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Journal Der Deutschen Dermatologischen... Sep 2020Dyskeratosis congenita is a rare hereditary disease that occurs predominantly in males and manifests clinically as the classic triad of reticulate hyperpigmentation,... (Review)
Review
Dyskeratosis congenita is a rare hereditary disease that occurs predominantly in males and manifests clinically as the classic triad of reticulate hyperpigmentation, nail dystrophy and leukoplakia. It increases the risk of malignancy and other potentially lethal complications such as bone marrow failure, lung and liver diseases. Mutations in 19 genes are associated with dyskeratosis congenita, and a fifth of the pathogenic mutations are found in DKC1, the gene coding for dyskerin. This review aims to address the clinical and genetic aspects of the disease.
Topics: Cell Cycle Proteins; Dyskeratosis Congenita; Humans; Hyperpigmentation; Male; Mutation; Nail Diseases; Nuclear Proteins
PubMed: 32930426
DOI: 10.1111/ddg.14268 -
Hematology. American Society of... Dec 2022Numerous 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... (Review)
Review
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.
Topics: Humans; Child; Dyskeratosis Congenita; Telomere; Germ-Line Mutation; Bone Marrow Failure Disorders; Anemia, Aplastic
PubMed: 36485133
DOI: 10.1182/hematology.2022000394 -
Mayo Clinic Proceedings Sep 2019
Review
Topics: Adolescent; Cell Cycle Proteins; Diagnosis, Differential; Dyskeratosis Congenita; Female; Genetic Predisposition to Disease; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Monitoring, Physiologic; Nuclear Proteins; Prognosis; Rare Diseases; Risk Assessment; Severity of Illness Index
PubMed: 31486376
DOI: 10.1016/j.mayocp.2019.04.032 -
Hematology. American Society of... 2011Dyskeratosis congenita (DC) is a multisystem inherited syndrome exhibiting marked clinical and genetic heterogeneity. In its classic form, it is characterized by... (Review)
Review
Dyskeratosis congenita (DC) is a multisystem inherited syndrome exhibiting marked clinical and genetic heterogeneity. In its classic form, it is characterized by mucocutaneous abnormalities, BM failure, and a predisposition to cancer. BM failure is the principal cause of premature mortality. Studies over the last 15 years have led to significant advances, with 8 DC genes (DKC1, TERC, TERT, NOP10, NHP2, TIN2, C16orf57, and TCAB1) having been characterized. Seven of these are important in telomere maintenance either because they encode components of the telomerase enzyme complex (DKC1, TERC, TERT, NOP10, NHP2, and TCAB1) or the shelterin complex (TINF2). DC is therefore principally a disease of defective telomere maintenance and patients usually have very short telomeres. The genetic advances have led to the unification of DC with several other disorders, including the severe multisystem disorders Hoyeraal-Hreidarsson and Revesz syndromes, as well as a subset of patients with aplastic anemia, myelodysplasia, leukemia, and idiopathic pulmonary fibrosis. This wide spectrum of diseases ranging from classic DC to aplastic anemia can be regarded as disorders of defective telomere maintenance-"the telomereopathies." These advances have increased our understanding of normal hematopoiesis and highlighted the important role of telomerase and telomeres in human biology. They are also facilitating the diagnosis (especially when presentation is atypical) and management of DC.
Topics: Dyskeratosis Congenita; Fetal Growth Retardation; Genes, Dominant; Genetic Diseases, X-Linked; Humans; Intellectual Disability; Microcephaly; Telomere
PubMed: 22160078
DOI: 10.1182/asheducation-2011.1.480 -
Advances in Experimental Medicine and... 2010Dyskeratosis congenita (DC) is an inheritable bone marrow failure syndrome characterized by reticulated hyperpigmentation, dystrophic nails and oral leukoplakia. Another... (Review)
Review
Dyskeratosis congenita (DC) is an inheritable bone marrow failure syndrome characterized by reticulated hyperpigmentation, dystrophic nails and oral leukoplakia. Another name for the condition is Zinsser-Cole-Engman syndrome. Hematologic manifestations usually do not appear in childhood but later in early adulthood. Patients are also prone to carcinomas, particularly of the head and neck. The disease has X-linked or autosomal dominant/recessive inheritance. Early childhood variants (Hoyeraal-Hreidarsson syndrome) are associated with immunological abnormalities in the form of low T- and B-cell numbers. Four genes, namely DKC1 (codes for dyskerin), TERC and TERT (code for telomerase) and NOP10, have been implicated in the pathogenesis; the short telomeres provide a marker for genetic linkage studies. Androgens, with or without granulocyte colony stimulating factor, have been tried in the treatment of the conditions with variable results. Stem cell transplantation from matched sibling donor is currently the treatment of choice. It requires modified nonmyeloablative conditioning protocols, since the patients with DC are prone to pulmonary and hepatic complications.
Topics: Adult; Androgens; B-Lymphocytes; Bone Marrow Diseases; Cell Cycle Proteins; Child; Child, Preschool; Dyskeratosis Congenita; Granulocyte Colony-Stimulating Factor; Humans; Lymphocyte Count; Nuclear Proteins; RNA; Ribonucleoproteins, Small Nucleolar; T-Lymphocytes; Telomerase; Telomere
PubMed: 20687509
DOI: 10.1007/978-1-4419-6448-9_20 -
Seminars in Hematology Jul 2006Dyskeratosis congenita (DC) is a rare inherited multi-system disorder. Although DC is classically characterized by mucocutaneous features, the vast majority of patients... (Review)
Review
Dyskeratosis congenita (DC) is a rare inherited multi-system disorder. Although DC is classically characterized by mucocutaneous features, the vast majority of patients develop hematologic abnormalities, and in its occult form the disease can present as aplastic anemia. The gene responsible for the X-linked form of the disease encodes a protein involved in ribosome biogenesis and in stabilizing the telomerase complex, while the autosomal dominant form is caused by mutations in the core RNA component of telomerase. It has been suggested that DC is primarily a disease of defective telomere maintenance. Premature shortening of telomeres resulting in a limited proliferative potential of stem cells would explain the pathology observed in DC, as the affected tissues are those that require constant renewal.
Topics: Amino Acid Sequence; Anemia, Aplastic; Dyskeratosis Congenita; Humans; Molecular Sequence Data; Mutation; Telomerase
PubMed: 16822458
DOI: 10.1053/j.seminhematol.2006.04.001 -
Oral Oncology Apr 2006Dyskeratosis congenita is an inherited disorder that usually presents in males, consisting of the triad of leukoplakia of the mucous membranes, nail dystrophy and skin... (Review)
Review
Dyskeratosis congenita is an inherited disorder that usually presents in males, consisting of the triad of leukoplakia of the mucous membranes, nail dystrophy and skin pigmentation. Whilst most cases are X-linked, autosomal dominant and recessive forms have been reported. The significance of the condition lies in premature mortality arising from either bone marrow failure or malignant change within the areas of leukoplakia. Various mucocutaneous and non-mucocutaneous manifestations have been reported. The syndrome arises from an inherited defect within the DKC1 gene that codes for the protein dyskerin in the X-linked recessive form of the disorder, whereas mutations in the RNA component of telomerase (TERC) result in the autosomal dominant form of the condition. The identification of a white patch within the mouth of a child in the absence of any other obvious cause should arouse suspicion of this rare condition. Greater understanding of the molecular biology surrounding this syndrome should lead to improvements in diagnosis, monitoring of disease progression and therapy.
Topics: Cell Cycle Proteins; Dyskeratosis Congenita; Female; Humans; Male; Nuclear Proteins; Telomerase
PubMed: 16140563
DOI: 10.1016/j.oraloncology.2005.06.007 -
Expert Review of Hematology Aug 2022Dyskeratosis congenita (DC) is a multisystem syndrome characterized by mucocutaneous abnormalities, bone marrow failure, and predisposition to cancer. Studies over the... (Review)
Review
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.
Topics: Biology; Danazol; Dyskeratosis Congenita; Humans; Mutation; Oxymetholone; Telomerase; Telomere
PubMed: 35929966
DOI: 10.1080/17474086.2022.2108784 -
British Journal of Haematology Apr 1999
Review
Topics: Chromosome Aberrations; Dyskeratosis Congenita; Female; Genetic Linkage; Genotype; Humans; Male; Phenotype
PubMed: 10330927
DOI: No ID Found -
Cellular and Molecular Life Sciences :... Mar 2003Dyskeratosis congenita is an inherited skin and bone marrow failure syndrome. There are X-linked, autosomal dominant and autosomal recessive forms of the disease. The... (Review)
Review
Dyskeratosis congenita is an inherited skin and bone marrow failure syndrome. There are X-linked, autosomal dominant and autosomal recessive forms of the disease. The X-linked form is due to mutations in the DKC1 gene at Xq28. The encoded protein, dyskerin, is a component of both small nucleolar ribonuclear protein particles and the telomerase complex. Mutations in DKC1 mainly lead to amino acid substitutions. The autosomal dominant form of the disease is due to mutations in hTR, the RNA component of telomerase, making it likely that the disease is due to defective telomerase activity. Mutations in hTR are predicted to either disrupt secondary structure or alter the template region. The gene or genes involved in the recessive forms of the disease remain elusive, though genes whose products are required for telomere maintenance are strong candidates.
Topics: Animals; Cell Cycle Proteins; Chromosome Mapping; Chromosomes, Human, X; Dyskeratosis Congenita; Female; Genes, Dominant; Genes, Recessive; Humans; Male; Mice; Mutation; Nuclear Proteins; Pedigree; Telomerase
PubMed: 12737310
DOI: 10.1007/s000180300042