Bloom's syndrome in an Indian man in the UK

Introduction: Bloom syndrome is a rare autosomal recessive disorder characterized by chromosomal instability caused by mutations in the BLM gene that increase the risk of developing neoplasia, particularly at an early age. Bloom syndrome is typically characterized by short stature, photosensitivity, telangiectatic erythema, learning difficulties, immunodeficiency, and malignancy. Case report: We report a case of an adolescent girl with short stature and recurrent infections, who does not present typical erythematous sun-sensitive skin lesions to the face and whose high-pitched voice led to the diagnosis of BS caused by a novel L753X mutation. Discussion: To date, she has not presented with any malignancy or characteristic malar rash.

Bloom's syndrome is a rare autosomal recessive disorder caused by germline mutation of the BLM gene. The objective of this study was to illustrate the clinical, biological and genetic characteristics of this syndrome through Tunisian series. We report in a retrospective study 8 case of bloom's syndrome observed during 20 years. Our patients were 4 males and 4 females issued from 5 families. For all patients, the parents were consanguineous. The age was 13 to 39 years. The telangiectatic erythema was developed in all the patients between 6 months and 2 years old on the cheeks, on the nose, on the lips and the lower eyebrows. The photosensitivity was constant and was complicated by vesicules and bullae for 5 patients who had extensive lesions, three patients noted accentuation of their telangiectasic erythema. An improvement with the age was noticed for the first four patients. The growth deficiency was observed for all patients. It was marked, between -2 and -4 DS (standard deviation). The number of sister chromatid exchange was increased to twelve fold comparatively to normal subjects. Two patients developed a breast cancer; the evolution was fatal in one. Another patient developed a leukaemia, the evolution was also fatal. Bloom's syndrome is a rare genodermatitis. All the patients presented three symptoms: telangiectatic erythema, growth delay and photosensitivity associated with immunodeficiency. There is significant risk of cancer, so that follow up of patients is mandatory.

Bloom syndrome: an oral potentially malignant disorders aiding in malignancy vigour

Bloom syndrome (BS) is an autosomal recessive genetic disorder caused by variants in the BLM gene. BS is characterized by distinct facial features, elongated limbs, and various dermatological complications including photosensitivity, poikiloderma, and telangiectatic erythema. The BLM gene encodes a RecQ helicase critical for genome maintenance, stability, and repair, and a deficiency in functional BLM protein leads to genomic instability and high predisposition to various types of cancers, particularly hematological and gastrointestinal malignancies. Here, we report a case of BS with a previously unreported variant in the BLM gene. The patient was a 34-year-old woman who presented with short stature, prominent facial features, and a history of malignancies, including lymphoma, breast cancer, and myelodysplastic syndromes (MDS). She was initially treated with azacitidine for MDS and showed transient improvement, but eventually died at age of 35 due to progression of MDS. Genetic screening revealed compound heterozygous variants in the BLM gene, with a recurrent variant previously reported in BS in one allele and a previously unreported variant in the other allele. Based on her characteristic clinical features and the presence of heterozygous variants in the BLM gene, she was diagnosed with BS harboring compound heterozygous BLM variants.

Bloom syndrome (BS) is a rare autosomal recessive genetic disorder characterized by growth deficiency, unusual facies, sun-sensitive telangiectatic erythema, immunodeficiency and predisposition to cancer. The causative gene for BS is the BLM gene which encodes the BLM RecQ helicase protein. The BLM gene has 4437 bp and encodes 1417 amino acids. The detection of BLM gene mutations for laboratory diagnosis of BS is laborious and impractical, unless there are common mutations in a population. Here we describe the immunoblot and immunohistochemical analyses for the detection of the BLM protein using a polyclonal BLM antibody. The BLM gene and protein were consistently and clearly detected in Epstein-Barr virus (EBV)-transformed or phytohemagglutinin (PHA)-stimulated lymphoblasts from control and various human hematopoietic cell lines. In a 7-week old human fetal brain, the BLM gene expression was strongly detected in contrast to an adult human brain. The BLM protein was not detected in EBV-transformed lymphoblasts from three BS patients. By immunohistochemistry, nuclear dots of the BLM protein were detected in both EBV-transformed lymphoblasts and PHA-stimulated lymphoblasts from the control. However, in lymphoblasts from BS patients no nuclear dots of the BLM protein were detected. These results indicate that the combinational analysis of immunoblotting and immunohistochemistry is a useful approach to screening of BS, although a mutation analysis is necessary for a definitive diagnosis of BS.

Objective: To expand the knowledge of the clinical and molecular characteristics of the children with Bloom syndrome. Methods: Clinical data of two siblings with classic Bloom syndrome of Shanghai Children's Medical Center from January 2009 to June 2017 were obtained and analyzed. The DNA of peripheral blood was collected from two Bloom syndrome siblings and their parents during 2015. The mutations were detected with high-throughput sequencing by Illumina sequencing platform. Results: The two siblings (probands) visited our department for short stature and growth retardation, they had full-term normal delivery after normal pregnancy of their mother. Both cases presented with feeding difficulties, malnutrition, microcephaly and mental retardation, repeated infection, symmetrical short stature and special faces. At first, the proband was an 8-year-3-month old girl, her height was 99.7 cm, body mass index (BMI) 12.07 kg/m(2), head circumference was 45.5 cm, and birth weight was 1.6 kg. Her younger brother was 3-year-11-month old, his height was 86.6 cm, BMI was 14 kg/m(2), birth weight was 1.95 kg, and the head circumference reached 36 cm at 16 months. No evidence of cancer and characteristic rash was detected at 8-year follow-up. Pathogenic complex heterozygous mutations c.772_773delCT, p.Leu258Glufs*7 and c.959+ 2T>A in BLM gene were detected in both siblings, which were separately inherited from their unaffected parents. Besides , c.959 + 2T>A has not been reported previously. Conclusions: Children with Bloom syndrome are characterized by short stature, microcephaly, special faces, feeding difficulties, and immunodeficiency. And butterfly erythematous rash may be absent. The c.959+2T>A mutation detected in our patients maybe a novel pathogenic mutation.

Bloom syndrome (BS) is an autosomal recessive rare disorder clinically characterized by primary microcephaly, growth deficiency, short stature, photosensitivity, immunodeficiency, and cancer predisposition. BS is caused by biallelic, compound heterozygous, or homozygous loss-of-function (LoF) mutations in BLM, which encodes the BLM RecQ-like helicase. BLM has important roles during DNA replication and repair processes. Recently, additional genes associated with BS-like phenotypes were identified by whole exome sequencing strategies, namely autosomal recessively inherited LoF mutations in TOP3A, RMI1, and RMI2. TOP3A encodes the DNA topoisomerase III al- pha, which is able to decatenate single-stranded DNA molecules, while RMI1 and RMI2 code for the DNA interacting proteins RecQ-mediated genome instability protein-1 and -2. In general, BLM, TOP3A, RMI1, and RMI2 form together the BTRR multiprotein complex. The BTRR complex participates in fundamental cellular processes for DNA replication and repair. The most well-studied role of the BTRR complex is to dissolve DNA intermediates during the homologous recombination DNA repair, namely the double Holliday junctions. Failure in proper dissolution of such structures can lead to crossovers between the sister chromatids, an event called the sister chromatid exchange (SCE). Increased SCE rates are prominent cellular characteristics of BS cells. In sum, the BTRR complex is important for the protection of genome stability based on its roles in DNA replication and repair processes. To broaden the clinical and mutational signatures of BS, I aimed to collect and characterize patients with BS-like phenotypes. For this reason, a BS flyer informing about phenotypic characteristics and mechanisms of BS, as well as the details of this project was prepared in German and Turkish languages. This flyer was printed and distributed to clinicians, human genetics institutes, and genetics centers in both countries. Prior to this doctoral thesis, eight patients with BS phenotype were diagnosed by molecular genetic approaches. During my project, I assessed the clinical and mutational findings of patients and compared the data between patients. Homozygous LoF mutations were found in BLM in six patients and one homozygous LoF variant was detected in RMI1 in two patients from a consanguineous family. One of the pathogenic BLM variants was a novel mutation. Further, the phenotypic characteristics were milder in RMI1-associated patients when compared to BLM-associated patients in terms of skin findings and immunodeficiency in BS. Next, I investigated the transcriptional changes in BLM-deficient cells. Three BS patient-derived fibroblast cell lines were subjected to single-cell transcriptome sequencing (scRNAseq) using ICELL8 Single-Cell System and a high data quality was achieved. Differentially expressed genes and pathway analyses in BS samples in comparison to wild-type (WT) fibroblasts revealed highly significant terms in relation to the BS pathogenesis, such as chromosome segregation or mitosis-related terms. Many known interaction partners of BLM from the Fanconi anemia pathway were significantly upregulated. Analysis of cell cycle stages, which was possible to perform with the single-cell data, revealed that there was no difference in cell cycle stages between samples. Furthermore, several genes associated with primary microcephaly were deregulated in BS single cells, among which were NCAPG2, NCAPH, and NCAPD2. These transcripts encode members of the condensin I/II complexes, hence gene expression levels of condensin I/II complex were analyzed in detail and found highly upregulated. The overexpression of condensin I/II complex genes was a novel link in BLM deficiency. In addition, replication stress revealed a mild sensitivity of BS cells in comparison to WT according to the transcriptional changes. I also generated isogenic BTRR complex-deficient induced pluripotent stem cell (iPSC) lines via CRISPR/Cas9 genome editing technology. Cell lines having biallelic truncating mutations in genes encoding members of the BTRR complex, namely BLM, TOP3A, and RMI1, maintained the pluripotency after genome editing experiments. The lack of full-length proteins for the corresponding gene was confirmed via Western blot for every knockout (KO) cell line. The generated cell lines were characterized in terms of cellular phenotypes of the BTRR complex deficiency. SCE rates of BLM-KO, TOP3A-KO, and RMI1-KO iPSCs, were significantly higher than the wild-type parental control. Interestingly, the SCE frequency was lower in the RMI1-KO clone than BLM- and TOP3A-KO clones, although it was still significantly higher than the wild type. Mitotic errors such as chromatin bridges and lagging chromatin were observed in the KO iPSC samples, only RMI1-KO did not show a significant difference. Ultrafine anaphase bridges (UFB) were quantified in the generated KO samples and all three BTRR complex-deficient cell lines showed significantly increased rates of UFBs, implying that the BTRR complex deficiency resulted in unresolved UFBs independent of which member of the BTRR complex was impaired. Next, transcriptional changes of BTRR complex-deficient iPSCs were determined by scRNAseq. The overall transcriptional profiles were similar in KO-iPSCs and the parental wild type, yet the TOP3A-KO clone showed a possible sensitivity to replication stress. In summary, by the use of several different cell models for BS, the data generated in this project is of interest for further characterization of the BTRR complex. Transcriptional changes in BS can further shed light on the pathogenesis of BS. The isogenic iPSC lines provide a source to study the roles and effects of each member of the complex while providing therapeutic screening opportunities. Future differentiation approaches will provide additional insights into disease-associated mechanisms of BS phenotypes such as microcephaly or cancer predisposition in somatic cells.

Ischemic Stroke with Positive Antiphospholipid Antibodies in Bloom Syndrome: A Case Report

P078 Aggressive T-anaplastic large cell non-Hodgkin lymphoma in patient with chromosome breakage syndrome - a case report

Detection of free radical-induced DNA damage with bromodeoxyuridine/Hoechst flow cytometry: implications for Bloom's syndrome

Bloom syndrome is a rare autosomal recessive genetic disorder characterized by growth deficiency, unusual facies, sun-sensitive telangiectatic erythema, immunodeficiency and predisposition to cancer. The causative gene for Bloom syndrome is BLM, which encodes the BLM RecQ helicase homolog protein. The first part of this review describes a long-term follow-up study of two Bloom syndrome siblings. Subsequently, the focus is placed on the functional domains of BLM. Laboratory diagnosis of Bloom syndrome by detecting mutations in BLM is laborious and impractical, unless there are common mutations in a population. Immunoblot and immunohistochemical analyses for the detection of the BLM protein using a polyclonal BLM antibody, which are useful approaches for clinical diagnosis of Bloom syndrome, are also described. In addition, a useful adjunct for the diagnosis of Bloom syndrome in terms of the BLM function is investigated, since disease cells must have the defective BLM helicase function. This review also discusses the nuclear localization signal of BLM, the proteins that interact with BLM and tumors originating from Bloom syndrome.

Bloom syndrome (BS) is a rare autosomal recessive genetic disorder characterized by photosensitivity, rashes on the nose and cheeks, short stature, and a predisposition to develop cancers. In thisreport, we discuss the diagnosis and management of a 34-year-old Canadian male BS patient, originally from Honduras, who developed B-cell lymphoma and a subsequent non-small cell lung carcinoma (NSCLC). Given the radiosensitivity of the patient due to his BS diagnosis and the early stage of the low-grade B-cell lymphoma, we relied on surveillance as the clinical approach to his management. Thetreatment forNSCLC was initiated in stage III of the disease and was palliative in intent. Chemotherapy (12 rounds of paclitaxel, with the dosage gradually increasing from 48 mg to 58 mg and finally to 72 mg) was employed to shrink the left upper lobe (LUL) lung mass. Subsequently, radiotherapy (3000 cGY in 20 fractions) was administered to improvesymptoms further. The radiotherapy dose schedule was modified given the patient's BS diagnosis to avoid excessive toxicity. The palliative treatment course was well tolerated by the patient and resulted in symptom relief. However, his cancer progressed over the course of the treatment, ultimately resulting in his death 18 months after the initial diagnosis of NSCLC; no autopsy was performed. We believe this report will spur clinicians to engage in fruitful discussions about tailoringchemotherapy and radiation therapy regimens for treating cancer in BS patients.

Bloom syndrome (BS) is an autosomal recessive disorder with characteristic clinical features of primary microcephaly, growth deficiency, cancer predisposition, and immunodeficiency. Here, we report the clinical and molecular findings of eight patients from six families diagnosed with BS. We identified causative pathogenic variants in all families including three different variants in BLM and one variant in RMI1. The homozygous c.581_582delTT;p.Phe194* and c.3164G>C;p.Cys1055Ser variants in BLM have already been reported in BS patients, while the c.572_573delGA;p.Arg191Lysfs*4 variant is novel. Additionally, we present the detailed clinical characteristics of two cases with BS in which we previously identified the biallelic loss-of-function variant c.1255_1259delAAGAA;p.Lys419Leufs*5 in RMI1. All BS patients had primary microcephaly, intrauterine growth delay, and short stature, presenting the phenotypic hallmarks of BS. However, skin lesions and upper airway infections were observed only in some of the patients. Overall, patients with pathogenic BLM variants had a more severe BS phenotype compared to patients carrying the pathogenic variants in RMI1, especially in terms of immunodeficiency, which should be considered as one of the most important phenotypic characteristics of BS.

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.

Bloom's syndrome is a genodermatosis characterized by a telangiectatic erythema of the face beginning in infancy, sensitivity to sunlight, small stature, and a low birth weight after a full-term gestation. A structural chromosome abnormality and an increased incidence of leukemia are associated. A classical example of this syndrome is presented in a patient who also exhibited low yA and γM levels in the serum. Bloom's syndrome is compared with four other syndromes that have some similarity to it: Rothmund-Thomson syndrome, Cockayne's syndrome, ataxiatelangiectasia, and dyskeratosis congenita. These syndromes may be unrelated or may represent variants of the same underlying condition.