Werner syndrome associated with poorly differentiated thyroid carcinoma and systemic sclerosis-like skin manifestations: A case report.

Werner syndrome (WS) is an autosomal recessive disorder characterised by premature ageing. WS patients often experience scleroderma-like manifestation including skin sclerosis and skin ulcer, making it difficult to differentiate WS from systemic sclerosis (SSc). Moreover, there is a high incidence of malignancy and arteriosclerosis-related disease in WS patients. We herein describe a 36-year-old woman with WS who had poorly differentiated thyroid carcinoma, one of the rare phenotypes of thyroid tumour. This case suggested the importance to distinguish WS from SSc and early diagnosis of malignancy.

Renal dysfunction, malignant neoplasms, atherosclerotic cardiovascular diseases, and sarcopenia as key outcomes observed in a three-year follow-up study using the Werner Syndrome Registry.

Werner syndrome is an adult-onset progeria syndrome that results in various complications. This study aimed to clarify the profile and secular variation of the disease. Fifty-one patients were enrolled and registered in the Werner Syndrome Registry. Their data were collected annually following registration. A cross-sectional analysis at registration and a longitudinal analysis between the baseline and each subsequent year was performed. Pearson's chi-squared and Wilcoxon signed-rank tests were used. Malignant neoplasms were observed from the fifth decade of life (mean onset: 49.7 years) and were observed in approximately 30% of patients during the 3-year survey period. Regarding renal function, the mean estimated glomerular filtration rate calculated from serum creatinine (eGFRcre) and eGFRcys, which were calculated from cystatin C in the first year, were 98.3 and 83.2 mL/min/1.73 m2, respectively, and differed depending on the index used. In longitudinal analysis, the average eGFRcre for the first and fourth years was 74.8 and 63.4 mL/min/1.73 m2, showing a rapid decline. Secular changes in Werner syndrome in multiple patients were identified. The prevalence of malignant neoplasms is high, and renal function may decline rapidly. It is, therefore, necessary to carry out active and detailed examinations and pay attention to the type and dose of the drugs used.

A Patient with Werner's Syndrome Who Underwent Aortic Valve Replacement through Minimally Invasive Cardiac Surgery.

Werner's syndrome (WS) is a genetic disorder presenting with premature senility. In the present study, we performed minimally invasive cardiac surgery (MICS)-aortic valve replacement (AVR) on a patient with Werner's syndrome who presented with aortic stenosis. The patient, a 49-year-old Japanese man, was brought to the emergency room with dyspnea during exercise. On echocardiography, severe aortic stenosis was found and surgery was planned. He had poorly controlled diabetes mellitus and underwent MICS-AVR to avoid the risk of sternal osteomyelitis, which resulted in a good outcome. The aortic valve had sclerotic changes and a genetic disease was suspected based on the onset of aortic stenosis at a young age, characteristic appearance, and various signs of aging. Genetic testing led to the diagnosis of WS.

A rare syndrome mimicking scleroderma: Werner syndrome.

Werner syndrome (WS), also known as adult progeria, is a premature ageing syndrome that can manifest itself with grey hair, hair loss, diabetes mellitus, hyperlipidaemia, hypertension, skin disorders, ocular cataracts, myocardial infarction, osteoporosis, and stroke, especially after puberty. Physical examination findings similar to systemic sclerosis may be seen. Therefore, it may mimic this disease as misleading. A 43-year-old female patient was admitted to our clinic with a pre-diagnosis of systemic sclerosis complaint of skin hardening up to the ankle. In the first physical examination, there were wrinkles and thinning of the lip, suggesting systemic sclerosis in the facial appearance. On her capillaroscopy, there was tortuosity and an old focus of microhemorrhage. She had a history of diabetes mellitus and chronic osteomyelitis. When all symptoms, clinical findings, and antibody results were combined, it was thought that the patient might have WS. WS was diagnosed with homozygous c.2221 C>P p.R741*(rs763089663) positive in genetic analysis. It is known that WS creates a predisposition to malignancies, and most patients die secondary to malignancies. Therefore, early diagnosis becomes essential. Early diagnosis is of vital importance both to prevent complications and to delay treatment. In particular, systemic sclerosis-like findings of this syndrome may cause delays in diagnosis. For this reason, small clues suggesting WS in the clinic should be well known and well defined.

Breast cancer in a Hispanic patient with Werner syndrome.

Werner Syndrome is a rare autosomal recessive condition characterized by premature aging and increased risk of malignancies due to gene mutations associated with DNA stability. We present the first case report of a 29-year-old Hispanic female with WS diagnosed with breast cancer. Diagnostic mammography and ultrasound, breast MRI and PET examinations revealed two lesions biopsy proven as invasive ductal carcinoma. The patient underwent neoadjuvant chemotherapy and radical mastectomy. Recurrence occurred 10 months postoperatively with molecular analysis demonstrating TP53 mutations. The multifactorial assessment of breast cancer in this case study is crucial towards optimizing screening, diagnosis and management of this disease in patients with WS.

Werner syndrome associated with acroosteolysis.

Werner syndrome (WS) is an autosomal recessive syndrome characterized by genomic instability that affects multiple body systems. The characteristic features of the disease include growth retardation, short stature, alopecia, scleroderma, atrophic skin with ulcerations, infertility, cataracts, premature arteriolosclerosis, diabetes, osteoporosis, and increased risk of malignancies. Werner syndrome protein (WRN) protein deficiency in this disease causes changes in gene expression, similar to those observed in normal aging. As the median age of death in WS is the fourth or fifth decade of life, early diagnosis leads to a better screening opportunity for malignancies. Herein, we present a 28-year-old woman who presented with growth arrest, dyspigmentation, and acroosteolysis and was later diagnosed with Werner syndrome.

Case Report: A novel WRN mutation in Werner syndrome patient with diabetic foot disease and myelodysplastic syndrome.

Werner syndrome is an autosomal recessive rare disease caused by a WRN gene mutation, which is rarely reported in the Chinese population. We report the clinical and genetic data of a Chinese patient with Werner syndrome. The proband was a 40-year-old male patient who presented with diabetic foot ulcers, accompanied by short stature, cataracts, hypogonadism, and hair thinning, and myelodysplastic syndrome (MDS) occurred after 18 months. Genetic sequencing showed there were compound heterozygous mutations as c.3384-1G>C and c.3744dupA in the WRN gene. The c.3744dupA mutation is a novel pathogenic variation for Werner syndrome.

Partial lipodystrophy, severe dyslipidaemia and insulin resistant diabetes as early signs of Werner syndrome.

Werner syndrome is a premature ageing disorder caused by biallelic variants in the WRN gene. WRN encodes a dual DNA helicase/exonuclease enzyme. Molecular diagnosis is commonly only made at a late disease stage in the third or fourth decade, when cardinal features have become apparent. We describe a 28 year-old woman who presented with early onset diabetes associated with partial lipodystrophy, severe dyslipidaemia and rapidly progressive liver fibrosis related to non-alcoholic steatohepatitis in the absence of progeroid features. Werner syndrome was diagnosed by trio exome analysis, which revealed compound heterozygous WRN mutations: the known variant c.1290_1293del (p.Asn430Lysfs*7) and the novel intronic splice site variant c.2732+5G>A. cDNA analysis demonstrated this to lead to in-frame skipping of exon 22, predicted to delete most of the zinc binding region of the helicase domain. We suggest that including the WRN gene in genetic analysis of early onset diabetes, lipodystrophy or dyslipidaemia would allow for the opportunity to diagnose some cases of Werner syndrome long before clinical criteria are met, thereby allowing early implementation of important primary prevention interventions.

A high prevalence of myeloid malignancies in progeria with Werner syndrome is associated with p53 insufficiency.

Werner syndrome (WS) is a progeroid syndrome caused by mutations in the WRN gene, which encodes the RecQ type DNA helicase for the unwinding of unusual DNA structures and is implicated in DNA replication, DNA repair, and telomere maintenance. patients with WS are prone to develop malignant neoplasms, including hematological malignancies. However, the pathogenesis of WS-associated hematological malignancies remains uncharacterized. Here we investigated the somatic gene mutations in WS-associated myelodysplastic syndrome/acute myeloid leukemia (MDS/AML). Whole-exome sequencing (WES) of 4 patients with WS with MDS/AML revealed that all patients had somatic mutations in TP53 but no other recurrent mutations in MDS/AML. TP53 mutations were identified at low allele frequencies at more than one year before the MDS/AML stage. All 4 patients had complex chromosomal abnormalities including those that involved TP53. Targeted sequencing of nine patients with WS without apparent blood abnormalities did not detect recurrent mutations in MDS/AML except for a PPM1D mutation. These results suggest that patients with WS are apt to acquire TP53 mutations and/or chromosomal abnormalities involving TP53, rather than other MDS/AML-related mutations. TP53 mutations are frequently associated with prior exposure to chemotherapy; however, all four patients with WS with TP53 mutations/deletions had not received any prior chemotherapy, suggesting a pathogenic link between WRN mutations and p53 insufficiency. These results indicate that WS hematopoietic stem cells with WRN insufficiency acquire competitive fitness by inactivating p53, which may cause complex chromosomal abnormalities and the subsequent development of myeloid malignancies. These findings promote our understanding of the pathogenesis of myeloid malignancies associated with progeria.

General anesthesia for old Werner syndrome patient: a case report.

Werner syndrome (WS) is a rare autosomal recessive, premature aging disorder whose clinical manifestations include short stature, bilateral cataracts, diabetes mellitus, hypertension, and atherosclerosis. WS first manifests during adolescence and patients usually die at 40-50 years of age. Only symptomatic treatment options available according to clinical manifestations. In anesthetic management, they need to be considered to elderly patients. Difficult intubation is expected and the patients are regarded as a high-risk group for anesthesia, owing to the concomitant cardiovascular and cerebrovascular disorders. The anesthetic management of WS requires a meticulous preoperative history taking, physical examination, and preparation for cardiovascular events.

Atherosclerosis and Cardiovascular Diseases in Progeroid Syndromes.

Hutchinson-Gilford progeria syndrome (HGPS) and Werner syndrome (WS) are two of the representative genetic progeroid syndromes and have been widely studied in the field of aging research. HGPS is a pediatric disease in which premature aging symptoms appear in early childhood, and death occurs at an average age of 14.5 years, mainly due to cardiovascular disease (CVD). Conversely, WS patients exhibit accelerated aging phenotypes after puberty and die in their 50s due to CVD and malignant tumors. Both diseases are models of human aging, leading to a better understanding of the aging-associated development of CVD. In this review, we discuss the pathogenesis and treatment of atherosclerotic diseases presented by both progeroid syndromes with the latest findings.

Werner syndrome presenting as early-onset diabetes: A case report.

Werner syndrome is a rare autosomal recessive premature progeroid syndrome caused by mutations in the WRN gene. It is characterized by early onset of age-related diseases, such as cataracts, atherosclerosis, diabetes mellitus, osteoporosis and malignancies, in which diabetes often onset in patients' 30-40s. Herein, we report a Chinese patient with Werner syndrome with uncommon early-onset diabetes at 18 years-of-age, who had low body mass index, insulin resistance, negative antibodies of diabetes and early onset of cataracts. Genome sequencing and reverse transcription polymerase chain reaction confirm the diagnosis. A novel heterozygous splice-site mutation in the WRN gene (c.1270-2A>T) was identified. The present case reminds clinicians that when young diabetes patients are encountered, if they are accompanied by premature aging, attention should be paid to identifying the possibility of Werner syndrome based on diagnostic criteria.

Werner Syndrome Protein Expression in Breast Cancer.

INTRODUCTION: Werner protein (WRN) plays an important role in DNA repair, replication, transcription, and consequently genomic stability via its DNA-helicase and exonuclease activity. Loss of function of WRN is associated with Werner syndrome (WS), which is characterized by premature aging and cancer predisposition. Malignancies that are commonly linked to WS are thyroid carcinoma, melanoma, breast cancer, meningioma, and soft tissue and bone sarcomas. Currently, the clinicopathologic significance of WRN in breast cancer is largely unknown. PATIENTS AND METHODS: We investigated the clinicopathologic and prognostic significance of WRN protein expression in a cohort of clinically annotated series of sporadic (n = 1650) and BRCA-mutated (n = 75) invasive breast cancers. We correlated WRN protein expression to clinicopathologic characteristics, DNA repair protein expression, and survival outcomes. RESULTS: There is strong evidence of association between low nuclear and cytoplasmic WRN co-expression and low levels of KU70/KU80, DNA-PK, DNA Pol-B, CKD18, cytoplasmic RECQL4, and nuclear BLM protein expression (adjusted P-values < .05). Tumors with low nuclear or cytoplasmic WRN expression have worse overall breast cancer-specific survival (BCSS) (adjusted P-values < .05). In topoisomerase I overexpressed tumors, low WRN nuclear expression was associated with poor BCSS (P-value < .05). In BRCA-mutated tumors, low WRN cytoplasmic expression conferred shortest BCSS (P < .05). CONCLUSIONS: Low WRN protein expression is associated with poor BCSS in patients with breast cancer. This can be used to optimize the risk stratification for personalized treatment.