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JPGN Reports May 2023We report a 3-year-old patient with suspected oropharyngeal graft-versus-host disease (GVHD) who developed progressive dysphagia to solids and liquids. The patient has a...
Endoscopic Assessment and Serial Balloon Dilatation in a Toddler With Dyskeratosis Congenita-Hoyeraal-Hreidarsson Syndrome Following Bone Marrow Transplant: A Case Report.
We report a 3-year-old patient with suspected oropharyngeal graft-versus-host disease (GVHD) who developed progressive dysphagia to solids and liquids. The patient has a history of Dyskeratosis Congenita-Hoyeraal-Hreidarsson Syndrome with associated bone marrow failure requiring a nonmyeloablative matched sibling hematopoietic stem cell transplant. Esophagram revealed significant narrowing in the cricopharyngeal region. Subsequent esophagoscopy showed a proximal, high-grade pinhole esophageal stricture that was very difficult to visualize and cannulate. High-grade esophageal strictures are uncommon in very young children with GVHD. We believe the patient's underlying Dyskeratosis Congenita-Hoyeraal-Hreidarsson Syndrome in the setting of inflammatory changes seen in GVHD following hematopoietic stem cell transplant set the stage for a high-grade esophageal obstruction. The patient's symptoms improved with serial endoscopic balloon dilation.
PubMed: 37200733
DOI: 10.1097/PG9.0000000000000291 -
Expert Review of Hematology 2023
Topics: Humans; Telomere; Telomerase; Biology; Dyskeratosis Congenita
PubMed: 37191632
DOI: 10.1080/17474086.2023.2215423 -
Hereditary Cancer in Clinical Practice May 2023The end of each chromosome consists of a DNA region termed the telomeres. The telomeres serve as a protective shield against degradation of the coding DNA sequence, as...
The end of each chromosome consists of a DNA region termed the telomeres. The telomeres serve as a protective shield against degradation of the coding DNA sequence, as the DNA strand inevitably ‒ with each cell division ‒ is shortened. Inherited genetic variants cause telomere biology disorders when located in genes (e.g. DKC1, RTEL1, TERC, TERT) playing a role in the function and maintenance of the telomeres. Subsequently patients with telomere biology disorders associated with both too short or too long telomeres have been recognized. Patients with telomere biology disorders associated with short telomeres are at increased risk of dyskeratosis congenita (nail dystrophy, oral leukoplakia, and hyper- or hypo-pigmentation of the skin), pulmonary fibrosis, hematologic disease (ranging from cytopenia to leukemia) and in rare cases very severe multiorgan manifestations and early death. Patients with telomere biology disorders associated with too long telomeres have in recent years been found to confer an increased risk of melanoma and chronic lymphocytic leukemia. Despite this, many patients have an apparently isolated manifestation rendering telomere biology disorders most likely underdiagnosed. The complexity of telomere biology disorders and many causative genes makes it difficult to design a surveillance program which will ensure identification of early onset disease manifestation without overtreatment.
PubMed: 37189188
DOI: 10.1186/s13053-023-00251-7 -
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 -
JPGN Reports Aug 2022Dyskeratosis congenita (DC) is a rare telomerase disorder affecting high turnover cells. Malfunction of protective proteins in DC results in patient genomes with...
Dyskeratosis congenita (DC) is a rare telomerase disorder affecting high turnover cells. Malfunction of protective proteins in DC results in patient genomes with shortened germline telomeres leading to genetic instability, cellular apoptosis, and overall cellular lifespan degradation. Classically, reports of DC described a triad of dysplastic nails, reticular skin pigmentation, and oral leukoplakia. However, more recent reports have focused on disease presentation affecting other high turnover organ systems including the gastrointestinal system. Patients may present with dysphagia because of esophageal stricture/web, diarrhea secondary to enteropathy or enterocolitis. We present a pediatric patient who presented with feeding difficulty secondary to an esophageal stricture as the primary manifestation of DC. She was diagnosed with Revesz Syndrome, a rare subtype of DC, along with a novel genetic variant not previously reported. This report serves to bring awareness to gastroenterologists that DC, though classically thought to present with dermatological findings, can present with primary gastrointestinal manifestations.
PubMed: 37168640
DOI: 10.1097/PG9.0000000000000242 -
Frontiers in Genetics 2023
PubMed: 37124624
DOI: 10.3389/fgene.2023.1194788 -
Aging Cell Jun 2023Telomere length (TL) limits somatic cell replication. However, the shortest among the telomeres in each nucleus, not mean TL, is thought to induce replicative...
Telomere length (TL) limits somatic cell replication. However, the shortest among the telomeres in each nucleus, not mean TL, is thought to induce replicative senescence. Researchers have relied on Southern blotting (SB), and techniques calibrated by SB, for precise measurements of TL in epidemiological studies. However, SB provides little information on the shortest telomeres among the 92 telomeres in the nucleus of human somatic cells. Therefore, little is known about the accumulation of short telomeres with age, or whether it limits the human lifespan. To fill this knowledge void, we used the Telomere-Shortest-Length-Assay (TeSLA), a method that tallies and measures single telomeres of all chromosomes. We charted the age-dependent buildup of short telomeres (<3 kb) in human hematopoietic cells from 334 individuals (birth-89 years) from the general population, and 18 patients with dyskeratosis congenita-telomere biology disorders (DC/TBDs), whose hematopoietic cells have presumably reached or are close to their replicative limit. For comparison, we also measured TL with SB. We found that in hematopoietic cells, the buildup of short telomeres occurs in parallel with the shortening with age of mean TL. However, the proportion of short telomeres was lower in octogenarians from the general population than in patients with DC/TBDs. At any age, mean TL was longer and the proportion of short telomeres lower in females than in males. We conclude that though converging to the TL-mediated replicative limit, hematopoietic cell telomeres are unlikely to reach this limit during the lifespan of most contemporary humans.
Topics: Male; Aged, 80 and over; Female; Humans; Telomere Shortening; Longevity; Cell Division; Telomere
PubMed: 37118904
DOI: 10.1111/acel.13844 -
HemaSphere May 2023Telomere biology disorders (TBD) result from premature telomere shortening due to pathogenic germline variants in telomere maintenance-associated genes. In adults, TBD...
Telomere biology disorders (TBD) result from premature telomere shortening due to pathogenic germline variants in telomere maintenance-associated genes. In adults, TBD are characterized by mono/oligosymptomatic clinical manifestations (cryptic TBD) contributing to severe underdiagnosis. We present a prospective multi-institutional cohort study where telomere length (TL) screening was performed in either newly diagnosed patients with aplastic anemia (AA) or if TBD was clinically suspected by the treating physician. TL of 262 samples was measured via flow-fluorescence in situ hybridization (FISH). TL was considered suspicious once below the 10th percentile of normal individuals (standard screening) or if below 6.5 kb in patients >40 years (extended screening). In cases with shortened TL, next generation sequencing (NGS) for TBD-associated genes was performed. The patients referred fell into 6 different screening categories: (1) AA/paroxysmal nocturnal hemoglobinuria, (2) unexplained cytopenia, (3) dyskeratosis congenita, (4) myelodysplastic syndrome/acute myeloid leukemia, (5) interstitial lung disease, and (6) others. Overall, TL was found to be shortened in 120 patients (n = 86 standard and n = 34 extended screening). In 17 of the 76 (22.4%) standard patients with sufficient material for NGS, a pathogenic/likely pathogenic TBD-associated gene variant was identified. Variants of uncertain significance were detected in 17 of 76 (22.4%) standard and 6 of 29 (20.7%) extended screened patients. Expectedly, mutations were mainly found in and . In conclusion, TL measured by flow-FISH represents a powerful functional in vivo screening for an underlying TBD and should be performed in every newly diagnosed patient with AA as well as other patients with clinical suspicion for an underlying TBD in both children and adults.
PubMed: 37096215
DOI: 10.1097/HS9.0000000000000874 -
Iranian Biomedical Journal Mar 2023Dyskeratosis congenita (DC), an inherited and rare disease prevalent in males, is clinically manifested by reticulate hyperpigmentation, nail dystrophy, and leukoplakia....
BACKGROUND
Dyskeratosis congenita (DC), an inherited and rare disease prevalent in males, is clinically manifested by reticulate hyperpigmentation, nail dystrophy, and leukoplakia. DC is associated with the increased risk of malignancy and other potentially lethal complications such as bone marrow failure, as well as lung and liver diseases. Mutations in 19 genes were found to be correlated with DC. Herein, we report a 12-year-old boy carrying a de novo mutation in TINF2 gene.
METHODS
Whole exome sequencing (WES) was performed on DNA sample of the proband, and the variant was investigated in the family by Sanger sequencing. Population and bioinformatics analysis were performed.
RESULTS
The NM_ 001099274.3(TINF2): c.844C>T (p.Arg282Cys) mutation was found by WES.
CONCLUSION
There was no history of the disease in the family, and the variant was classified as a de novo mutation.
Topics: Male; Humans; Child; Mutation; Family; Dyskeratosis Congenita; High-Throughput Nucleotide Sequencing; Telomere-Binding Proteins
PubMed: 37070599
DOI: 10.61186/ibj.3783 -
QJM : Monthly Journal of the... Jul 2023
Topics: Humans; Dyskeratosis Congenita; Idiopathic Noncirrhotic Portal Hypertension; Hypertension, Portal; Nuclear Proteins; Ribonucleoproteins, Small Nuclear
PubMed: 36943377
DOI: 10.1093/qjmed/hcad039