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Journal of Clinical and Translational... Feb 2022Dyskeratosis congenita (DC) is a rare disease and is a heterogenous disorder, with its inheritance patterns as autosomal dominant, autosomal recessive, and X-linked... (Review)
Review
BACKGROUND
Dyskeratosis congenita (DC) is a rare disease and is a heterogenous disorder, with its inheritance patterns as autosomal dominant, autosomal recessive, and X-linked recessive. This disorder occurs due to faulty maintenance of telomeres in stem cells. This congenital condition is diagnosed with three symptoms: oral leukoplakia, nail dystrophy, and abnormal skin pigmentation. However, because it has a wide range of symptoms, it may have phenotypes similar to other diseases. For this reason, it is necessary to use methods of measuring the Telomere Length (TL) and determining the shortness of the telomere in these patients so that it can be distinguished from other diseases. Today, the Next Generation Sequencing technique accurately detects mutations in the target genes.
AIM
This work aims to review and summarize how each of the DC genes is involved in TL, and how to diagnose and differentiate the disease using clinical signs and methods to measure TL. It also offers treatments for DC patients, such as Hematopoietic Stem Cell Transplantation and Androgen therapy.
RELEVANCE FOR PATIENTS
In DC patients, the genes involved in telomere homeostasis are mutated. Because these patients may have an overlapping phenotype with other diseases, it is best to perform whole-exome sequencing after genetics counseling to find the relevant mutation. As DC is a multi-systemic disease, we need to monitor patients frequently through annual lung function tests, ultrasounds, gynecological examinations, and skin examinations.
PubMed: 35097237
DOI: No ID Found -
Expert Review of Hematology Dec 2019: Telomere biology disorders (TBDs) encompass a group of illnesses caused by germline mutations in genes regulating telomere maintenance, resulting in very short... (Review)
Review
: Telomere biology disorders (TBDs) encompass a group of illnesses caused by germline mutations in genes regulating telomere maintenance, resulting in very short telomeres. Possible TBD manifestations range from complex multisystem disorders with onset in childhood such as dyskeratosis congenita (DC), Hoyeraal-Hreidarsson syndrome, Revesz syndrome and Coats plus to adults presenting with one or two DC-related features.: The discovery of multiple genetic causes and inheritance patterns has led to the recognition of a spectrum of clinical features affecting multiple organ systems. Patients with DC and associated TBDs are at high risk of bone marrow failure, cancer, liver and pulmonary disease. Recently, vascular diseases, including pulmonary arteriovenous malformations and gastrointestinal telangiectasias, have been recognized as additional manifestations. Diagnostics include detection of very short leukocyte telomeres and germline genetic testing. Hematopoietic cell transplantation and lung transplantation are the only current therapeutic modalities but are complicated by numerous comorbidities. This review summarizes the pathophysiology underlying TBDs, associated clinical features, management recommendations and therapeutic options.: Understanding TBDs as complex, multisystem disorders with a heterogenous genetic background and diverse phenotypes, highlights the importance of clinical surveillance and the urgent need to develop new therapeutic strategies to improve health outcomes.
Topics: Dyskeratosis Congenita; Germ-Line Mutation; Humans; Telomere
PubMed: 31478401
DOI: 10.1080/17474086.2019.1662720 -
F1000Research 2018Studies of rare and common illnesses have led to remarkable progress in the understanding of the role of telomeres (nucleoprotein complexes at chromosome ends essential... (Review)
Review
Studies of rare and common illnesses have led to remarkable progress in the understanding of the role of telomeres (nucleoprotein complexes at chromosome ends essential for chromosomal integrity) in human disease. Telomere biology disorders encompass a growing spectrum of conditions caused by rare pathogenic germline variants in genes encoding essential aspects of telomere function. Dyskeratosis congenita, a disorder at the severe end of this spectrum, typically presents in childhood with the classic triad of abnormal skin pigmentation, nail dystrophy, and oral leukoplakia, accompanied by a very high risk of bone marrow failure, cancer, pulmonary fibrosis, and other medical problems. In contrast, the less severe end of the telomere biology disorder spectrum consists of middle-age or older adults with just one feature typically seen in dyskeratosis congenita, such as pulmonary fibrosis or bone marrow failure. In the common disease realm, large-scale molecular epidemiology studies have discovered novel associations between illnesses, such as cancer, heart disease, and mental health, and both telomere length and common genetic variants in telomere biology genes. This review highlights recent findings of telomere biology in human disease from both the rare and common disease perspectives. Multi-disciplinary collaborations between clinicians, basic scientists, and epidemiologist are essential as we seek to incorporate new telomere biology discoveries to improve health outcomes.
PubMed: 29770205
DOI: 10.12688/f1000research.14068.1 -
Hematology/oncology and Stem Cell... Dec 2017Bone marrow failure syndrome is an epithet of bone marrow failure (all or single-cell lineage) that is attributable to an underlying genetic aberration usually with a... (Review)
Review
Bone marrow failure syndrome is an epithet of bone marrow failure (all or single-cell lineage) that is attributable to an underlying genetic aberration usually with a constellation of somatic abnormalities. Multiple inheritance patterns have been described in these disorders; many are transmitted in an autosomal recessive pattern, which may consequently lead to a higher prevalence of such illnesses in homogeneous societies such as Saudi Arabia, where consanguineous marriages are not uncommon. At King Faisal Specialist Hospital and Research Center, the most common entity referred for allogeneic hematopoietic cell transplantation (HCT) is Fanconi anemia, followed by pure red aplasia, and, less commonly, dyskeratosis congenita, congenital neutropenia, and others. Of all the congenital bone marrow failure syndromes, two of them-Fanconi anemia and dyskeratosis congenita-represent a real challenge in terms of conditioning for HCT and require special attention. This minireview is a snapshot of the recent international and local experience of HCT in these two entities.
Topics: Allografts; Dyskeratosis Congenita; Fanconi Anemia; Hematopoietic Stem Cell Transplantation; Humans; Red-Cell Aplasia, Pure
PubMed: 28644950
DOI: 10.1016/j.hemonc.2017.05.014 -
Hepatology (Baltimore, Md.) Dec 2023Dyskeratosis congenita (DC) and related telomere biology disorders (TBD) are characterized by very short telomeres and multisystem organ involvement including liver...
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.
Topics: Humans; Male; Female; Dyskeratosis Congenita; Digestive System Diseases; Telomere; Hypertension, Portal; Vascular Diseases; Disease Progression; Biology; Mutation; Telomerase
PubMed: 37184208
DOI: 10.1097/HEP.0000000000000461 -
Best Practice & Research. Clinical... Mar 2015Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders characterized by cytopenias, ineffective hematopoiesis, myelodysplasia, and an increased risk of acute... (Review)
Review
Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders characterized by cytopenias, ineffective hematopoiesis, myelodysplasia, and an increased risk of acute myeloid leukemia (AML). While sporadic MDS is primarily a disease of the elderly, MDS in children and young and middle-aged adults is frequently associated with underlying genetic predisposition syndromes. In addition to the classic hereditary bone marrow failure syndromes (BMFS) such as Fanconi Anemia and Dyskeratosis Congenita, in recent years there has been an increased awareness of non-syndromic familial MDS/AML predisposition syndromes such as those caused by mutations in GATA2, RUNX1, CEBPA, and SRP72 genes. Here, we will discuss the importance of recognizing an underlying genetic predisposition syndrome a patient with MDS, will review clinical scenarios when genetic predisposition should be considered, and will provide a practical overview of the common BMFS and familial MDS/AML syndromes which may be encountered in adult patients with MDS.
Topics: Adolescent; Aged; Antineoplastic Agents; CCAAT-Enhancer-Binding Proteins; Core Binding Factor Alpha 2 Subunit; Dyskeratosis Congenita; Fanconi Anemia; GATA2 Transcription Factor; Genetic Predisposition to Disease; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Mutation; Myelodysplastic Syndromes; Signal Recognition Particle
PubMed: 25659730
DOI: 10.1016/j.beha.2014.11.004 -
British Journal of Haematology May 2017The inherited bone marrow failure syndromes (IBMFS) typically present with significant cytopenias in at least one haematopoietic cell lineage that may progress to... (Review)
Review
The inherited bone marrow failure syndromes (IBMFS) typically present with significant cytopenias in at least one haematopoietic cell lineage that may progress to pancytopenia, and are associated with increased risk of cancer. Although the clinical features of the IBMFS are often diagnostic, variable disease penetrance and expressivity may result in diagnostic dilemmas. The discovery of the genetic aetiology of the IBMFS has been greatly facilitated by next-generation sequencing methods. This has advanced understanding of the underlying biology of the IBMFS and been essential in improving clinical management and genetic counselling for affected patients. Herein we review the clinical features, underlying biology, and new genomic discoveries in the IBMFS, including Fanconi anaemia, dyskeratosis congenita, Diamond Blackfan anaemia, Shwachman Diamond syndrome and some disorders of the myeloid and megakaryocytic lineages.
Topics: Anemia, Aplastic; Anemia, Diamond-Blackfan; Blood Platelet Disorders; Bone Marrow Diseases; Bone Marrow Failure Disorders; DNA Repair-Deficiency Disorders; Dyskeratosis Congenita; Exocrine Pancreatic Insufficiency; Fanconi Anemia; Genetic Counseling; Genomics; Hemoglobinuria, Paroxysmal; Humans; Lipomatosis; Neutropenia; Ribosomes; Shwachman-Diamond Syndrome; Telomere
PubMed: 28211564
DOI: 10.1111/bjh.14535 -
Blood Feb 2022
Topics: Biology; Dyskeratosis Congenita; Family; Humans; Telomere
PubMed: 35175322
DOI: 10.1182/blood.2021014533 -
Genes Mar 2022Dyskeratosis congenital (DC) is the first genetic syndrome described among telomeropathies. Its classical phenotype is characterized by the mucocutaneous triad of... (Review)
Review
Dyskeratosis congenital (DC) is the first genetic syndrome described among telomeropathies. Its classical phenotype is characterized by the mucocutaneous triad of reticulated pigmentation of skin lace, nail dystrophy and oral leukoplakia. The clinical presentation, however, is heterogeneous and serious clinical complications include bone marrow failure, hematological and solid tumors. It may also involve immunodeficiencies, dental, pulmonary and liver disorders, and other minor complication. Dyskeratosis congenita shows marked genetic heterogeneity, as at least 14 genes are responsible for the shortening of telomeres characteristic of this disease. This review discusses clinical characteristics, molecular genetics, disease evolution, available therapeutic options and differential diagnosis of dyskeratosis congenita to provide an interdisciplinary and personalized medical assessment that includes family genetic counseling.
Topics: Dyskeratosis Congenita; Humans; Leukoplakia, Oral; Nails, Malformed; Rare Diseases; Telomere
PubMed: 35328050
DOI: 10.3390/genes13030496 -
International Journal of Molecular... May 2016Myelodysplastic syndromes (MDS) are heterogeneous clonal hematopoietic disorders characterized by ineffective hematopoiesis, bone marrow dysplasia, and peripheral... (Review)
Review
Myelodysplastic syndromes (MDS) are heterogeneous clonal hematopoietic disorders characterized by ineffective hematopoiesis, bone marrow dysplasia, and peripheral cytopenias. Familial forms of MDS have traditionally been considered rare, especially in adults; however, the increasing availability of somatic and germline genetic analyses has identified multiple susceptibility loci. Bone marrow failure syndromes have been well-described in the pediatric setting, e.g., Fanconi anemia (FA), dyskeratosis congenita (DC), Diamond-Blackfan anemia (DBA), and Shwachman-Diamond syndrome (SBS), hallmarked by clinically-recognizable phenotypes (e.g., radial ray anomalies in FA) and significantly increased risks for MDS and/or acute myeloid leukemia (AML) in the setting of bone marrow failure. However, additional families with multiple cases of MDS or AML have long been reported in the medical literature with little known regarding potential hereditary etiologies. Over the last decade, genomic investigation of such families has revealed multiple genes conferring inherited risks for MDS and/or AML as the primary malignancy, including RUNX1, ANKRD26, DDX41, ETV6, GATA2, and SRP72. As these syndromes are increasingly appreciated in even apparently de novo presentations of MDS, it is important for hematologists/oncologists to become familiar with these newly-described syndromes. Herein, we provide a review of familial MDS syndromes and practical aspects of management in patients with predisposition syndromes.
Topics: Anemia, Aplastic; Bone Marrow Diseases; Bone Marrow Failure Disorders; Core Binding Factor Alpha 2 Subunit; DEAD-box RNA Helicases; Female; GATA2 Transcription Factor; Genetic Counseling; Genetic Predisposition to Disease; Genetic Testing; Hemoglobinuria, Paroxysmal; Heredity; Humans; Intercellular Signaling Peptides and Proteins; Leukemia, Myeloid, Acute; Male; Myelodysplastic Syndromes; Nuclear Proteins; Proto-Oncogene Proteins c-ets; Repressor Proteins; Signal Recognition Particle; ETS Translocation Variant 6 Protein
PubMed: 27248996
DOI: 10.3390/ijms17060838