Clinical mutations in the TERT and TERC genes coding for telomerase components induced oxidative stress, DNA damage at telomeres and cell apoptosis besides decreased telomerase activity.

Telomeres are nucleoprotein structures at the end of chromosomes that maintain their integrity. Mutations in genes coding for proteins involved in telomere protection and elongation produce diseases such as dyskeratosis congenita or idiopathic pulmonary fibrosis known as telomeropathies. These diseases are characterized by premature telomere shortening, increased DNA damage and oxidative stress. Genetic diagnosis of telomeropathy patients has identified mutations in the genes TERT and TERC coding for telomerase components but the functional consequences of many of these mutations still have to be experimentally demonstrated. The activity of twelve TERT and five TERC mutants, five of them identified in Spanish patients, has been analyzed. TERT and TERC mutants were expressed in VA-13 human cells that express low telomerase levels and the activity induced was analyzed. The production of reactive oxygen species, DNA oxidation and TRF2 association at telomeres, DNA damage response and cell apoptosis were determined. Most mutations presented decreased telomerase activity, as compared to wild-type TERT and TERC. In addition, the expression of several TERT and TERC mutants induced oxidative stress, DNA oxidation, DNA damage, decreased recruitment of the shelterin component TRF2 to telomeres and increased apoptosis. These observations might indicate that the increase in DNA damage and oxidative stress observed in cells from telomeropathy patients is dependent on their TERT or TERC mutations. Therefore, analysis of the effect of TERT and TERC mutations of unknown function on DNA damage and oxidative stress could be of great utility to determine the possible pathogenicity of these variants.

Linking Gene Fusions to Bone Marrow Failure and Malignant Transformation in Dyskeratosis Congenita.

Dyskeratosis Congenita (DC) is a multisystem disorder intrinsically associated with telomere dysfunction, leading to bone marrow failure (BMF). Although the pathology of DC is largely driven by mutations in telomere-associated genes, the implications of gene fusions, which emerge due to telomere-induced genomic instability, remain unexplored. We meticulously analyzed gene fusions in RNA-Seq data from DC patients to provide deeper insights into DC's progression. The most significant DC-specific gene fusions were subsequently put through in silico assessments to ascertain biophysical and structural attributes, including charge patterning, inherent disorder, and propensity for self-association. Selected candidates were then analyzed using deep learning-powered structural predictions and molecular dynamics simulations to gauge their potential for forming higher-order oligomers. Our exploration revealed that genes participating in fusion events play crucial roles in upholding genomic stability, facilitating hematopoiesis, and suppressing tumors. Notably, our analysis spotlighted a particularly disordered polyampholyte fusion protein that exhibits robust higher-order oligomerization dynamics. To conclude, this research underscores the potential significance of several high-confidence gene fusions in the progression of BMF in DC, particularly through the dysregulation of genomic stability, hematopoiesis, and tumor suppression. Additionally, we propose that these fusion proteins might hold a detrimental role, specifically in inducing proteotoxicity-driven hematopoietic disruptions.

The Use of Social Media to Express and Manage Medical Uncertainty in Dyskeratosis Congenita: Content Analysis.

BACKGROUND: Social media has the potential to provide social support for rare disease communities; however, little is known about the use of social media for the expression of medical uncertainty, a common feature of rare diseases. OBJECTIVE: This study aims to evaluate the expression of medical uncertainty on social media in the context of dyskeratosis congenita, a rare cancer-prone inherited bone marrow failure and telomere biology disorder (TBD). METHODS: We performed a content analysis of uncertainty-related posts on Facebook and Twitter managed by Team Telomere, a patient advocacy group for this rare disease. We assessed the frequency of uncertainty-related posts, uncertainty sources, issues, and management and associations between uncertainty and social support. RESULTS: Across all TBD social media platforms, 45.98% (1269/2760) of posts were uncertainty related. Uncertainty-related posts authored by Team Telomere on Twitter focused on scientific (306/434, 70.5%) or personal (230/434, 53%) issues and reflected uncertainty arising from probability, ambiguity, or complexity. Uncertainty-related posts in conversations among patients and caregivers in the Facebook community group focused on scientific (429/511, 84%), personal (157/511, 30.7%), and practical (114/511, 22.3%) issues, many of which were related to prognostic unknowns. Both platforms suggested uncertainty management strategies that focused on information sharing and community building. Posts reflecting response-focused uncertainty management strategies (eg, emotional regulation) were more frequent on Twitter compared with the Facebook community group (χ21=3.9; P=.05), whereas posts reflecting uncertainty-focused management strategies (eg, ordering information) were more frequent in the Facebook community group compared with Twitter (χ21=55.1; P<.001). In the Facebook community group, only 36% (184/511) of members created posts during the study period, and those who created posts did so with a low frequency (median 3, IQR 1-7 posts). Analysis of post creator characteristics suggested that most users of TBD social media are White, female, and parents of patients with dyskeratosis congenita. CONCLUSIONS: Although uncertainty is a pervasive and multifactorial issue in TBDs, our findings suggest that the discussion of medical uncertainty on TBD social media is largely limited to brief exchanges about scientific, personal, or practical issues rather than ongoing supportive conversation. The nature of uncertainty-related conversations also varied by user group: patients and caregivers used social media primarily to discuss scientific uncertainties (eg, regarding prognosis), form social connections, or exchange advice on accessing and organizing medical care, whereas Team Telomere used social media to express scientific and personal issues of uncertainty and to address the emotional impact of uncertainty. The higher involvement of female parents on TBD social media suggests a potentially greater burden of uncertainty management among mothers compared with other groups. Further research is needed to understand the dynamics of social media engagement to manage medical uncertainty in the TBD community.

Dyskeratosis congenita associated with a novel missense variant in TERT: Approach for the dermatologists.

Dyskeratosis congenita (DC) is a telomeropathy presenting diagnostic and therapeutic challenges across multiple specialties; yet, subtle dermatological signs enable early detection, altering patient prognosis. A specific DC genetic sequencing was performed according to the clinical criteria of our patient in study. Subsequently, cross-checked information in the main genetic databases was carried out. Additionally, an extensive review of the literature was made to organize the main dermatological aspects in DC. We report a novel variant of DC. Additionally, we share 10 useful and practical messages for dermatologists and any specialist caring for this group of patients.

Can telomeric changes orchestrate the development of autoinflammatory skin diseases?

Telomeres, the safeguarding caps at the tips of chromosomes, are pivotal in the aging process of cells and have been linked to skin ailments and inflammatory conditions. Telomeres undergo a gradual reduction in length and factors such as oxidative stress hasten this diminishing process. Skin diseases including inflammatory conditions can be correlated with the shortening of telomeres and the persistent activation of DNA damage response in skin tissues. Telomere dysfunction could disrupt the balance of the skin, impairs wound healing, and may contribute to abnormal cytokine production. Skin aging and processes related to telomeres may function as one of the triggers for skin diseases. The presence of proinflammatory cytokines and dysfunctional telomeres in conditions such as Dyskeratosis Congenita implies a possible connection between the shortening of telomeres and the onset of chronic inflammatory skin disorders. In autoinflammatory skin diseases, chronic inflammation hinders wound healing thus aggravating the progression of the disease. The NF-ĸB pathway might contribute to the initiation or progression of chronic disorders by influencing mechanisms associated with telomere biology. The intricate connections between telomeres, telomerase, telomere-associated proteins, and skin diseases are still a complex puzzle to be solved. Here, we provide an overview of the impact of telomeres on both health and disease with a specific emphasis on their role in skin, inflammation and autoinflammatory skin disorders.

Integrated proteogenomic analysis for inherited bone marrow failure syndrome.

Recent advances in in-depth data-independent acquisition proteomic analysis have enabled comprehensive quantitative analysis of >10,000 proteins. Herein, an integrated proteogenomic analysis for inherited bone marrow failure syndrome (IBMFS) was performed to reveal their biological features and to develop a proteomic-based diagnostic assay in the discovery cohort; dyskeratosis congenita (n = 12), Fanconi anemia (n = 11), Diamond-Blackfan anemia (DBA, n = 9), Shwachman-Diamond syndrome (SDS, n = 6), ADH5/ALDH2 deficiency (n = 4), and other IBMFS (n = 18). Unsupervised proteomic clustering identified eight independent clusters (C1-C8), with the ribosomal pathway specifically downregulated in C1 and C2, enriched for DBA and SDS, respectively. Six patients with SDS had significantly decreased SBDS protein expression, with two of these not diagnosed by DNA sequencing alone. Four patients with ADH5/ALDH2 deficiency showed significantly reduced ADH5 protein expression. To perform a large-scale rapid IBMFS screening, targeted proteomic analysis was performed on 417 samples from patients with IBMFS-related hematological disorders (n = 390) and healthy controls (n = 27). SBDS and ADH5 protein expressions were significantly reduced in SDS and ADH5/ALDH2 deficiency, respectively. The clinical application of this first integrated proteogenomic analysis would be useful for the diagnosis and screening of IBMFS, where appropriate clinical screening tests are lacking.

Dyskeratosis congenita and a rare brain abscess / Disqueratosis congénita y absceso del sistema nervioso central

Abstract Dyskeratosis congenita is a rare inheritable disease which causes peculiar dermatological features and bone marrow failure with an increased risk of severe infections and neoplasia. Actinomyces spp. is part of the oral cavity flora. Invasive infections are mostly seen in immunocompromised hosts. We report a case of a rare central nervous infection and an underling inheritable disease.

Resumen La disqueratosis congénita es una enfermedad hereditaria, caracterizada por alteraciones cutáneas y aplasia medular. La principal causa de muerte son las infecciones y el desarrollo de neoplasias. Actinomices spp. son patógenos comensales de la cavidad oral y el tracto urinario, que en raras ocasiones suelen causar infecciones invasivas en el ser humano. Suelen ser más frecuentes en pacientes inmunocomprometidos o con mala higiene dental. Presentamos el caso de una lesión ocupante de espacio a nivel del sistema nervioso central con una inmuno deficiencia heredable.

Dyskeratosis congenita

Dyskeratosis congenita (DC) is a genetic syndrome with progressive multisystem involvement classically characterized by the clinical triad of oral leukoplakia, nail dystrophy, and reticular hyperpigmentation. Frequent complications are bone marrow failure, increased rate of malignancy, lung and liver diseases. DC results from an anomalous progressive shortening of telomeres resulting in DNA replication problems inducing replicative senescence. We report a death due to DC in a 16-year-old male with bone marrow failure and multiple organ dysfunction. At autopsy, nail dystrophy and skin hypopigmentation were observed. Gross and microscopic examinations of the internal organs showed cardiac hypertrophy, multiple lung consolidations and prominent interstitial fibrosis, liver cirrhosis, and fibrosis. Multiple foci of extramedullary hematopoiesis were identified, including on the epidural surface of the dura, that is an infrequent location, mimicking a focal area of epidural hemorrhage. Only a few autopsy studies about DC are reported in the literature. Further research should be done to understand the pathophysiology of the disease and its complications.

Disceratose congênita - relato de caso e revisão de literatura / Dyskeratosis congenita - case report and literature review

A Disceratose Congênita (DC) é uma síndrome hereditária rara que exibe marcada heterogeneidade clínica e genética, constituindo-se em anormalidades cutaneomucosas, falência medular e predisposição ao câncer. Esta é caracterizada pela tríade de pigmentação reticulada da pele, distrofia ungueal e leucoplasia em mucosas. Alterações dentárias, gastrintestinais, geniturinárias, neurológicas, oftalmológicas, pulmonares e esqueléticas associadas têm sido relatadas. A falência medular é a principal causa de morte precoce e também é descrita predisposição para doenças malignas. Afeta principalmente homens e, reconhecem-se formas recessivas ligadas ao X, autossômicas dominantes e recessivas. Relata-se o caso de um paciente de 40 anos, sexo masculino, que há 7 evolui com quadro de anemia e necessidades transfusionais (sanguíneas). Investigadas causas hemofílica e carencial sem êxito. Mielograma com normocelularidade das linhagens; solicitada biópsia de medula óssea por suspeita de Disceratose Congênita, tendo em vista sintomatologia com presença da tríade da Disceratose Congênita: leucoplasia mucosa, distrofia ungueal, e áreas de hiperpigmentação reticular. Paciente progride sob acompanhamento no serviço hematológico do Hemocentro do Pará. Em função da raridade da doença, pouco mais de 500 casos relatados no mundo, da dificuldade de se chegar ao seu diagnóstico, e de sua gravidade, é de fundamental importância a difusão do conhecimento e ratifica-se a necessidade do acompanhamento médico multidisciplinar, de modo a permitir diagnóstico e tratamento precoce das possíveis complicações.

Dyskeratosis Congenita (DC) is a rare hereditary syndrome that shows marked clinical and genetic heterogeneity, like mucocutaneous abnormalities, bone marrow failure and predisposition to cancer. Dyskeratosis congenita triad is: abnormal skin pigmentation, nail dystrophy and mucosal leukoplakia. Dental, gastrointestinal, genitourinary, neurological, ophthalmic, pulmonary and skeletal disorders have been reported. The leading cause of early death and an additional predisposition to malignancy is bone marrow failure. Dyskeratosis congenita mainly affects men and recessive X-linked, autosomal dominant and recessive forms are recognized. We report the case of a 40-year-old male, 7 years evolving symptoms of anemia and transfusion requirements. Unsuccessfully research by deficiency causes and hemophilia were done. Normal cellular lineages myelogram. Patient progresses under supervision of Hemocenter of Pará (HEMOPA). Depending on the rarity of the disease, little more than 500 cases reported worldwide, the difficulty of arriving at a diagnosis, and its severity, is crucial to spreading knowledge and it confirms the need for a multidisciplinary approach, the to enable early diagnosis and treatment of possible complications.

Revesz syndrome

Revesz syndrome is a rare variant of dyskeratosis congenita and is characterized by bilateral exudative retinopathy, alterations in the anterior ocular segment, intrauterine growth retardation, fine sparse hair, reticulate skin pigmentation, bone marrow failure, cerebral calcification, cerebellar hypoplasia and psychomotor retardation. Few patients with this syndrome have been reported, and significant clinical variations exist among patients. This report describes the first Brazilian case of Revesz syndrome and its ocular and clinical features.

A síndrome de Revesz é uma rara variante de disceratose congênita caracterizada por retinopatia exsudativa bilateral, alterações no segmento anterior ocular, retardo do crescimento intrauterino, pilificação fina e escassa, pigmentação cutânea reticular, falência da medula óssea, calcificações cerebrais, hipoplasia cerebelar e retardo neuropsicomotor. Há variações clínicas significativas entre os poucos relatos desta patologia existentes na literatura. Descrevemos o primeiro caso brasileiro de síndrome Revesz e suas características clínicas e oculares.

Disqueratosis congénita: presentación de un caso clínico / Congenital dyskeratosis: a clinical report

La disqueratosis congénita o síndrome de Zinsser Egman Cole es una forma muy poco frecuente de dermatosis que se caracteriza por hiperpigmentación reticulada cutánea, distrofia de faneras, leucoplasia premaligna de la mucosa oral y pancitopenia progresiva. El objetivo de este trabajo fue la presentación de un paciente de sexo masculino, actualmente de 8 años, que consultó por anemia ferropénica, trastornos tróficos de piel y mucosas, leucoplasia severa de lengua y disfagia para sólidos semi sólidos, a quien se hizo diagnóstico inicial de síndrome de Plummer Vinson por la presencia de membranas esofágicas altas. La persistencia de la clínica con la aparición de hiperpigmentación reticulada en cuello y tronco y leucopenia progresiva hizo sospechar esta patología que fue confirmada por el estudio genético correspondiente

Disceratose congênita: relato de caso e revisäo da literatura / Dyskeratosis congenita: case report and literature review

A disceratose congênita é doença hereditária rara, caracterizada pela tríade de pigmentaçäo reticulada da pele, distrofia ungueal e leucoceratose em mucosas. Alteraçöes dentárias, gastrintestinais, geniturinárias, neurológicas, oftalmológicas, pulmonares e esqueléticas associadas têm sido relatadas. A falência medular é a principal causa de morte precoce e também é descrita predisposiçäo para doenças malignas. Afeta principalmente homens, e reconhecem-se formas recessivas ligadas ao X, autossômicas dominantes e recessivas. Relata-se o caso de uma criança do sexo masculino, que apresentava a tríade clássica das lesöes sem antecedentes familiares. Faz-se revisäo da literatura com o objetivo de enfatizar a necessidade do acompanhamento médico multidisciplinar, de modo a permitir diagnóstico precoce das possíveis complicaçöes.

Patología ungueal en la infancia / Nail pathology in childhood

Las alteraciones ungueales en los niños representan un número de consultas no despreciable tanto en atención primaria y pediatría como en dermatología. Algunas alteraciones son idénticas a las de los adultos, pero existen otras que son características de esta etapa de la vida y que nos pueden ayudar en el diagnóstico. En este resumen describimos las principales alteraciones ungueales en la infancia

Patología blanca de la mucosa oral / White lesions of the oral mucosa

La patología blanca de la mucosa oral comprende una constelación de enfermedades cuyos cuadros clínicos se asemejan mucho entre sí y se caracterizan por la presentación de una lesión de aspecto blanquesino en la cavidad bucal. Con el fin de remarcar las diferencias entre cada afección, sus diversas evoluciones y pronósticos y alertar sobre aquellas con tendencia cancerígena y pronóstico más ominoso es que se realiza este trabajo. Es también nuestro interés señalar que no debemos olvidar a la cavidad bucal en el examen dermatológico de rutina

Spontaneous chromosomal instability in a female child with dyskeratosis congenita

Disceratose congênita é genodermatose rara com manifestaçöes hematológicas e incidência aumentada de câncer. Cerca de duzentos casos foram descritos, sendo apenas 10 porcento em pacientes do sexo feminino. É relatado o caso de paciente feminina de seis anos, sem antecedentes familiares da doença, a qual apresentou característica hiperpigmentaçäo reticular, associada a distrofia ungueal incipiente, sem leucoplasia ou envolvimento hematológico. A análise cromossômica em linfócitos cultivados mostrou 43 porcento de quebra cromossômica, 21 porcento de disjunçäo prematura de centrômero e presença de micronúcleos em 1,7 porcento das células epiteliais näo-cultivadas examinadas. Instabilidade cromossômica pode desempenhar um papel nas manifestaçöes cutâneas e hematológicas nos casos de disceratose congênitas näo-ligados ao cromossoma X