A Novel Variant in the WRN Gene Detected in a Case of Early-Onset Severe Insulin Resistance Displaying Some but Not All Hallmarks of Progeroid Werner Syndrome.

OBJECTIVE: Determining the cause of severe insulin resistance and early-onset diabetes in the case of a young woman in which a wide range of differential diagnoses did not apply. RESEARCH DESIGN AND METHODS: Diagnostic workup including medical history, physical examination, specialist consultations, imaging methods, laboratory assessment, and genetic testing carried out by next-generation panel sequencing. RESULTS: After ruling out several differential diagnoses, genetic testing revealed a previously unknown homozygous variant within the canonical splice site of intron 4 in the WRN gene classified as pathogenic. Thus, although not all cardinal clinical criteria according to existing guidelines had been met, the phenotype of our patient was attributed to Werner syndrome (WS), an autosomal-recessive inherited progeroid syndrome. CONCLUSIONS: WS, although rare, must be considered as a differential diagnosis in cases of severe insulin resistance. Moreover, recognized clinical criteria of WS may not lead to diagnosis in all cases.

Sex differences in symptom presentation and their impact on diagnostic accuracy in Werner syndrome.

AIM: Whether sex differences exist in hereditary progeroid syndromes remains unclear. In this study, we investigated sex differences in patients with Werner syndrome (WS), a model of human aging, using patient data at the time of diagnosis. METHODS: The presence of six cardinal signs in the diagnostic criteria was retrospectively evaluated. RESULTS: We found that the percentage of patients with all cardinal signs was higher in males than in females (54.2% vs. 21.2%). By the age of 40 years, 57.1% of male patients with WS presented with all the cardinal signs, whereas none of the female patients developed all of them. In particular, the frequency of having a high-pitched, hoarse voice, a characteristic of WS, was lower in female patients. The positive and negative predictive values for clinical diagnosis were 100% for males and females, indicating the helpfulness of diagnostic criteria regardless of sex. More female patients than male (86.7% vs. 64%) required genetic testing for their diagnosis because their clinical symptoms were insufficient, suggesting the importance of genetic testing for females even if they do not show typical symptoms of WS. Finally, the frequency of abnormal voice was lower in patients with WS harboring the c.3139-1G > C homozygous mutation. CONCLUSION: These results indicate, for the first time, that there are sex differences in the phenotypes of hereditary progeroid syndromes. The analysis of this mechanism in this human model of aging may lead to the elucidation of sex differences in the various symptoms of normal human aging. Geriatr Gerontol Int 2024; 24: 161-167.

Early-onset diabetes mellitus as a presenting feature of Werner's syndrome in an Indian family.

BACKGROUND: Diabetes mellitus (DM) in children and adolescents is typically caused by type 1 DM, followed by type 2 DM and maturity-onset diabetes of the young (MODY). We report an unusual Asian Indian family in which three members presented with DM at ages 15, 20, and 30, but not fitting the typical clinical picture of type 1 DM, type 2 DM, or MODY. The primary objective was to elucidate the molecular genetic basis of DM in this family. METHODS: The proband, a 22-year-old man, had short stature, gray hair, osteoporosis, and markedly reduced subcutaneous fat on the body, especially on the extremities along with acanthosis nigricans, and developed myxoid malignant peripheral nerve sheath tumor. Detailed family history revealed multiple loops of consanguinity. The proband underwent whole-genome sequencing, and seven relatives underwent whole-exome sequencing. RESULTS: The proband and three additional family members were found to have the homozygous c.561A>G nucleotide variant of WRN RecQ-like helicase (WRN) gene consistent with the diagnosis of Werner's syndrome. The c.561A>G variant induces a new splicing site on exon 6 resulting in a truncated WRN protein, p.Lys187Trpfs*13. CONCLUSION: Our report brings to attention the onset of DM during childhood or early adulthood in patients with Werner's syndrome who typically develop type 2 DM around the age of 30-40 years. Presence of consanguinity among parents, dysmorphic features, and malignancy should prompt consideration of diagnosis of Werner's syndrome.

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.

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.

Optical coherence tomography findings in three patients with Werner syndrome.

BACKGROUND: Werner syndrome is a rare, autosomal recessive disorder characterised by premature aging. It is a typical hereditary progeroid syndrome that can be difficult to diagnose owing to its rarity and the similarity of some of its symptoms, such as juvenile cataracts, to other common ophthalmologic conditions. Early onset of bilateral cataracts is currently used as the ophthalmological feature for Werner syndrome; however, ophthalmologists often find performing a detailed examination of the medical history and genetic testing for Werner syndrome at the time of an ophthalmologic consultation challenging. If a unique ocular finding was observed on ocular examinations in cases of juvenile bilateral cataracts, we could consider Werner syndrome as a differential diagnosis.  CASE PRESENTATION: We documented the cases of three patients with Werner syndrome in whom thinning of the retina in the retinal nerve fiber layer (RNFL) and ganglion cell complex (GCC) were observed using optical coherence tomography (OCT). Visual field tests revealed the loss of visual field mainly owing to glaucoma. The thinnig of the choroidal thickness (CT) in three patients was also observed using enhanced depth imaging (EDI)-OCT. CONCLUSIONS: Three patients have thinning of the RNFL, GCC, and choroidal thickness and the loss of visual field. These findings suggest the need for including Werner syndrome in the differential diagnosis when patients presenting with juvenile cataracts of unknown cause also show abnormal retinal and choroidal thinning in the OCT images.

Adult progeria: a new mutation in the WRN gene.

Werner syndrome (WS), also known as adult progeria, is a rare autosomal recessive inherited progeroid syndrome characterised by multiple features consistent with accelerated ageing. This disease is associated with several rheumatic conditions such as early osteoarthritis and osteoporosis, sarcopenia, soft-tissue calcifications, gout, limb ulcers and scleroderma-like skin features. WS should be included in the differential diagnosis of systemic sclerosis. The diagnosis is clinical, and in 90% of cases, a genetic test reveals a pathogenic variant of the WRN gene.WRN encodes a member of the RecQ family of DNA helicases and has a role in DNA repair. 86 different pathological WRN mutations have been identified so far. Here we present a case report of a typical WS patient associated with a newly described genetic variant of the WRN gene.

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.

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.

Lifetime extension and the recent cause of death in Werner syndrome: a retrospective study from 2011 to 2020.

BACKGROUND: Werner syndrome (WS) is an autosomal recessive premature ageing disease that causes accelerated ageing-like symptoms after puberty. Previous studies conducted in the late 2000s reported that malignant neoplasms and atherosclerotic diseases were the two leading causes of death, with life expectancies in the mid-50 s. However, the recent lifespan and cause of death in patients with WS remain unclear. OBJECTIVE: To clarify the latest lifespan and causes of death in patients with WS. METHOD: We conducted a questionnaire-based survey in 2020 among the primary doctors of WS patients who were identified in previous nationwide surveys in Japan and clarified the following: the age of WS patients (age of death, if the patient had already died), sex, and cause of death. Patients who died in 2010 or earlier were excluded from the analysis. RESULTS: A total of 123 living patients were identified at the time of the survey in 2020. Fourteen WS patients died between 2011 and 2020, with a mean age of 59.0 ± 8.9 years (mean ± SD). The most common cause of death was non-epithelial tumours, accounting for eight deaths, while no patient died of atherosclerotic diseases. CONCLUSIONS: Compared to previous studies, this study suggests that the lifespan of patients with WS has been extended. Although there were no deaths due to atherosclerotic diseases, non-epithelial tumours were still the leading cause of death. Further development of screening and treatment methods for these tumours is required.

Werner syndrome in a Lebanese family.

Werner syndrome (WS) is an extremely rare, autosomal recessive segmental progeroid disorder caused by biallelic pathogenic variants in the WRN, which encodes a multifunctional nuclear protein that belongs to the RecQ family of DNA helicases. Despite extensive research on WS in the last years, the population-specific mutational spectrum still needs to be elucidated. Moreover, there is an evident lack of detailed clinical descriptions accompanied with photographs of affected individuals. Here, we report a consanguineous Lebanese family in whom we identified a pathogenic homozygous nonsense variant c.1111G>T, p.Glu371* in the WRN. The index individual, at the age of 54 years, was suspected to have WS due to a history of early-onset cataracts, premature hair loss and graying, chronic nonhealing leg ulcers, Achilles' tendon calcifications, type 2 diabetes mellitus, dyslipidemia, hypothyroidism, and premature coronary artery disease. His four sisters, three of which deceased in the fifth decade, had clinical signs suggestive of WS. Moreover, his daughter, aged 23 years, had short stature, hair loss and flat feet. Taken together, we report a detailed clinical course of disease in several affected members of a consanguineous family, which is additionally documented by photographs.

Síndrome de Werner: relato de caso / Werner's syndrome: case report / Síndrome de Werner: reporte de un caso

Introdução: Síndrome de Werner, doença autossômica recessiva, tem como característica o envelhecimento precoce e acelerado. Objetivo: Descrever a evolução clínica favorável da síndrome de Werner em paciente acompanhada periodicamente no ambulatório de geriatria para promover atenção ao processo de envelhecimento por meio de abordagem preventiva e tratamento precoce das alterações que caracterizam a doença. Material e Método: Paciente de 31 anos de idade, sexo feminino, admitida no ambulatório de Aconselhamento Genético de um hospital-escola do noroeste paulista, apresentando baixa estatura, ulcerações, dor em região plantar e dificuldade para deambular, alterações cutâneas pigmentares com fissuras e ressecamento de toda a pele, além de cabelos grisalhos e quebradiços, catarata bilateral, hipotireoidismo e osteoporose. Tinha antecedentes familiares compatíveis com pais consanguíneos, um casal de irmãos hígidos e mãe com histórico de ocorrência de dois abortos espontâneos consecutivos. Apresentava, portanto, critérios diagnósticos para síndrome de Werner. Foi tratada nos ambulatórios de geriatria, endocrinologia, dermatologia, oftalmologia e ortopedia da mesma Instituição. Resultado: O tratamento consistiu na remoção cirúrgica de catarata, uso de levotiroxina 75 mcg/dia e de creme hidratante para pele (ácido salicílico 20% e vaselina sólida 30g), calçado ortopédico para pé neuropático com solado em EVA de média compressão, antiderrapante, confeccionado sob medida. Houve melhora na sintomatologia, especialmente quanto à deambulação com as medidas terapêuticas adotadas. Conclusão: A avaliação interdisciplinar inicial da paciente foi fundamental, pois possibilitou a elaboração precoce do diagnóstico e o acompanhamento no ambulatório de geriatria, promovendo maior atenção ao processo de envelhecimento preconizado por uma abordagem preventiva e tratamento subsequente das alterações que caracterizam a síndrome de Werner.(AU)

Introduction: Werner syndrome, an autosomal recessive disease, is characterized by premature and accelerated aging. Objective: To describe the favorable clinical evolution of Werner's syndrome in a patient periodically followed in the geriatric outpatient clinic to promote attention to the aging process through a preventive approach and early treatment of the changes that characterize the disease. Material and Method: A 31-year-old female patient, admitted to the Genetic Counseling outpatient clinic of a school hospital in northwestern pigmentary skin changes with cracks and dryness of the entire skin, as well as gray and brittle hair, bilateral cataract, hypothyroidism and osteoporosis. She had a family history compatible with consanguineous parents, a couple of healthy siblings and a mother with a history of two consecutive miscarriages. It therefore presented diagnostic criteria for Werner syndrome. She was treated in geriatric, endocrinology, dermatology, ophthalmology and orthopedics clinics of the same institution. Result: The treatment consisted of surgical removal of cataract, use of levothyroxine 75 mcg/day and moisturizing cream for skin (salicylic acid 20% and solid petroleum jelly 30g), orthopedic footwear for neuropathic foot anti-slip, made to measure. There was improvement in symptomatology, especially regarding ambulation with the therapeutic measures adopted. Conclusion: The initial interdisciplinary evaluation of the patient was fundamental, since it enabled the early preparation of the diagnosis and the follow-up in the geriatric outpatient clinic, promoting greater attention to the aging process recommended by a preventive approach and subsequent treatment of the changes that characterize Werner's syndrome.(AU)

Introducción: El síndrome de Werner, una enfermedad autosómica recesiva, se caracteriza por un envejecimiento prematuro y acelerado. Objetivo: Describir la evolución clínica favorable del síndrome de Werner en un paciente en seguimiento periódico en la consulta externa de geriatría para promover la atención al proceso de envejecimiento a través de un abordaje...(AU)

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.

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.

Severe metabolic disorders coexisting with Werner syndrome: a case report.

Werner syndrome, also called adult progeria, is a heritable autosomal recessive human disorder characterized by the premature onset of numerous age-related diseases including juvenile cataracts, dyslipidemia, diabetes mellitus (DM), osteoporosis, atherosclerosis, and cancer. Werner syndrome is a segmental progeroid syndrome whose presentation resembles accelerated aging. The most common causes of death for WS patients are atherosclerosis and cancer. A 40-year-old female presented with short stature, bird-like facies, canities with alopecia, scleroderma-like skin changes, and non-healing foot ulcers. The patient reported a history of delayed puberty, abortion, hypertriglyceridemia, and juvenile cataracts. A clinical diagnosis of WS was made and subsequently confirmed. We discovered two WRN gene mutations in the patient, Variant 1 was the most common WRN mutation, nonsense mutation (c.1105C>T:p.R369Ter) in exon 9, which caused a premature termination codon (PTC) at position 369. Variant 2 was a frameshift mutation (c.1134delA:p.E379KfsTer5) in exon 9, which caused a PTC at position 383 and has no published reports describing. Patients with WS can show a wide variety of clinical and biological manifestations in endocrine-metabolic systems (DM, thyroid dysfunction, and hyperlipidemia). Doctors must be cognizant of early manifestations of WS and treatment options.