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JAAD Case Reports Nov 2022
PubMed: 36275875
DOI: 10.1016/j.jdcr.2022.09.011 -
Journal of Assisted Reproduction and... May 2020To determine the impact of accelerated telomere shortening on the fertility parameters and treatment outcomes of a woman with dyskeratosis congenita (DKC).
PURPOSE
To determine the impact of accelerated telomere shortening on the fertility parameters and treatment outcomes of a woman with dyskeratosis congenita (DKC).
METHODS
A case study of the clinical data, blood, discarded oocytes, and arrested embryos of a woman with DKC and donated cryopreserved embryos from unaffected patients. Mean telomere length in blood cells was analyzed by flow cytometry-fluorescence in situ hybridization (flow-FISH) and qPCR. The load of short telomeres in blood cells was measured by universal single telomere length analysis (Universal STELA). The mean telomere length in embryos was analyzed by single-cell amplification of telomere repeats (SCATR) PCR.
RESULTS
Comparison of clinical parameters revealed that the DKC patient had reduced anti-Mullerian hormone (0.3 vs 4.1 ± 5.7 ng/ML), reduced oocytes retrieved (7 vs 18.5 ± 9.5), reduced fertilization rate, and reduced euploidy rate relative to unaffected patients. Additionally, mean telomere length in DKC embryos were shorter than unaffected embryos. However, hormone treatment led to increased leukocyte telomere length, while the load of short telomeres was also shown to decrease during the course of treatment.
CONCLUSIONS
We demonstrate for the first time the direct detrimental impacts of short telomeres on female fertility. We further demonstrate positive effects of hormone treatments for people with telomere disorders.
Topics: Dyskeratosis Congenita; Female; Fertility Preservation; Flow Cytometry; Humans; In Situ Hybridization, Fluorescence; Oocytes; Telomerase; Telomere; Telomere Homeostasis; Telomere Shortening
PubMed: 32405899
DOI: 10.1007/s10815-020-01758-x -
Hematology Reports Oct 2022Classic dyskeratosis congenita is a hereditary disease where the majority of patients present with bone marrow failure and mucocutaneous changes: mainly skin...
Classic dyskeratosis congenita is a hereditary disease where the majority of patients present with bone marrow failure and mucocutaneous changes: mainly skin pigmentation, nail dystrophy, oral premalignant leukoplakia, in addition to increased risk for malignancies. A 63-year-old man with a long history of untreated chronic pulmonary disease, a smoker in the past, presented initially with pancytopenia and a clinical diagnosis of myelodysplastic syndrome with excess blasts returned a month later with leukocytosis (WBC 215.9 × 10/μL) and diagnosed with acute myeloid leukemia (AML) with deletion of chromosome 7 and -TKD mutation. The patient's mother and sister died in their 6th decade from rapidly progressing fulminant pulmonary fibrosis. He had abnormal skin pigmentation and oral leukoplakia on presentation. He was induced with 7 + 3 chemotherapy and started on midostaurin but experienced prolonged cytopenias, complicated by hypoxic acute on chronic respiratory failure requiring intubation and mechanical ventilation. D + 28 and D + 36 bone marrow examination showed trilineage hypoplasia but no blasts, though the D + 28 bone marrow biopsy revealed one metaphase with del (7) that was cleared on D + 35. The constellation of clinical features and strong family history along with del 7 and -TKD AML with preceding MDS highly suggests a germline predisposition state dyskeratosis congenita. Germline predispositions are often underrecognized as delayed onset conditions leading to AML and may have treatment and preventative implications especially genetic counseling for blood-related family members.
PubMed: 36278519
DOI: 10.3390/hematolrep14040042 -
Case Reports in Ophthalmology 2021Dyskeratosis congenita (DKC) is a rare, multisystem, bone marrow failure disease characterized by abnormalities such as in the skin, mucosa, nervous system, and lungs....
Dyskeratosis congenita (DKC) is a rare, multisystem, bone marrow failure disease characterized by abnormalities such as in the skin, mucosa, nervous system, and lungs. Here we report a rare case of presumed DKC causing total retinal detachment in the right eye and severe peripheral retinal vascular occlusion in the left eye. A 3-year-old boy was presented with vitreous hemorrhage and total retinal detachment in the right eye and was scheduled to undergo vitreous surgery in the right eye and detailed ophthalmologic examination of the left eye under general anesthesia. Since a systemic examination revealed anemia and marked thrombocytopenia, he underwent a detailed pediatric examination. Although genetic testing revealed no significant pathologic mutations, the presence of shortened telomere length and other clinical findings suggested the possibility of DKC. His right eye had severe proliferative vitreoretinopathy, and retinal reattachment was not achieved with vitreous surgery, thus resulting in phthisis bulbi. The left eye showed a wide retinal avascular area in the temporal retina, retinal neovascularization, and hard exudates on fluorescein fundus angiography and was treated with laser photocoagulation using a binocular indirect ophthalmoscopic photocoagulator. Following laser surgery, the new blood vessels regressed, and the visual acuity was maintained at 1.0. The findings in this rare case indicate that DKC can cause severe retinal vascular occlusion, thus leading to vitreous hemorrhage and retinal detachment. Therefore, early detection with fundus examination and early treatment with photocoagulation are important.
PubMed: 34054482
DOI: 10.1159/000513484 -
Cells Oct 2020A number of different defects in the process of ribosome production can lead to a diversified spectrum of disorders that are collectively identified as ribosomopathies.... (Review)
Review
A number of different defects in the process of ribosome production can lead to a diversified spectrum of disorders that are collectively identified as ribosomopathies. The specific factors involved may either play a role only in ribosome biogenesis or have additional extra-ribosomal functions, making it difficult to ascribe the pathogenesis of the disease specifically to an altered ribosome biogenesis, even if the latter is clearly affected. We reviewed the available literature in the field from this point of view with the aim of distinguishing, among ribosomopathies, the ones due to specific alterations in the process of ribosome production from those characterized by a multifactorial pathogenesis.
Topics: Anemia, Diamond-Blackfan; Anemia, Macrocytic; Chromosome Deletion; Chromosomes, Human, Pair 5; Dyskeratosis Congenita; Fetal Growth Retardation; Genetic Predisposition to Disease; Hair; Hirschsprung Disease; Humans; Mandibulofacial Dysostosis; Osteochondrodysplasias; Primary Immunodeficiency Diseases; Psychomotor Disorders; RNA, Ribosomal; Rare Diseases; Ribosomal Proteins; Ribosomes; Shwachman-Diamond Syndrome
PubMed: 33076379
DOI: 10.3390/cells9102300 -
British Journal of Haematology Nov 2019
Topics: Dyskeratosis Congenita; Female; Humans; Middle Aged
PubMed: 31385294
DOI: 10.1111/bjh.16131 -
Respiratory Medicine Case Reports 2023Dyskeratosis congenita is a rare genetic disorder of telomere insufficiency characterized by a mucocutaneous triad of nail dystrophy, abnormal skin pigmentation, and...
Dyskeratosis congenita is a rare genetic disorder of telomere insufficiency characterized by a mucocutaneous triad of nail dystrophy, abnormal skin pigmentation, and mucosal leukoplakia. Early diagnosis is important for multidisciplinary approach to its complications including bone marrow failure, malignancy, interstitial lung disease, and liver disease which cause significant morbidity and mortality. We report a genetically confirmed case of dyskeratosis congenita who presented with fibrotic hypersensitivity pneumonitis, highlighting non-mucocutaneous features of dyskeratosis congenita and the need to consider genetic predisposition in a patient with interstitial lung disease and combined unusual manifestations.
PubMed: 36655009
DOI: 10.1016/j.rmcr.2023.101810 -
Blood Advances Dec 2021Gene expression profiling has long been used in understanding the contribution of genes and related pathways in disease pathogenesis and susceptibility. We have...
Gene expression profiling has long been used in understanding the contribution of genes and related pathways in disease pathogenesis and susceptibility. We have performed whole-blood transcriptomic profiling in a subset of patients with inherited bone marrow failure (IBMF) whose diseases are clinically and genetically characterized as Fanconi anemia (FA), Shwachman-Diamond syndrome (SDS), and dyskeratosis congenita (DC). We hypothesized that annotating whole-blood transcripts genome wide will aid in understanding the complexity of gene regulation across these IBMF subtypes. Initial analysis of these blood-derived transcriptomes revealed significant skewing toward upregulated genes in patients with FA when compared with controls. Patients with SDS or DC also showed similar skewing profiles in their transcriptional status revealing a common pattern across these different IBMF subtypes. Gene set enrichment analysis revealed shared pathways involved in protein translation and elongation (ribosome constituents), RNA metabolism (nonsense-mediated decay), and mitochondrial function (electron transport chain). We further identified a discovery set of 26 upregulated genes at stringent cutoff (false discovery rate < 0.05) that appeared as a unified signature across the IBMF subtypes. Subsequent transcriptomic analysis on genetically uncharacterized patients with BMF revealed a striking overlap of genes, including 22 from the discovery set, which indicates a unified transcriptional drive across the classic (FA, SDS, and DC) and uncharacterized BMF subtypes. This study has relevance in disease pathogenesis, for example, in explaining the features (including the BMF) common to all patients with IBMF and suggests harnessing this transcriptional signature for patient benefit.
Topics: Bone Marrow Diseases; Bone Marrow Failure Disorders; Dyskeratosis Congenita; Fanconi Anemia; Gene Expression Profiling; Humans
PubMed: 34625797
DOI: 10.1182/bloodadvances.2021005360 -
Proceedings of the National Academy of... Aug 2021Dyskeratosis congenita (DC) is a rare inherited bone marrow failure and cancer predisposition syndrome caused by mutations in telomerase or telomeric proteins. Here, we...
Dyskeratosis congenita (DC) is a rare inherited bone marrow failure and cancer predisposition syndrome caused by mutations in telomerase or telomeric proteins. Here, we report that zebrafish telomerase RNA () binds to specific DNA sequences of master myeloid genes and controls their expression by recruiting RNA Polymerase II (Pol II). Zebrafish harboring the CR4-CR5 domain mutation found in DC patients hardly interacted with Pol II and failed to regulate myeloid gene expression in vivo and to increase their transcription rates in vitro. Similarly, regulated myeloid gene expression and Pol II promoter occupancy in human myeloid progenitor cells. Strikingly, induced pluripotent stem cells derived from DC patients with a mutation in the CR4-CR5 domain showed impaired myelopoiesis, while those with mutated telomerase catalytic subunit differentiated normally. Our findings show that acts as a transcription factor, revealing a target for therapeutic intervention in DC patients.
Topics: Animals; Animals, Genetically Modified; Binding Sites; Cells, Cultured; Dyskeratosis Congenita; Gene Expression Regulation; Humans; Induced Pluripotent Stem Cells; Larva; Mutation; Myelopoiesis; Promoter Regions, Genetic; Protein Domains; RNA; RNA Polymerase II; Telomerase; Zebrafish; Zebrafish Proteins
PubMed: 34353901
DOI: 10.1073/pnas.2015528118 -
Acta Dermato-venereologica May 2022
Topics: DNA Helicases; Dyskeratosis Congenita; Humans; Intellectual Disability; Telomere
PubMed: 35199181
DOI: 10.2340/actadv.v102.919