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Frontiers in Oncology 2023Dyskeratosis congenita (DKC), also known as Zinsser-Cole-Engman syndrome, is a telomeropathy typically presenting as a triad of leukoplakia, nail dystrophy, and...
Dyskeratosis congenita (DKC), also known as Zinsser-Cole-Engman syndrome, is a telomeropathy typically presenting as a triad of leukoplakia, nail dystrophy, and reticular hyperpigmentation. Reported genetic mutations linked to DKC include , , , , , , , , and . Homozygous, compound heterozygous, and heterozygous mutations in (, regulator of telomere elongation helicase 1) gene on chromosome 20q13 are known to cause autosomal dominant as well as recessive DKC. Pathogenic variants of gene in patients include c.2288G>T (p. Gly763Val), c.3791G>A (p. Arg1264His), and p. Arg981Trp. We report a novel homozygous variant of , transcript ID: ENST00000360203.11, exon 24, c.2060C>T (p.Ala687Val), in a patient of DKC presenting with leukoplakia, dystrophic nails, reticulate pigmentation, and positive family history of a similar phenotype. The novel variant, reported as a variant of uncertain significance, may therefore be considered diagnostic for DKC in a Pakistani population.
PubMed: 36937416
DOI: 10.3389/fonc.2023.1098876 -
GeroScience Aug 2023Short telomeres are a defining feature of telomere biology disorders (TBDs), including dyskeratosis congenita (DC), for which there is no effective general cure....
Short telomeres are a defining feature of telomere biology disorders (TBDs), including dyskeratosis congenita (DC), for which there is no effective general cure. Patients with TBDs often experience bone marrow failure. NAD, an essential metabolic coenzyme, is decreased in models of DC. Herein, using telomerase reverse transcriptase null (Tert) mice with critically short telomeres, we investigated the effect of NAD supplementation with the NAD precursor, nicotinamide riboside (NR), on features of health span disrupted by telomere impairment. Our results revealed that NR ameliorated body weight loss in Tert mice and improved telomere integrity and telomere dysfunction-induced systemic inflammation. NR supplementation also mitigated myeloid skewing of Tert hematopoietic stem cells. Furthermore, NR alleviated villous atrophy and inflammation in the small intestine of Tert transplant recipient mice. Altogether, our findings support NAD intervention as a potential therapeutic strategy to enhance aspects of health span compromised by telomere attrition.
Topics: Humans; Animals; Mice; NAD; Telomere; Dyskeratosis Congenita; Inflammation; Hematopoietic Stem Cell Transplantation
PubMed: 36826621
DOI: 10.1007/s11357-023-00752-2 -
Pediatric Blood & Cancer Jun 2023
Topics: Female; Humans; Infant, Newborn; Microcephaly; Mutation; Fetal Growth Retardation; Intellectual Disability; Dyskeratosis Congenita; Intestinal Obstruction; DNA Helicases
PubMed: 36776130
DOI: 10.1002/pbc.30250 -
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 -
The Journals of Gerontology. Series A,... May 2023The underlying mechanisms of plasma metabolite signatures of human aging and age-related diseases are not clear but telomere attrition and dysfunction are central to...
The underlying mechanisms of plasma metabolite signatures of human aging and age-related diseases are not clear but telomere attrition and dysfunction are central to both. Dyskeratosis congenita (DC) is associated with mutations in the telomerase enzyme complex (TERT, TERC, and DKC1) and progressive telomere attrition. We analyzed the effect of telomere attrition on senescence-associated metabolites in fibroblast-conditioned media and DC patient plasma. Samples were analyzed by gas chromatography/mass spectrometry and liquid chromatography/mass spectrometry. We showed extracellular citrate was repressed by canonical telomerase function in vitro and associated with DC leukocyte telomere attrition in vivo, leading to the hypothesis that altered citrate metabolism detects telomere dysfunction. However, elevated citrate and senescence factors only weakly distinguished DC patients from controls, whereas elevated levels of other tricarboxylic acid cycle (TCA) metabolites, lactate, and especially pyruvate distinguished them with high significance. The DC plasma signature most resembled that of patients with loss of function pyruvate dehydrogenase complex mutations and that of older subjects but significantly not those of type 2 diabetes, lactic acidosis, or elevated mitochondrial reactive oxygen species. Additionally, our data are consistent with further metabolism of citrate and lactate in the liver and kidneys. Citrate uptake in certain organs modulates age-related disease in mice and our data have similarities with age-related disease signatures in humans. Our results have implications for the role of telomere dysfunction in human aging in addition to its early diagnosis and the monitoring of anti-senescence therapeutics, especially those designed to improve telomere function.
Topics: Humans; Animals; Mice; Dyskeratosis Congenita; Telomerase; Diabetes Mellitus, Type 2; Telomere; Mutation; Citrates; Lactates; Nuclear Proteins; Cell Cycle Proteins
PubMed: 36651908
DOI: 10.1093/gerona/glad018 -
Folia Biologica 2023Head and neck squamous cell carcinoma (HNSCC) presents a significant global health problem with variable geographic distribution and risk factors, including tobacco and...
Head and neck squamous cell carcinoma (HNSCC) presents a significant global health problem with variable geographic distribution and risk factors, including tobacco and alcohol abuse, human papillomavirus infections, and genetic predisposition. While the majority of cases are sporadic, several well-defined hereditary syndromes have been associated with a higher risk of developing HNSCC including Li-Fraumeni syndrome, Fanconi anaemia, Bloom syndrome, familial atypical multiple mole melanoma, and dyskeratosis congenita. There is also evidence of familial clusters of HNSCC, suggesting a genetic component in the development of the disease. Germ-line genetic testing in HNSCC using next-generation sequencing has revealed a wide range of germline variants, some of which were not anticipated based on standard guidelines. These variants may influence treatment decisions and have the potential to be targeted with precision medicine in the future. Despite these advances, routine germline genetic testing for HNSCC is not currently recommended and remains reserved for HNSCC cases with early onset or strong family cancer history. However, the increasing availability of germline genetic testing warrants development of more comprehensive and standardized testing protocols. Germline genetic testing also has the potential to influence precision-guided treatment in HNSCC patients carrying germline pathogenic variants.
Topics: Humans; Squamous Cell Carcinoma of Head and Neck; Head and Neck Neoplasms; Carcinoma, Squamous Cell; Genetic Predisposition to Disease; Risk Factors
PubMed: 38410968
DOI: 10.14712/fb2023069040107 -
Canadian Journal of Ophthalmology.... Jun 2023
Topics: Humans; Dyskeratosis Congenita; Macular Degeneration; Retinal Drusen; Retina
PubMed: 36535381
DOI: 10.1016/j.jcjo.2022.11.012 -
International Journal of Molecular... Nov 2022In recent years, the knowledge about the immune-mediated impairment of bone marrow precursors in immune-dysregulation and autoimmune disorders has increased. In...
In recent years, the knowledge about the immune-mediated impairment of bone marrow precursors in immune-dysregulation and autoimmune disorders has increased. In addition, immune-dysregulation, secondary to marrow failure, has been reported as being, in some cases, the most evident and early sign of the disease and making the diagnosis of both groups of disorders challenging. Dyskeratosis congenita is a disorder characterized by premature telomere erosion, typically showing marrow failure, nail dystrophy and leukoplakia, although incomplete genetic penetrance and phenotypes with immune-dysregulation features have been described. We report on a previously healthy 17-year-old girl, with a cousin successfully treated for acute lymphoblastic leukemia, who presented with leukopenia and neutropenia. The diagnostic work-up showed positive anti-neutrophil antibodies, leading to the diagnosis of autoimmune neutropenia, a slightly low NK count and high TCR-αβ+-double-negative T-cells. A next-generation sequencing (NGS) analysis showed the 734C>A variant on exon 6 of the TINF2 gene, leading to the p.Ser245Tyr. The telomere length was short on the lymphocytes and granulocytes, suggesting the diagnosis of an atypical telomeropathy showing with immune-dysregulation. This case underlines the importance of an accurate diagnostic work-up of patients with immune-dysregulation, who should undergo NGS or whole exome sequencing to identify specific disorders that deserve targeted follow-up and treatment.
Topics: Humans; Dyskeratosis Congenita; Telomere; Exons; Neutropenia; Bone Marrow; Telomere-Binding Proteins
PubMed: 36498862
DOI: 10.3390/ijms232314535