
| | - Anjali Sharathkumar
- Stead Family Department of Pediatrics University of Iowa Carver College of Medicine Iowa City Iowa USA
| | - Evan Shereck
- Department of Pediatrics Oregon Health and Science University Portland Oregon USA
| | - Adrianna Vlachos
- Hematology, Oncology and Cellular Therapy Cohen Children's Medical Center New Hyde Park New York USA
| | - Timothy S. Olson
- Cell Therapy and Transplant Section, Division of Oncology and Bone Marrow Failure, Division of Hematology, Department of Pediatrics Children's Hospital of Philadelphia and University of Pennsylvania Philadelphia Pennsylvania USA
| | | | | | - Akiko Shimamura
- Cancer and Blood Disorders Center Boston Children's Hospital and Dana Farber Cancer Institute Boston Massachusetts USA
| | - Jessica Boklan
- Center for Cancer and Blood Disorders Phoenix Children's Hospital Phoenix Arizona USA
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28
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Bhoopalan SV, Wlodarski M, Reiss U, Triplett B, Sharma A. Reduced-intensity conditioning-based hematopoietic cell transplantation for dyskeratosis congenita: Single-center experience and literature review. Pediatr Blood Cancer 2021; 68:e29177. [PMID: 34086408 DOI: 10.1002/pbc.29177] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 04/30/2021] [Accepted: 05/16/2021] [Indexed: 11/09/2022]
Abstract
BACKGROUND Bone marrow failure in dyskeratosis congenita (DKC) is progressive, and allogeneic hematopoietic cell transplantation (HCT) is the only curative treatment. However, outcomes after HCT are suboptimal because of mucosal, vascular, pulmonary, and hepatic fragility, which can be exacerbated by chemotherapy conditioning and graft-versus-host disease (GVHD). These toxicities can be mitigated by reducing the intensity of the conditioning regimen. PROCEDURES We performed a retrospective analysis on pediatric patients with DKC who underwent HCT at our institution between 2008 and 2019. RESULTS We identified nine patients (median age, 5.7 years) who underwent HCT with a fludarabine-based reduced-intensity conditioning (RIC) regimen. GVHD prophylaxis consisted of tacrolimus plus mycophenolate mofetil (MMF) (n = 8), tacrolimus/pentostatin (n = 1), or cyclosporine/MMF (n = 1). The median time to neutrophil engraftment was 19 days (range, 13-26 days), and the median time to platelet engraftment was 18 days (range, 17-43 days). Lung function, as measured by spirometry in six patients, remained stable during post-HCT observation. Six patients (67%) remain alive, with a median follow-up of 73.5 months. CONCLUSION Because of toxicity after myeloablative conditioning, RIC is becoming standard for HCT in DKC. These results suggest that RIC regimen is feasible and safe for patients with DKC and does not accelerate pulmonary damage in the short-to-medium term after HCT.
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Affiliation(s)
| | - Marcin Wlodarski
- Department of Hematology, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Ulrike Reiss
- Department of Hematology, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Brandon Triplett
- Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Akshay Sharma
- Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, Tennessee
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29
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Roake CM, Juntilla M, Agarwal-Hashmi R, Artandi S, Kuo CS. Tissue-specific telomere shortening and degenerative changes in a patient with TINF2 mutation and dyskeratosis congenita. HUMAN PATHOLOGY: CASE REPORTS 2021; 25:200517. [PMID: 34522616 PMCID: PMC8437149 DOI: 10.1016/j.ehpc.2021.200517] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022] Open
Abstract
Dyskeratosis congenita is a disease of impaired tissue maintenance downstream of telomere dysfunction. Characteristically, patients present with the clinical triad of nail dystrophy, oral leukoplakia, and skin pigmentation defects, but the disease involves degenerative changes in multiple organs. Mutations in telomere-binding proteins such as TINF2 (TRF1-interacting nuclear factor 2) or in telomerase, the enzyme that counteracts age related telomere shortening, are causative in dyskeratosis congenita. We present a patient who presented with severe hypoxemia at age 13. The patient had a history of myelodysplastic syndrome treated with bone marrow transplant at the age of 5. At age 18 she was hospitalized for an acute pneumonia progressing to respiratory failure, developed renal failure and ultimately, she and her family opted to withdraw support as she was not a candidate for a lung transplant. Sequencing of the patient's TINF2 locus revealed a heterozygous mutation (c.844C > T, Arg282Cys) which has previously been reported in a subset of dyskeratosis congenita patients. Tissue sections from multiple organs showed degenerative changes including disorganized bone remodeling, diffuse alveolar damage and small vessel proliferation in the lung, and hyperkeratosis with hyperpigmentation of the skin. Autopsy samples revealed a bimodal distribution of telomere length, with telomeres from donor hematopoietic tissues being an age-appropriate length and those from patient tissues showing pathogenic shortening, with the shortest telomeres in lung, liver, and kidney. We report for the first time a survey of degenerative changes and telomere lengths in multiple organs in a patient with dyskeratosis congenita.
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Affiliation(s)
- Caitlin M Roake
- Stanford University School of Medicine, Stanford, CA 94305, United States
| | - Marisa Juntilla
- Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, United States
| | - Rajni Agarwal-Hashmi
- Department of Pediatrics, Stem-cell Transplantation, Stanford University School of Medicine, Stanford, CA 94305, United States
| | - Steven Artandi
- Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, United States
| | - Christin S Kuo
- Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, United States
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30
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Luchkin AV, Mikhailova EA, Fidarova ZT, Troitskaya VV, Galtseva IV, Kovrigina AM, Glinkina SA, Dvirnyk VN, Raykina EV, Pavlova AV, Demina IA, Parovichnikova EN. A case report of familial dyskeratosis congenital. Case report. TERAPEVT ARKH 2021; 93:818-825. [DOI: 10.26442/00403660.2021.07.200955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Accepted: 07/21/2021] [Indexed: 11/22/2022]
Abstract
Dyskeratosis congenita (DC) is a hereditary syndrome of bone marrow failure, which develops because of telomeres defects and combines with cancer predisposition. Its classical clinical features are skin pigmentation, nail dystrophy, oral leukoplakia (skin-mucosa triad). The goal is to describe the algorithm of diagnosis, clinical specificities of DC and specific treatment for cases of DC in one family. The present report includes descriptions of diagnosis and treatment of family members diagnosed for the first time as having a DC. The report shows an importance of all diagnostic stages: from a medical history and clinical picture to an application of modern high-tech diagnostic methods (flow-FISH, NGS). The report underlines an importance of diagnosis of all family members for excluding an asymptomatic form after a case of DC has been already detected in that family. A high frequency of a toxicity and secondary neoplasia makes it necessary to realize an individual approach at treatment of each patient with DC (the earliest start of androgen treatment, prompt decision of implementation of allogenic hematopoietic stem cell transplantation). The knowledge of pathogenesis, clinical features and principles of diagnosis and therapy of this disease is relevant to pediatricians and hematologists.
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31
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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: 12] [Impact Index Per Article: 3.0] [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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32
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DNA-methylation-based telomere length estimator: comparisons with measurements from flow FISH and qPCR. Aging (Albany NY) 2021; 13:14675-14686. [PMID: 34083495 PMCID: PMC8221337 DOI: 10.18632/aging.203126] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Accepted: 05/14/2021] [Indexed: 12/18/2022]
Abstract
Telomere length (TL) is a marker of biological aging associated with several health outcomes. High throughput reproducible TL measurements are needed for large epidemiological studies. We compared the novel DNA methylation-based estimator (DNAmTL) with the high-throughput quantitative PCR (qPCR) and the highly accurate flow cytometry with fluorescent in situ hybridization (flow FISH) methods using blood samples from healthy adults. We used Pearson’s correlation coefficient, Bland Altman plots and linear regression models for statistical analysis. Shorter DNAmTL was associated with older age, male sex, white race, and cytomegalovirus seropositivity (p<0.01 for all). DNAmTL was moderately correlated with qPCR TL (N=635, r=0.41, p < 0.0001) and flow FISH total lymphocyte TL (N=144, r=0.56, p < 0.0001). The agreements between flow FISH TL and DNAmTL or qPCR were acceptable but with wide limits of agreement. DNAmTL correctly classified >70% of TL categorized above or below the median, but the accuracy dropped with increasing TL categories. The ability of DNAmTL to detect associations with age and other TL-related factors in the absence of strong correlation with measured TL may indicate its capture of aspects of telomere maintenance mechanisms and not necessarily TL. The inaccuracy of DNAmTL prediction should be considered during data interpretation and across-study comparisons.
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33
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Abstract
Telomere biology disorders (TBD) are a heterogeneous group of diseases arising from germline mutations affecting genes involved in telomere maintenance. Telomeres are DNA-protein structures at chromosome ends that maintain chromosome stability; their length affects cell replicative potential and senescence. A constellation of bone marrow failure, pulmonary fibrosis, liver cirrhosis and premature greying is suggestive, however incomplete penetrance results in highly variable manifestations, with idiopathic pulmonary fibrosis as the most common presentation. Currently, the true extent of TBD burden is unknown as there is no established diagnostic criteria and the disorder often is unrecognised and underdiagnosed. There is no gold standard for measuring telomere length and not all TBD-related mutations have been identified. There is no specific cure and the only treatment is organ transplantation, which has poor outcomes. This review summarises the current literature and discusses gaps in understanding and areas of need in managing TBD.
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34
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Giri N, Alter BP, Savage SA, Stratton P. Gynaecological and reproductive health of women with telomere biology disorders. Br J Haematol 2021; 193:1238-1246. [PMID: 34019708 DOI: 10.1111/bjh.17545] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Accepted: 04/18/2021] [Indexed: 12/19/2022]
Abstract
Reproductive health may be adversely impacted in women with dyskeratosis congenita (DC) and related telomere biology disorders (TBD). We evaluated gynaecological problems, fertility, and pregnancy outcomes in 39 females aged 10-81 years who were followed longitudinally in our DC/TBD cohort. Twenty-six had bone marrow failure and 12 underwent haematopoietic cell transplantation. All attained menarche at a normal age. Thirteen women reported menorrhagia; ten used hormonal contraception to reduce bleeding. Nine experienced natural normal-aged menopause. Gynaecological problems (endometriosis = 3, pelvic varicosities = 1, cervical intraepithelial neoplasia = 1, and uterine prolapse = 2) resulted in surgical menopause in seven. Twenty-five of 26 women attempting fertility carried 80 pregnancies with 49 (61%) resulting in livebirths. Ten (38%) women experienced 28 (35%) miscarriages, notably recurrent pregnancy loss in five (19%). Preeclampsia (n = 6, 24%) and progressive cytopenias (n = 10, 40%) resulted in maternal-fetal compromise, including preterm (n = 5) and caesarean deliveries (n = 18, 37%). Gynaecological/reproductive problems were noted mainly in women with autosomal-dominant inheritance; others were still young or died early. Although women with TBDs had normal menarche, fertility, and menopause, gynaecological problems and pregnancy complications leading to caesarean section, preterm delivery, or transfusion support were frequent. Women with TBDs will benefit from multidisciplinary, coordinated care by haematology, gynaecology and maternal-fetal medicine.
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Affiliation(s)
- Neelam Giri
- Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
| | - Blanche P Alter
- Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
| | - Sharon A Savage
- Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
| | - Pamela Stratton
- National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.,Program in Reproductive and Adult Endocrinology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
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35
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Telomere biology disorder prevalence and phenotypes in adults with familial hematologic and/or pulmonary presentations. Blood Adv 2021; 4:4873-4886. [PMID: 33035329 DOI: 10.1182/bloodadvances.2020001721] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Accepted: 08/11/2020] [Indexed: 12/15/2022] Open
Abstract
Telomere biology disorders (TBDs) present heterogeneously, ranging from infantile bone marrow failure associated with very short telomeres to adult-onset interstitial lung disease (ILD) with normal telomere length. Yield of genetic testing and phenotypic spectra for TBDs caused by the expanding list of telomere genes in adults remain understudied. Thus, we screened adults aged ≥18 years with a personal and/or family history clustering hematologic disorders and/or ILD enrolled on The University of Chicago Inherited Hematologic Disorders Registry for causative variants in 13 TBD genes. Sixteen (10%) of 153 probands carried causative variants distributed among TERT (n = 6), TERC (n = 4), PARN (n = 5), or RTEL1 (n = 1), of which 19% were copy number variants. The highest yield (9 of 22 [41%]) was in families with mixed hematologic and ILD presentations, suggesting that ILD in hematology populations and hematologic abnormalities in ILD populations warrant TBD genetic testing. Four (3%) of 117 familial hematologic disorder families without ILD carried TBD variants, making TBD second to only DDX41 in frequency for genetic diagnoses in this population. Phenotypes of 17 carriers with heterozygous PARN variants included 4 (24%) with hematologic abnormalities, 67% with lymphocyte telomere lengths measured by flow cytometry and fluorescence in situ hybridization at or above the 10th percentile, and a high penetrance for ILD. Alternative etiologies for cytopenias and/or ILD such as autoimmune features were noted in multiple TBD families, emphasizing the need to maintain clinical suspicion for a TBD despite the presence of alternative explanations.
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36
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Arthur JW, Pickett HA, Barbaro PM, Kilo T, Vasireddy RS, Beilharz TH, Powell DR, Hackett EL, Bennetts B, Curtin JA, Jones K, Christodoulou J, Reddel RR, Teo J, Bryan TM. A novel cause of DKC1-related bone marrow failure: Partial deletion of the 3' untranslated region. EJHAEM 2021; 2:157-166. [PMID: 35845273 PMCID: PMC9175968 DOI: 10.1002/jha2.165] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/22/2020] [Revised: 01/03/2021] [Accepted: 01/07/2021] [Indexed: 12/11/2022]
Abstract
Telomere biology disorders (TBDs), including dyskeratosis congenita (DC), are a group of rare inherited diseases characterized by very short telomeres. Mutations in the components of the enzyme telomerase can lead to insufficient telomere maintenance in hematopoietic stem cells, resulting in the bone marrow failure that is characteristic of these disorders. While an increasing number of genes are being linked to TBDs, the causative mutation remains unidentified in 30-40% of patients with DC. There is therefore a need for whole genome sequencing (WGS) in these families to identify novel genes, or mutations in regulatory regions of known disease-causing genes. Here we describe a family in which a partial deletion of the 3' untranslated region (3' UTR) of DKC1, encoding the protein dyskerin, was identified by WGS, despite being missed by whole exome sequencing. The deletion segregated with disease across the family and resulted in reduced levels of DKC1 mRNA in the proband. We demonstrate that the DKC1 3' UTR contains two polyadenylation signals, both of which were removed by this deletion, likely causing mRNA instability. Consistent with the major function of dyskerin in stabilization of the RNA subunit of telomerase, hTR, the level of hTR was also reduced in the proband, providing a molecular basis for his very short telomeres. This study demonstrates that the terminal region of the 3' UTR of the DKC1 gene is essential for gene function and illustrates the importance of analyzing regulatory regions of the genome for molecular diagnosis of inherited disease.
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Affiliation(s)
- Jonathan W. Arthur
- Children's Medical Research InstituteFaculty of Medicine and Health, University of SydneyWestmeadNew South WalesAustralia
| | - Hilda A. Pickett
- Children's Medical Research InstituteFaculty of Medicine and Health, University of SydneyWestmeadNew South WalesAustralia
| | - Pasquale M. Barbaro
- Children's Medical Research InstituteFaculty of Medicine and Health, University of SydneyWestmeadNew South WalesAustralia
| | - Tatjana Kilo
- Haematology DepartmentChildren's Hospital at WestmeadWestmeadNew South WalesAustralia
| | - Raja S. Vasireddy
- Haematology DepartmentChildren's Hospital at WestmeadWestmeadNew South WalesAustralia
| | - Traude H. Beilharz
- Monash Biomedicine Discovery InstituteDepartment of Biochemistry and Molecular Biology, Monash UniversityClaytonVictoriaAustralia
| | - David R. Powell
- Monash Bioinformatics PlatformMonash UniversityClaytonVictoriaAustralia
| | - Emma L. Hackett
- Department of Molecular GeneticsChildren's Hospital WestmeadWestmeadNew South WalesAustralia
| | - Bruce Bennetts
- Department of Molecular GeneticsChildren's Hospital WestmeadWestmeadNew South WalesAustralia
- Disciplines of Genetic Medicine and Child and Adolescent Health, Faculty of Medicine and HealthUniversity of SydneyWestmeadNew South WalesAustralia
| | - Julie A. Curtin
- Haematology DepartmentChildren's Hospital at WestmeadWestmeadNew South WalesAustralia
| | - Kristi Jones
- Disciplines of Genetic Medicine and Child and Adolescent Health, Faculty of Medicine and HealthUniversity of SydneyWestmeadNew South WalesAustralia
- Department of Clinical GeneticsChildren's Hospital WestmeadWestmeadNew South WalesAustralia
| | - John Christodoulou
- Disciplines of Genetic Medicine and Child and Adolescent Health, Faculty of Medicine and HealthUniversity of SydneyWestmeadNew South WalesAustralia
- Murdoch Children's Research Institute and Department of PaediatricsMelbourne Medical SchoolParkvilleVictoriaAustralia
| | - Roger R. Reddel
- Children's Medical Research InstituteFaculty of Medicine and Health, University of SydneyWestmeadNew South WalesAustralia
| | - Juliana Teo
- Haematology DepartmentChildren's Hospital at WestmeadWestmeadNew South WalesAustralia
| | - Tracy M. Bryan
- Children's Medical Research InstituteFaculty of Medicine and Health, University of SydneyWestmeadNew South WalesAustralia
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Scheinberg P. Acquired severe aplastic anaemia: how medical therapy evolved in the 20th and 21st centuries. Br J Haematol 2021; 194:954-969. [PMID: 33855695 DOI: 10.1111/bjh.17403] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2020] [Accepted: 02/16/2021] [Indexed: 11/28/2022]
Abstract
The progress in aplastic anaemia (AA) management is one of success. Once an obscure entity resulting in death in most affected can now be successfully treated with either haematopoietic stem cell transplantation (HSCT) or immunosuppressive therapy (IST). The mechanisms that underly the diminution of haematopoietic stem cells (HSCs) are now better elucidated, and include genetics and immunological alterations. Advances in supportive care with better antimicrobials, safer blood products and iron chelation have greatly impacted AA outcomes. Working somewhat 'mysteriously', anti-thymocyte globulin (ATG) forms the base for both HSCT and IST protocols. Efforts to augment immunosuppression potency have not, unfortunately, led to better outcomes. Stimulating HSCs, an often-sought approach, has not been effective historically. The thrombopoietin receptor agonists (Tpo-RA) have been effective in stimulating early HSCs in AA despite the high endogenous Tpo levels. Dosing, timing and best combinations with Tpo-RAs are being defined to improve HSCs expansion in AA with minimal added toxicity. The more comprehensive access and advances in HSCT and IST protocols are likely to benefit AA patients worldwide. The focus of this review will be on the medical treatment advances in AA.
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Affiliation(s)
- Phillip Scheinberg
- Division of Haematology, Hospital A Beneficência Portuguesa, São Paulo, Brazil
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Imran SAM, Yazid MD, Idrus RBH, Maarof M, Nordin A, Razali RA, Lokanathan Y. Is There an Interconnection between Epithelial-Mesenchymal Transition (EMT) and Telomere Shortening in Aging? Int J Mol Sci 2021; 22:ijms22083888. [PMID: 33918710 PMCID: PMC8070110 DOI: 10.3390/ijms22083888] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Revised: 04/07/2021] [Accepted: 04/07/2021] [Indexed: 12/12/2022] Open
Abstract
Epithelial–Mesenchymal Transition (EMT) was first discovered during the transition of cells from the primitive streak during embryogenesis in chicks. It was later discovered that EMT holds greater potential in areas other than the early development of cells and tissues since it also plays a vital role in wound healing and cancer development. EMT can be classified into three types based on physiological functions. EMT type 3, which involves neoplastic development and metastasis, has been the most thoroughly explored. As EMT is often found in cancer stem cells, most research has focused on its association with other factors involving cancer progression, including telomeres. However, as telomeres are also mainly involved in aging, any possible interaction between the two would be worth noting, especially as telomere dysfunction also contributes to cancer and other age-related diseases. Ascertaining the balance between degeneration and cancer development is crucial in cell biology, in which telomeres function as a key regulator between the two extremes. The essential roles that EMT and telomere protection have in aging reveal a potential mutual interaction that has not yet been explored, and which could be used in disease therapy. In this review, the known functions of EMT and telomeres in aging are discussed and their potential interaction in age-related diseases is highlighted.
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Affiliation(s)
- Siti A. M. Imran
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latiff, Bandar Tun Razak, Cheras, Kuala Lumpur 56000, Malaysia; (S.A.M.I.); (M.D.Y.); (R.B.H.I.); (M.M.); (A.N.); (R.A.R.)
| | - Muhammad Dain Yazid
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latiff, Bandar Tun Razak, Cheras, Kuala Lumpur 56000, Malaysia; (S.A.M.I.); (M.D.Y.); (R.B.H.I.); (M.M.); (A.N.); (R.A.R.)
| | - Ruszymah Bt Hj Idrus
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latiff, Bandar Tun Razak, Cheras, Kuala Lumpur 56000, Malaysia; (S.A.M.I.); (M.D.Y.); (R.B.H.I.); (M.M.); (A.N.); (R.A.R.)
- Department of Physiology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latiff, Bandar Tun Razak, Cheras, Kuala Lumpur 56000, Malaysia
| | - Manira Maarof
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latiff, Bandar Tun Razak, Cheras, Kuala Lumpur 56000, Malaysia; (S.A.M.I.); (M.D.Y.); (R.B.H.I.); (M.M.); (A.N.); (R.A.R.)
| | - Abid Nordin
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latiff, Bandar Tun Razak, Cheras, Kuala Lumpur 56000, Malaysia; (S.A.M.I.); (M.D.Y.); (R.B.H.I.); (M.M.); (A.N.); (R.A.R.)
- Department of Physiology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latiff, Bandar Tun Razak, Cheras, Kuala Lumpur 56000, Malaysia
| | - Rabiatul Adawiyah Razali
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latiff, Bandar Tun Razak, Cheras, Kuala Lumpur 56000, Malaysia; (S.A.M.I.); (M.D.Y.); (R.B.H.I.); (M.M.); (A.N.); (R.A.R.)
- Department of Physiology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latiff, Bandar Tun Razak, Cheras, Kuala Lumpur 56000, Malaysia
| | - Yogeswaran Lokanathan
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latiff, Bandar Tun Razak, Cheras, Kuala Lumpur 56000, Malaysia; (S.A.M.I.); (M.D.Y.); (R.B.H.I.); (M.M.); (A.N.); (R.A.R.)
- Correspondence: ; Tel.: +60-391457704
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Ishitsuka Y, Hanaoka Y, Tanemura A, Fujimoto M. Cutaneous Squamous Cell Carcinoma in the Age of Immunotherapy. Cancers (Basel) 2021; 13:1148. [PMID: 33800195 PMCID: PMC7962464 DOI: 10.3390/cancers13051148] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 03/02/2021] [Accepted: 03/03/2021] [Indexed: 12/11/2022] Open
Abstract
Cutaneous squamous cell carcinoma (cSCC) is the second most prevalent skin cancer globally. Because most cSCC cases are manageable by local excision/radiotherapy and hardly become life-threatening, they are often excluded from cancer registries in most countries. Compared with cutaneous melanoma that originates from the melanin-producing, neural crest-derived epidermal resident, keratinocyte (KC)-derived cancers are influenced by the immune system with regards to their pathogenetic behaviour. Congenital or acquired immunosurveillance impairments compromise tumoricidal activity and raises cSCC incidence rates. Intriguingly, expanded applications of programmed death-1 (PD-1) blockade therapies have revealed cSCC to be one of the most amenable targets, particularly when compared with the mucosal counterparts arisen in the esophagus or the cervix. The clinical observation reminds us that cutaneous tissue has a peculiarly high immunogenicity that can evoke tumoricidal recall responses topically. Here we attempt to redefine cSCC biology and review current knowledge about cSCC from multiple viewpoints that involve epidemiology, clinicopathology, molecular genetics, molecular immunology, and developmental biology. This synthesis not only underscores the primal importance of the immune system, rather than just a mere accumulation of ultraviolet-induced mutations but also reinforces the following hypothesis: PD-1 blockade effectively restores the immunity specially allowed to exist within the fully cornified squamous epithelium, that is, the epidermis.
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Affiliation(s)
- Yosuke Ishitsuka
- Department of Dermatology Integrated Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan; (Y.H.); (A.T.); (M.F.)
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Himes RW, Chiou EH, Queliza K, Shouval DS, Somech R, Agarwal S, Jajoo K, Ziegler DS, Kratz CP, Huang J, Lucas TL, Myers KC, Nelson AS, DiNardo CD, Alter BP, Giri N, Khincha PP, McReynolds LJ, Dufour C, Pierri F, Goldman FD, Sherif Y, Savage SA, Miloh T, Bertuch AA. Gastrointestinal Hemorrhage: A Manifestation of the Telomere Biology Disorders. J Pediatr 2021; 230:55-61.e4. [PMID: 32971146 DOI: 10.1016/j.jpeds.2020.09.038] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Revised: 08/17/2020] [Accepted: 09/16/2020] [Indexed: 12/20/2022]
Abstract
OBJECTIVE To describe the clinical features, therapeutic interventions, and patient outcomes of gastrointestinal (GI) hemorrhage in individuals with a telomere biology disorder, including dyskeratosis congenita, Hoyeraal-Hreidarsson syndrome, Revesz syndrome, and Coats plus. STUDY DESIGN Clinical Care Consortium for Telomere Associated Ailments members were invited to contribute data on individuals with telomere biology disorders at their institutions who experienced GI bleeding. Patient demographic, laboratory, imaging, procedural, and treatment information and outcomes were extracted from the medical record. RESULTS Sixteen patients who experienced GI hemorrhage were identified at 11 centers. Among 14 patients who underwent genetic testing, 8 had mutations in TINF2, 4 had mutations in CTC1 or STN1, and 1 patient each had a mutation in TERC and RTEL1. Ten patients had a history of hematopoietic cell transplantation. The patients with Coats plus and those without Coats plus had similar clinical features and courses. Angiodysplasia of the stomach and/or small bowel was described in 8 of the 12 patients who underwent endoscopy; only 4 had esophageal varices. Various medical interventions were trialed. No single intervention was uniformly associated with cessation of bleeding, although 1 patient had a sustained response to treatment with bevacizumab. Recurrence was common, and the overall long-term outcome for affected patients was poor. CONCLUSIONS GI bleeding in patients with telomere biology disorders is associated with significant morbidity and with vascular ectasias rather than varices.
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Affiliation(s)
- Ryan W Himes
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, Baylor College of Medicine and Texas Children's Hospital, Houston, TX; Section of Gastroenterology and Hepatology, Department of Pediatrics, Ochsner Health, New Orleans, LA.
| | - Eric H Chiou
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, Baylor College of Medicine and Texas Children's Hospital, Houston, TX
| | - Karen Queliza
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, Baylor College of Medicine and Texas Children's Hospital, Houston, TX; Gastroenterology, Hepatology and Nutrition Service, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Dror S Shouval
- Pediatric Gastroenterology Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Raz Somech
- Pediatric Gastroenterology Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel
| | - Suneet Agarwal
- Boston Children's Hospital, Dana-Farber Cancer Institute, and Harvard Medical School, Boston, MA
| | - Kunal Jajoo
- Brigham and Women's Hospital and Harvard Medical School, Boston, MA
| | - David S Ziegler
- Kids Cancer Centre, Sydney Children's Hospital, Randwick, NSW, Australia
| | - Christian P Kratz
- Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany
| | - James Huang
- Division of Hematology/Oncology, Department of Pediatrics, UCSF Benioff Children's Hospital, University of California, San Francisco, CA
| | - Tiffany L Lucas
- Division of Hematology/Oncology, Department of Pediatrics, UCSF Benioff Children's Hospital, University of California, San Francisco, CA
| | - Kasiani C Myers
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
| | - Adam S Nelson
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
| | | | - Blanche P Alter
- Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD
| | - Neelam Giri
- Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD
| | - Payal P Khincha
- Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD
| | - Lisa J McReynolds
- Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD
| | - Carlo Dufour
- Hemato-Oncology-Stem Cell Transplant Pole, IRCCS Giannina Gaslini, Genoa, Italy
| | - Filomena Pierri
- Hemato-Oncology-Stem Cell Transplant Pole, IRCCS Giannina Gaslini, Genoa, Italy
| | | | - Youmna Sherif
- Department of Surgery, Baylor College of Medicine and Texas Children's Hospital, Houston, TX
| | - Sharon A Savage
- Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD
| | - Tamir Miloh
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, Baylor College of Medicine and Texas Children's Hospital, Houston, TX; Miami Transplant Institute, University of Miami, Miami, FL
| | - Alison A Bertuch
- Section of Hematology/Oncology, Department of Pediatrics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX
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Gutierrez-Rodrigues F, Alves-Paiva RM, Scatena NF, Martinez EZ, Scheucher PS, Calado RT. Association between leukocyte telomere length and sex by quantile regression analysis. Hematol Transfus Cell Ther 2021; 44:346-351. [PMID: 33593713 PMCID: PMC9477766 DOI: 10.1016/j.htct.2020.12.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Revised: 11/20/2020] [Accepted: 12/03/2020] [Indexed: 12/02/2022] Open
Abstract
Introduction Telomere length (TL) is a biomarker of cellular proliferative history. In healthy individuals, leukocyte TL shortens with age and associates with the lifespan of men and women. However, most of studies had used linear regression models to address the association of the TL attrition, aging and sex. Methods We evaluated the association between the TL, aging and sex in a cohort of 180 healthy subjects by quantile regression. The TL of nucleated blood cells was measured by fluorescent in situ hypridization (flow-FISH) in a cohort of 89 men, 81 women, and 10 umbilical cord samples. The results were validated by quantitative polymerase chain reaction (qPCR) and compared to a linear regression analysis. Results By quantile regression, telomere dynamics slightly differed between sexes with aging: women had longer telomeres at birth and slower attrition rate than men until the sixth decade of life; after that, TL eroded faster and became shorter than that in men. These differences were not observed by linear regression analysis, as the overall telomere attrition rates in women and men were similar (42 pb per year, p < 0.0001 vs. 45 pb kb per year, p < 0.0001). Also, qPCR did not recapitulate flow-FISH findings, as the telomere dynamics by qPCR followed a linear model. Conclusion The quantile regression analysis accurately reproduced a third-order polynomial TL attrition rate in both women and men, but it depended on the technique applied to measure TL. The Flow-FISH reproduced the expected telomere dynamics through life and, differently from the qPCR, was able to detect the subtle TL variations associated with sex and aging.
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Affiliation(s)
| | | | - Natália F Scatena
- Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo (FMRP-USP), Ribeirão Preto, SP, Brazil
| | - Edson Z Martinez
- Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo (FMRP-USP), Ribeirão Preto, SP, Brazil
| | - Priscila S Scheucher
- Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo (FMRP-USP), Ribeirão Preto, SP, Brazil
| | - Rodrigo T Calado
- Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo (FMRP-USP), Ribeirão Preto, SP, Brazil
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Henslee G, Williams CL, Liu P, Bertuch AA. Identification and characterization of novel ACD variants: modulation of TPP1 protein level offsets the impact of germline loss-of-function variants on telomere length. Cold Spring Harb Mol Case Stud 2021; 7:a005454. [PMID: 33446513 PMCID: PMC7903889 DOI: 10.1101/mcs.a005454] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2020] [Accepted: 02/04/2021] [Indexed: 12/13/2022] Open
Abstract
Telomere biology disorders, largely characterized by telomere lengths below the first centile for age, are caused by variants in genes associated with telomere replication, structure, or function. One of these genes, ACD, which encodes the shelterin protein TPP1, is associated with both autosomal dominantly and autosomal recessively inherited telomere biology disorders. TPP1 recruits telomerase to telomeres and stimulates telomerase processivity. Several studies probing the effect of various synthetic or patient-derived variants have mapped specific residues and regions of TPP1 that are important for interaction with TERT, the catalytic component of telomerase. However, these studies have come to differing conclusions regarding ACD haploinsufficiency. Here, we report a proband with compound heterozygous novel variants in ACD (NM_001082486.1)-c.505_507delGAG, p.(Glu169del); and c.619delG, p.(Asp207Thrfs*22)-and a second proband with a heterozygous chromosomal deletion encompassing ACD: arr[hg19] 16q22.1(67,628,846-67,813,408)x1. Clinical data, including symptoms and telomere length within the pedigrees, suggested that loss of one ACD allele was insufficient to induce telomere shortening or confer clinical features. Further analyses of lymphoblastoid cell lines showed decreased nascent ACD RNA and steady-state mRNA, but normal TPP1 protein levels, in cells containing heterozygous ACD c.619delG, p.(Asp207Thrfs*22), or the ACD-encompassing chromosomal deletion compared to controls. Based on our results, we conclude that cells are able to compensate for loss of one ACD allele by activating a mechanism to maintain TPP1 protein levels, thus maintaining normal telomere length.
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Affiliation(s)
- Gabrielle Henslee
- Baylor College of Medicine, Integrated Molecular and Biomedical Sciences Graduate Program, Houston, Texas 77030, USA
- Baylor College of Medicine, Department of Pediatrics, Hematology/Oncology, Houston, Texas 77030, USA
- Texas Children's Hospital, Cancer and Hematology Centers, Houston, Texas 77030, USA
| | - Christopher L Williams
- Baylor College of Medicine, Department of Pediatrics, Hematology/Oncology, Houston, Texas 77030, USA
- Texas Children's Hospital, Cancer and Hematology Centers, Houston, Texas 77030, USA
| | - Pengfei Liu
- Baylor College of Medicine, Department of Molecular and Human Genetics, Houston, Texas 77030, USA
- Baylor Genetics, Houston, Texas 77021, USA
| | - Alison A Bertuch
- Baylor College of Medicine, Integrated Molecular and Biomedical Sciences Graduate Program, Houston, Texas 77030, USA
- Baylor College of Medicine, Department of Pediatrics, Hematology/Oncology, Houston, Texas 77030, USA
- Texas Children's Hospital, Cancer and Hematology Centers, Houston, Texas 77030, USA
- Baylor College of Medicine, Department of Molecular and Human Genetics, Houston, Texas 77030, USA
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Myllymäki M, Redd R, Reilly CR, Saber W, Spellman SR, Gibson CJ, Hu ZH, Wang T, Orr EH, Grenier JG, Chen MM, Steensma DP, Cutler C, De Vivo I, Antin JH, Neuberg D, Agarwal S, Lindsley RC. Short telomere length predicts nonrelapse mortality after stem cell transplantation for myelodysplastic syndrome. Blood 2020; 136:3070-3081. [PMID: 33367544 PMCID: PMC7770569 DOI: 10.1182/blood.2020005397] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Accepted: 07/30/2020] [Indexed: 12/31/2022] Open
Abstract
Allogeneic hematopoietic stem cell transplantation is the only potentially curative treatment for patients with myelodysplastic syndrome (MDS), but long-term survival is limited by the risk of transplant-related complications. Short telomere length, mediated by inherited or acquired factors, impairs cellular response to genotoxic and replicative stress and could identify patients at higher risk for toxicity after transplantation. We measured relative telomere length in pretransplant recipient blood samples in 1514 MDS patients and evaluated the association of telomere length with MDS disease characteristics and transplantation outcomes. Shorter telomere length was significantly associated with older age, male sex, somatic mutations that impair the DNA damage response, and more severe pretransplant cytopenias, but not with bone marrow blast count, MDS treatment history, or history of prior cancer therapy. Among 1267 patients ≥40 years old, telomere length in the shortest quartile was associated with inferior survival (P < .001) because of a high risk of nonrelapse mortality (NRM; P = .001) after adjusting for significant clinical and genetic variables. The adverse impact of shorter telomeres on NRM was independent of recipient comorbidities and was observed selectively among patients receiving more intensive conditioning, including myeloablative regimens and higher dose melphalan-based reduced-intensity regimens. The effect of shorter telomeres on NRM was prominent among patients who developed severe acute graft-versus-host disease, suggesting that short telomere length may limit regenerative potential of mucosal tissues after acute injury. MDS patients with shorter telomere length, who have inferior survival driven by excess toxicity, could be considered for strategies focused on minimizing toxic effects of transplantation.
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Affiliation(s)
- Mikko Myllymäki
- Division of Hematological Malignancies, Department of Medical Oncology, and
| | - Robert Redd
- Department of Data Sciences, Dana-Farber Cancer Institute, Boston MA
| | | | - Wael Saber
- Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, Milwaukee, WI
| | - Stephen R Spellman
- Center for International Blood and Marrow Transplant Research, National Marrow Donor Program/Be The Match, Minneapolis, MN
| | | | - Zhen-Huan Hu
- Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, Milwaukee, WI
| | - Tao Wang
- Center for International Blood and Marrow Transplant Research, National Marrow Donor Program/Be The Match, Minneapolis, MN
| | - Esther H Orr
- Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA
| | - Jaclyn G Grenier
- Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA
| | - Maxine M Chen
- Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA
| | - David P Steensma
- Division of Hematological Malignancies, Department of Medical Oncology, and
| | - Corey Cutler
- Division of Hematological Malignancies, Department of Medical Oncology, and
| | - Immaculata De Vivo
- Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA
- Channing Division of Network Medicine, Brigham and Women's Hospital-Harvard Medical School, Boston, MA; and
| | - Joseph H Antin
- Division of Hematological Malignancies, Department of Medical Oncology, and
| | - Donna Neuberg
- Department of Data Sciences, Dana-Farber Cancer Institute, Boston MA
| | - Suneet Agarwal
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA
| | - R Coleman Lindsley
- Division of Hematological Malignancies, Department of Medical Oncology, and
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Schratz KE. Extrahematopoietic manifestations of the short telomere syndromes. HEMATOLOGY. AMERICAN SOCIETY OF HEMATOLOGY. EDUCATION PROGRAM 2020; 2020:115-122. [PMID: 33275732 PMCID: PMC7727508 DOI: 10.1182/hematology.2020000170] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/23/2023]
Abstract
The short telomere syndromes encompass a spectrum of clinical manifestations that present from infancy to late adulthood. They are caused by mutations in telomerase and other telomere maintenance genes and have a predominantly degenerative phenotype characterized by organ failure across multiple systems. They are collectively one of the most common inherited bone marrow failure syndromes; however, their most prevalent presentations are extrahematopoietic. This review focuses on these common nonhematologic complications, including pulmonary fibrosis, liver pathology, and immunodeficiency. The short telomere syndrome diagnosis informs clinical care, especially in guiding diagnostic evaluations as well as in the solid organ transplant setting. Early recognition allows an individualized approach to screening and management. This review illustrates a myriad of extrahematopoietic presentations of short telomere syndromes and how they impact clinical decisions.
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Affiliation(s)
- Kristen E Schratz
- Department of Oncology and Telomere Center at Johns Hopkins, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD
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Schmutz I, Mensenkamp AR, Takai KK, Haadsma M, Spruijt L, de Voer RM, Choo SS, Lorbeer FK, van Grinsven EJ, Hockemeyer D, Jongmans MCJ, de Lange T. TINF2 is a haploinsufficient tumor suppressor that limits telomere length. eLife 2020; 9:e61235. [PMID: 33258446 PMCID: PMC7707837 DOI: 10.7554/elife.61235] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Accepted: 11/11/2020] [Indexed: 12/20/2022] Open
Abstract
Telomere shortening is a presumed tumor suppressor pathway that imposes a proliferative barrier (the Hayflick limit) during tumorigenesis. This model predicts that excessively long somatic telomeres predispose to cancer. Here, we describe cancer-prone families with two unique TINF2 mutations that truncate TIN2, a shelterin subunit that controls telomere length. Patient lymphocyte telomeres were unusually long. We show that the truncated TIN2 proteins do not localize to telomeres, suggesting that the mutations create loss-of-function alleles. Heterozygous knock-in of the mutations or deletion of one copy of TINF2 resulted in excessive telomere elongation in clonal lines, indicating that TINF2 is haploinsufficient for telomere length control. In contrast, telomere protection and genome stability were maintained in all heterozygous clones. The data establish that the TINF2 truncations predispose to a tumor syndrome. We conclude that TINF2 acts as a haploinsufficient tumor suppressor that limits telomere length to ensure a timely Hayflick limit.
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Affiliation(s)
- Isabelle Schmutz
- Laboratory for Cell Biology and Genetics, Rockefeller UniversityNew YorkUnited States
| | - Arjen R Mensenkamp
- Department of Human Genetics, Radboud University Medical CenterNijmegenNetherlands
| | - Kaori K Takai
- Laboratory for Cell Biology and Genetics, Rockefeller UniversityNew YorkUnited States
| | - Maaike Haadsma
- Department of Human Genetics, Radboud University Medical CenterNijmegenNetherlands
| | - Liesbeth Spruijt
- Department of Human Genetics, Radboud University Medical CenterNijmegenNetherlands
| | - Richarda M de Voer
- Department of Human Genetics, Radboud University Medical CenterNijmegenNetherlands
| | - Seunga Sara Choo
- Department of Molecular and Cellular Biology, University of California, BerkeleyBerkeleyUnited States
| | - Franziska K Lorbeer
- Department of Molecular and Cellular Biology, University of California, BerkeleyBerkeleyUnited States
| | - Emma J van Grinsven
- Department of Molecular and Cellular Biology, University of California, BerkeleyBerkeleyUnited States
| | - Dirk Hockemeyer
- Department of Molecular and Cellular Biology, University of California, BerkeleyBerkeleyUnited States
- Chan Zuckerberg BiohubSan FranciscoUnited States
| | | | - Titia de Lange
- Laboratory for Cell Biology and Genetics, Rockefeller UniversityNew YorkUnited States
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Alebrahim M, Akateh C, Arnold CA, Benissan-Messan D, Chavez JA, Singh N, Al-Adwan Y, El-Hinnawi A, Michaels A, Black SM. Liver Transplant for Management of Hepatic Complications of Dyskeratosis Congenita: A Case Report. EXP CLIN TRANSPLANT 2020; 20:702-705. [PMID: 33272154 DOI: 10.6002/ect.2020.0073] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Dyskeratosis congenita, a rare genetic disorder typified by progressive bone marrow failure, is classically characterized by the triad of abnormal skin pigmentation, nail dystrophy, and oral leukoplakia; however, it is a multisystem disease. Although hepatic involvement occurs in about 7% of patients with dyskeratosis congenita, end-stage liver disease is rare. Treatment of dyskeratosis congenita generally involves hematopoietic stem cell transplant. For patients with hepatic failure, liver transplant can be an option. Here, we describe a case of a patient with dyskeratosis congenita who presented with liver failure and pulmonary failure, precluding him from hematopoietic stem cell transplant. After liver transplant, the patient had significant improvements in pulmonary function and transfusion requirements, allowing the patient to qualify for hematopoietic stem cell transplant. Although hematopoietic stem cell transplant is typically the first step in the management of dyskeratosis congenita, for patients with severe hepatic manifestations of the disease, a liver transplant first approach may result in better disease management.
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Affiliation(s)
- Musab Alebrahim
- From the Division of Transplant Surgery, Department of Surgery, Ohio State University Wexner Medical Center, Columbus, Ohio, USA
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Jahan D, Al Hasan MM, Haque M. Diamond-Blackfan anemia with mutation in RPS19: A case report and an overview of published pieces of literature. J Pharm Bioallied Sci 2020; 12:163-170. [PMID: 32742115 PMCID: PMC7373105 DOI: 10.4103/jpbs.jpbs_234_19] [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: 10/20/2019] [Revised: 02/20/2020] [Accepted: 02/21/2020] [Indexed: 11/04/2022] Open
Abstract
Introduction Diamond-Blackfan anemia (DBA), one of a rare group of inherited bone marrow failure syndromes, is characterized by red cell failure, the presence of congenital anomalies, and cancer predisposition. It can be caused by mutations in the RPS19 gene (25% of the cases). Methods This case report describes a 10-month-old boy who presented with 2 months' history of gradually increasing weakness and pallor. Results The patient was diagnosed as a case of DBA based on peripheral blood finding, bone marrow aspiration with trephine biopsy reports, and genetic mutation analysis of the RPS19 gene. His father refused hematopoietic stem cell transplantation for financial constraints. Patient received prednisolone therapy with oral folic acid and iron supplements. Conclusion Hemoglobin raised from 6.7 to 9.8g/dL after 1 month of therapeutic intervention.
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Affiliation(s)
- Dilshad Jahan
- Department of Hematology, Apollo Hospitals, Dhaka, Bangladesh
| | | | - Mainul Haque
- Unit of Pharmacology, Faculty of Medicine and Defence Health, Universiti Pertahanan Nasional Malaysia (National Defence University of Malaysia), Kuala Lumpur, Malaysia
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Pseudouridylation defect due to DKC1 and NOP10 mutations causes nephrotic syndrome with cataracts, hearing impairment, and enterocolitis. Proc Natl Acad Sci U S A 2020; 117:15137-15147. [PMID: 32554502 DOI: 10.1073/pnas.2002328117] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
RNA modifications play a fundamental role in cellular function. Pseudouridylation, the most abundant RNA modification, is catalyzed by the H/ACA small ribonucleoprotein (snoRNP) complex that shares four core proteins, dyskerin (DKC1), NOP10, NHP2, and GAR1. Mutations in DKC1, NOP10, or NHP2 cause dyskeratosis congenita (DC), a disorder characterized by telomere attrition. Here, we report a phenotype comprising nephrotic syndrome, cataracts, sensorineural deafness, enterocolitis, and early lethality in two pedigrees: males with DKC1 p.Glu206Lys and two children with homozygous NOP10 p.Thr16Met. Females with heterozygous DKC1 p.Glu206Lys developed cataracts and sensorineural deafness, but nephrotic syndrome in only one case of skewed X-inactivation. We found telomere attrition in both pedigrees, but no mucocutaneous abnormalities suggestive of DC. Both mutations fall at the dyskerin-NOP10 binding interface in a region distinct from those implicated in DC, impair the dyskerin-NOP10 interaction, and disrupt the catalytic pseudouridylation site. Accordingly, we found reduced pseudouridine levels in the ribosomal RNA (rRNA) of the patients. Zebrafish dkc1 mutants recapitulate the human phenotype and show reduced 18S pseudouridylation, ribosomal dysregulation, and a cell-cycle defect in the absence of telomere attrition. We therefore propose that this human disorder is the consequence of defective snoRNP pseudouridylation and ribosomal dysfunction.
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Toufektchan E, Lejour V, Durand R, Giri N, Draskovic I, Bardot B, Laplante P, Jaber S, Alter BP, Londono-Vallejo JA, Savage SA, Toledo F. Germline mutation of MDM4, a major p53 regulator, in a familial syndrome of defective telomere maintenance. SCIENCE ADVANCES 2020; 6:eaay3511. [PMID: 32300648 PMCID: PMC7148086 DOI: 10.1126/sciadv.aay3511] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Accepted: 01/16/2020] [Indexed: 05/08/2023]
Abstract
Dyskeratosis congenita is a cancer-prone inherited bone marrow failure syndrome caused by telomere dysfunction. A mouse model recently suggested that p53 regulates telomere metabolism, but the clinical relevance of this finding remained uncertain. Here, a germline missense mutation of MDM4, a negative regulator of p53, was found in a family with features suggestive of dyskeratosis congenita, e.g., bone marrow hypocellularity, short telomeres, tongue squamous cell carcinoma, and acute myeloid leukemia. Using a mouse model, we show that this mutation (p.T454M) leads to increased p53 activity, decreased telomere length, and bone marrow failure. Variations in p53 activity markedly altered the phenotype of Mdm4 mutant mice, suggesting an explanation for the variable expressivity of disease symptoms in the family. Our data indicate that a germline activation of the p53 pathway may cause telomere dysfunction and point to polymorphisms affecting this pathway as potential genetic modifiers of telomere biology and bone marrow function.
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Affiliation(s)
- Eléonore Toufektchan
- Genetics of Tumor Suppression, Institut Curie, Paris, France
- CNRS UMR 3244, Paris, France
- Sorbonne Université, Paris, France
- PSL Research University, Paris, France
| | - Vincent Lejour
- Genetics of Tumor Suppression, Institut Curie, Paris, France
- CNRS UMR 3244, Paris, France
- Sorbonne Université, Paris, France
- PSL Research University, Paris, France
| | - Romane Durand
- Genetics of Tumor Suppression, Institut Curie, Paris, France
- CNRS UMR 3244, Paris, France
- Sorbonne Université, Paris, France
- PSL Research University, Paris, France
| | - Neelam Giri
- Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
| | - Irena Draskovic
- CNRS UMR 3244, Paris, France
- Sorbonne Université, Paris, France
- PSL Research University, Paris, France
- Telomeres and Cancer, Institut Curie, Paris, France
| | - Boris Bardot
- Genetics of Tumor Suppression, Institut Curie, Paris, France
- CNRS UMR 3244, Paris, France
- Sorbonne Université, Paris, France
- PSL Research University, Paris, France
| | - Pierre Laplante
- Genetics of Tumor Suppression, Institut Curie, Paris, France
- CNRS UMR 3244, Paris, France
- Sorbonne Université, Paris, France
- PSL Research University, Paris, France
| | - Sara Jaber
- Genetics of Tumor Suppression, Institut Curie, Paris, France
- CNRS UMR 3244, Paris, France
- Sorbonne Université, Paris, France
- PSL Research University, Paris, France
| | - Blanche P. Alter
- Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
| | - José-Arturo Londono-Vallejo
- CNRS UMR 3244, Paris, France
- Sorbonne Université, Paris, France
- PSL Research University, Paris, France
- Telomeres and Cancer, Institut Curie, Paris, France
| | - Sharon A. Savage
- Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
| | - Franck Toledo
- Genetics of Tumor Suppression, Institut Curie, Paris, France
- CNRS UMR 3244, Paris, France
- Sorbonne Université, Paris, France
- PSL Research University, Paris, France
- Corresponding author.
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Giri N, Ravichandran S, Wang Y, Gadalla SM, Alter BP, Fontana J, Savage SA. Prognostic significance of pulmonary function tests in dyskeratosis congenita, a telomere biology disorder. ERJ Open Res 2019; 5:00209-2019. [PMID: 31754622 PMCID: PMC6856494 DOI: 10.1183/23120541.00209-2019] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2019] [Accepted: 08/28/2019] [Indexed: 11/23/2022] Open
Abstract
Pulmonary fibrosis and pulmonary arteriovenous malformations are known manifestations of dyskeratosis congenita (DC), a telomere biology disorder (TBD) and inherited bone marrow failure syndrome caused by germline mutations in telomere maintenance genes resulting in very short telomeres. Baseline pulmonary function tests (PFTs) and long-term clinical outcomes have not been thoroughly studied in DC/TBDs. In this retrospective study, 43 patients with DC and 67 unaffected relatives underwent baseline PFTs and were followed for a median of 8 years (range 1–14). Logistic regression and competing risk models were used to compare PFT results in relation to clinical and genetic characteristics, and patient outcomes. Restrictive abnormalities on spirometry and moderate-to-severe reduction in diffusing capacity of the lung for carbon monoxide were significantly more frequent in patients with DC than relatives (42% versus 12%; p=0.008). The cumulative incidence of pulmonary disease by age 20 years was 55% in patients with DC with baseline PFT abnormalities compared with 17% in those with normal PFTs (p=0.02). None of the relatives developed pulmonary disease. X-linked recessive, autosomal recessive inheritance or heterozygous TINF2 variants were associated with early-onset pulmonary disease that mainly developed after haematopoietic cell transplantation (HCT). Overall, seven of 14 patients developed pulmonary disease post-HCT at a median of 4.7 years (range 0.7–12). The cumulative incidence of pulmonary fibrosis in patients with heterozygous non-TINF2 pathogenic variants was 70% by age 60 years. Baseline PFT abnormalities are common in patients with DC and associated with progression to significant pulmonary disease. Prospective studies are warranted to facilitate clinical trial development for patients with DC and related TBDs. About 40% of patients with dyskeratosis congenita, a telomere biology disorder, have abnormal pulmonary function tests and progress to life-threatening pulmonary disease (PD). Prospective therapeutic studies of PD in these disorders are urgently needed.http://bit.ly/2HBSNCO
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Affiliation(s)
- Neelam Giri
- Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Sandhiya Ravichandran
- Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Youjin Wang
- Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Shahinaz M Gadalla
- Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Blanche P Alter
- Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Joseph Fontana
- National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.,These authors contributed equally
| | - Sharon A Savage
- Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.,These authors contributed equally
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