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JMIR Dermatology Oct 2023Congenital telangiectatic erythema (CTE), also known as Bloom syndrome, is a rare autosomal recessive disorder characterized by below-average height, a narrow face, a... (Review)
Review
BACKGROUND
Congenital telangiectatic erythema (CTE), also known as Bloom syndrome, is a rare autosomal recessive disorder characterized by below-average height, a narrow face, a red skin rash occurring on sun-exposed areas of the body, and an increased risk of cancer. CTE is one of many genodermatoses and photodermatoses associated with defects in DNA repair. CTE is caused by a mutation occurring in the BLM gene, which causes abnormal breaks in chromosomes.
OBJECTIVE
We aimed to analyze the existing literature on CTE to provide additional insight into its heredity, the spectrum of clinical presentations, and the management of this disorder. In addition, the gaps in current research and the use of artificial intelligence to streamline clinical diagnosis and the management of CTE are outlined.
METHODS
A literature search was conducted on PubMed, DOAJ, and Scopus using search terms such as "congenital telangiectatic erythema," "bloom syndrome," and "bloom-torre-machacek." Due to limited current literature, studies published from January 2000 to January 2023 were considered for this review. A total of 49 sources from the literature were analyzed.
RESULTS
Through this scoping review, the researchers were able to identify several publications focusing on Bloom syndrome. Some common subject areas included the heredity of CTE, clinical presentations of CTE, and management of CTE. In addition, the literature on rare diseases shows the potential advancements in understanding and treatment with artificial intelligence. Future studies should address the causes of heterogeneity in presentation and examine potential therapeutic candidates for CTE and similarly presenting syndromes.
CONCLUSIONS
This review illuminated current advances in potential molecular targets or causative pathways in the development of CTE as well as clinical features including erythema, increased cancer risk, and growth abnormalities. Future studies should continue to explore innovations in this space, especially in regard to the use of artificial intelligence, including machine learning and deep learning, for the diagnosis and clinical management of rare diseases such as CTE.
PubMed: 37796556
DOI: 10.2196/48413 -
Advances in Anatomic Pathology Jul 2018Osteosarcoma (OS) is the most common primary bone tumor affecting predominantly adolescents and young adults. It accounts for about 5% of all childhood cancers. Although... (Review)
Review
Osteosarcoma (OS) is the most common primary bone tumor affecting predominantly adolescents and young adults. It accounts for about 5% of all childhood cancers. Although the majority of OSs are sporadic, a small percentage occur as a component of hereditary cancer syndromes. Early onset, bilateral, multifocal, and metachronous tumors suggest genetic predisposition. The inheritance patterns can be autosomal dominant or recessive. These syndromes predispose to a wide variety of mesenchymal and epithelial cancers with propensity for certain mutations being prevalent in specific cancer subtypes. Li-Fraumeni syndrome, retinoblastoma, Rothmund-Thompson syndrome (type 2), Werner syndrome, and Bloom syndrome, constitute the majority of the tumor syndromes predisposing to OS and will be the focus for this review.
Topics: Bone Neoplasms; Genetic Predisposition to Disease; Humans; Neoplastic Syndromes, Hereditary; Osteosarcoma
PubMed: 29668499
DOI: 10.1097/PAP.0000000000000190 -
Genetics in Medicine : Official Journal... Jul 2022This study aimed to describe the spectrum of cancers observed in Bloom Syndrome and the observed survival and age of first cancer diagnosis in Bloom syndrome as these...
PURPOSE
This study aimed to describe the spectrum of cancers observed in Bloom Syndrome and the observed survival and age of first cancer diagnosis in Bloom syndrome as these are not well-defined.
METHODS
Data from the Bloom Syndrome Registry (BSR) was used for this study. Cancer history, ages of first cancer diagnosis, and ages of death were compiled from the BSR and analyzed.
RESULTS
Among the 290 individuals in the BSR, 155 (53%) participants developed 251 malignant neoplasms; 100 (65%) were diagnosed with 1 malignancy, whereas the remaining 55 (35%) developed multiple malignancies. Of the 251 neoplasms, 83 (33%) were hematologic and 168 (67%) were solid tumors. Hematologic malignancies (leukemia and lymphoma) were more common than any of the solid tumors. The most commonly observed solid tumors were colorectal, breast, and oropharyngeal. The cumulative incidence of any malignancy by age 40 was 83%. The median survival for all participants in the BSR was 36.2 years. There were no significant differences in time to first cancer diagnosis or survival by genotype among the study participants.
CONCLUSION
We describe the spectrum of cancers observed in Bloom syndrome and the observed survival and age of first cancer diagnosis in Bloom syndrome. We also highlight the significant differences in survival and age of diagnosis seen among different tumor types and genotypes.
Topics: Adult; Bloom Syndrome; Hematologic Neoplasms; Humans; Incidence; Neoplasms; Registries
PubMed: 35420546
DOI: 10.1016/j.gim.2022.03.008 -
Journal of Clinical Medicine Feb 2020Chromothripsis is a mutational mechanism leading to complex and relatively clustered chromosomal rearrangements, resulting in diverse phenotypic outcomes depending on... (Review)
Review
Chromothripsis is a mutational mechanism leading to complex and relatively clustered chromosomal rearrangements, resulting in diverse phenotypic outcomes depending on the involved genomic landscapes. It may occur both in the germ and the somatic cells, resulting in congenital and developmental disorders and cancer, respectively. Asymptomatic individuals may be carriers of chromotriptic rearrangements and experience recurrent reproductive failures when two or more chromosomes are involved. Several mechanisms are postulated to underlie chromothripsis. The most attractive hypothesis involves chromosome pulverization in micronuclei, followed by the incorrect reassembly of fragments through DNA repair to explain the clustered nature of the observed complex rearrangements. Moreover, exogenous or endogenous DNA damage induction and dicentric bridge formation may be involved. Chromosome instability is commonly observed in the cells of patients with DNA repair disorders, such as ataxia telangiectasia, Nijmegen breakage syndrome, and Bloom syndrome. In addition, germline variations of have been associated with chromothripsis in sonic hedgehog medulloblastoma and acute myeloid leukemia. In the present review, we focus on the underlying mechanisms of chromothripsis and the involvement of defective DNA repair genes, resulting in chromosome instability and chromothripsis-like rearrangements.
PubMed: 32106411
DOI: 10.3390/jcm9030613 -
Scientific Reports Jan 2021Bloom Syndrome (BS; OMIM #210900; ORPHA #125) is a rare genetic disorder that is associated with growth deficits, compromised immune system, insulin resistance, genome...
Bloom Syndrome (BS; OMIM #210900; ORPHA #125) is a rare genetic disorder that is associated with growth deficits, compromised immune system, insulin resistance, genome instability and extraordinary predisposition to cancer. Most efforts thus far have focused on understanding the role of the Bloom syndrome DNA helicase BLM as a recombination factor in maintaining genome stability and suppressing cancer. Here, we observed increased levels of reactive oxygen species (ROS) and DNA base damage in BLM-deficient cells, as well as oxidative-stress-dependent reduction in DNA replication speed. BLM-deficient cells exhibited increased mitochondrial mass, upregulation of mitochondrial transcription factor A (TFAM), higher ATP levels and increased respiratory reserve capacity. Cyclin B1, which acts in complex with cyclin-dependent kinase CDK1 to regulate mitotic entry and associated mitochondrial fission by phosphorylating mitochondrial fission protein Drp1, fails to be fully degraded in BLM-deficient cells and shows unscheduled expression in G1 phase cells. This failure to degrade cyclin B1 is accompanied by increased levels and persistent activation of Drp1 throughout mitosis and into G1 phase as well as mitochondrial fragmentation. This study identifies mitochondria-associated abnormalities in Bloom syndrome patient-derived and BLM-knockout cells and we discuss how these abnormalities may contribute to Bloom syndrome.
Topics: Autophagy; Bloom Syndrome; Cyclin B1; DNA Damage; DNA Replication; DNA-Binding Proteins; Energy Metabolism; Fibroblasts; G1 Phase; Humans; Mitochondria; Mitochondrial Proteins; Mitosis; Oxidative Stress; Reactive Oxygen Species; RecQ Helicases; Transcription Factors; Up-Regulation
PubMed: 33495511
DOI: 10.1038/s41598-021-81075-0 -
Cell Cycle (Georgetown, Tex.) 2018
Topics: DNA; DNA Breaks, Double-Stranded; DNA Helicases; DNA Repair; Recombination, Genetic
PubMed: 29278995
DOI: 10.1080/15384101.2017.1421045 -
Cellular and Molecular Life Sciences :... May 2000Studying monogenic hereditary disorders that manifest age-related phenotypes in cells, tissues, and the total organism would be helpful for clarifying the mechanisms of... (Review)
Review
Studying monogenic hereditary disorders that manifest age-related phenotypes in cells, tissues, and the total organism would be helpful for clarifying the mechanisms of aging. In this context, seven human disorders that manifest age-related phenotypes have been found to be caused by aberrations of five proteins with seven helicase motifs conserved in most of the helicases. These disorders are xeroderma pigmentosum, Cockayne syndrome, trichothiodystrophy, Bloom syndrome, Werner syndrome, X-linked alpha-thalassemia/mental retardation syndrome, and Juberg-Marsidi syndrome. A decline of probably pleiotropic and fundamental function of helicases in these disorders is, therefore, implied to underlie not only the various age-related phenotypes of the disorders but also the pleiotropic and universal nature of ordinary aging. Consistent with this implication, studies of these seven disorders suggest that their various age-related phenotypes are caused by aberrations in multiple processes, especially transcription. Furthermore, a few studies imply some association between aberration of the helicases and phenotypes in ordinary aging.
Topics: Aging; Bloom Syndrome; Cockayne Syndrome; DNA Helicases; Humans; Intellectual Disability; Mutation; Progeria; Syndrome; Werner Syndrome; Xeroderma Pigmentosum; alpha-Thalassemia
PubMed: 10892338
DOI: 10.1007/s000180050036 -
Proceedings of the National Academy of... Feb 2022The RecQ-like helicase BLM cooperates with topoisomerase IIIα, RMI1, and RMI2 in a heterotetrameric complex (the "Bloom syndrome complex") for dissolution of double...
The RecQ-like helicase BLM cooperates with topoisomerase IIIα, RMI1, and RMI2 in a heterotetrameric complex (the "Bloom syndrome complex") for dissolution of double Holliday junctions, key intermediates in homologous recombination. Mutations in any component of the Bloom syndrome complex can cause genome instability and a highly cancer-prone disorder called Bloom syndrome. Some heterozygous carriers are also predisposed to breast cancer. To understand how the activities of BLM helicase and topoisomerase IIIα are coupled, we purified the active four-subunit complex. Chemical cross-linking and mass spectrometry revealed a unique architecture that links the helicase and topoisomerase domains. Using biochemical experiments, we demonstrated dimerization mediated by the N terminus of BLM with a 2:2:2:2 stoichiometry within the Bloom syndrome complex. We identified mutations that independently abrogate dimerization or association of BLM with RMI1, and we show that both are dysfunctional for dissolution using in vitro assays and cause genome instability and synthetic lethal interactions with GEN1/MUS81 in cells. Truncated BLM can also inhibit the activity of full-length BLM in mixed dimers, suggesting a putative mechanism of dominant-negative action in carriers of BLM truncation alleles. Our results identify critical molecular determinants of Bloom syndrome complex assembly required for double Holliday junction dissolution and maintenance of genome stability.
Topics: Alleles; Bloom Syndrome; Carrier Proteins; Cell Line; DNA Topoisomerases, Type I; DNA, Cruciform; Genomic Instability; Humans; Mutation; Protein Binding; RecQ Helicases; Recombination, Genetic; Solubility
PubMed: 35115399
DOI: 10.1073/pnas.2109093119 -
Journal of Clinical Immunology Jan 2018Bloom's syndrome (BS) is an autosomal recessive disease, caused by mutations in the BLM gene. This gene codes for BLM protein, which is a helicase involved in DNA...
Bloom's syndrome (BS) is an autosomal recessive disease, caused by mutations in the BLM gene. This gene codes for BLM protein, which is a helicase involved in DNA repair. DNA repair is especially important for the development and maturation of the T and B cells. Since BLM is involved in DNA repair, we aimed to study if BLM deficiency affects T and B cell development and especially somatic hypermutation (SHM) and class switch recombination (CSR) processes. Clinical data of six BS patients was collected, and immunoglobulin serum levels were measured at different time points. In addition, we performed immune phenotyping of the B and T cells and analyzed the SHM and CSR in detail by analyzing IGHA and IGHG transcripts using next-generation sequencing. The serum immunoglobulin levels were relatively low, and patients had an increased number of infections. The absolute number of T, B, and NK cells were low but still in the normal range. Remarkably, all BS patients studied had a high percentage (20-80%) of CD4+ and CD8+ effector memory T cells. The process of SHM seems normal; however, the Ig subclass distribution was not normal, since the BS patients had more IGHG1 and IGHG3 transcripts. In conclusion, BS patients have low number of lymphocytes, but the immunodeficiency seems relatively mild since they have no severe or opportunistic infections. Most changes in the B cell development were seen in the CSR process; however, further studies are necessary to elucidate the exact role of BLM in CSR.
Topics: Adult; B-Lymphocytes; Bloom Syndrome; Cell Differentiation; Child; DNA Repair; Female; Humans; Immunoglobulin A; Immunoglobulin Class Switching; Immunoglobulin G; Immunologic Deficiency Syndromes; Immunophenotyping; Lymphocyte Activation; Male; Middle Aged; Mutation; RecQ Helicases; Somatic Hypermutation, Immunoglobulin; T-Lymphocytes
PubMed: 29098565
DOI: 10.1007/s10875-017-0454-y -
Cold Spring Harbor Molecular Case... Apr 2018Bloom syndrome (BS) is a rare, autosomal recessive genetic disorder characterized by short stature, a skin rash associated with sun exposure, and an elevated likelihood... (Review)
Review
Bloom syndrome (BS) is a rare, autosomal recessive genetic disorder characterized by short stature, a skin rash associated with sun exposure, and an elevated likelihood of developing cancers of essentially all types, beginning at an early age. Cancer is the leading cause of death for persons with BS, and its early onset results in a reported median lifespan of <30 years. With fewer than 300 documented cases since BS was first described in 1954, its rarity has challenged progress in advancing both the care of and the cure for persons with BS. Presently, there are no known clinically actionable targets specific to persons with this cancer predisposition syndrome, despite the fact that standard cancer treatments are often contraindicated or must be substantially modified for persons with BS. Herein, Zachary Rogers recounts his experience as a cancer patient with BS contemplating a substantially customized chemotherapy regimen that highlights the need for development of individualized treatments in the BS community. We also outline a patient-centered research and community action road map with the goal of improving and prolonging the lives of persons with Bloom syndrome, including the facilitation of precision medicine development specific to this condition.
Topics: Bloom Syndrome; Family; Health Priorities; History, 20th Century; History, 21st Century; Humans; Precision Medicine; Research
PubMed: 29610394
DOI: 10.1101/mcs.a002816