Continuing Education Activity

Hutchinson-Gilford and Werner syndromes are rare inherited disorders collectively termed "premature aging syndromes," or progeria. Hutchinson-Gilford progeria syndrome (HGPS) arises from sporadic de novo mutations in the LMNA gene, resulting in defective lamin A (progerin) and nuclear envelope abnormalities, which accelerate cellular senescence. Werner syndrome, an autosomal recessive condition, results from mutations in the WRN gene, impairing DNA helicase function and genomic stability. Both conditions manifest with features suggestive of premature aging, including skin atrophy, loss of subcutaneous fat, wrinkles, graying hair, alopecia, nail dystrophy, abnormal pigmentation, and ulceration.

HGPS typically presents between 6 and 12 months with growth retardation and altered skin texture. Werner syndrome emerges in late adolescence or early adulthood, often with metabolic and cardiovascular abnormalities. Diagnosis hinges on clinical criteria and genetic testing. Management is primarily supportive, focusing on cardiovascular risk reduction, metabolic control, and skin care. Complications include diabetes, hypertension, osteoporosis, myocardial infarction, stroke, and malignancy. Prognosis is poor in HGPS, with death usually in the 2nd decade, whereas Werner syndrome carries a shortened lifespan due to age-related comorbidities.

This activity for healthcare professionals is designed to improve learners' proficiency in evaluating and managing premature aging syndromes. Participants will broaden their grasp of these conditions' etiology, epidemiology, pathophysiology, clinical presentation, and best diagnostic and management practices. Greater competence will enable clinicians to collaborate with interprofessional teams caring for affected individuals.

Objectives:

• Identify the clinical features indicative of progeria.
• Develop a clinically appropriate diagnostic plan for individuals with suspected progeria.
• Implement best practices for managing progeria and mitigating its potential complications.
• Collaborate with the interprofessional team to treat and monitor patients with progeria and educate affected families regarding genetic implications, treatment adherence, and prognosis to optimize health outcomes.

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Introduction

Hutchinson-Gilford and Werner syndromes are rare inherited disorders classified as premature aging syndromes, commonly referred to as "progeria." Both conditions exhibit cutaneous changes indicative of accelerated aging, including skin atrophy, loss of subcutaneous fat, wrinkles, graying hair, alopecia, nail dystrophy, abnormal pigmentation, and ulceration. In progeria, these changes occur at an accelerated rate compared with normal aging.

In Hutchinson-Gilford progeria syndrome (HGPS), manifestations typically appear between 6 and 12 months of age and include poor weight gain and altered skin texture. Other characteristic features comprise alopecia, prominent scalp veins and eyes, micrognathia, and delayed dental development. The mean life expectancy is approximately 13 years, with nearly 75% of patients succumbing to cardiovascular disease.

Werner syndrome is the most prevalent among premature aging disorders and is also known as progeria adultorum, adult progeria, or pangeria. The syndrome affects roughly 1 in 1 million individuals. Initial signs appear during puberty, often involving failure to undergo a normal growth spurt, which may be delayed until the 3rd decade of life. Distinguishing features include a marked discrepancy between appearance and chronological age. Patients may demonstrate graying hair and alopecia, facial wrinkling, sunken cheeks, micrognathia, short stature (typically below 1.6 meters), muscular weakness, and a high-pitched voice. Mortality usually occurs between 30 and 50 years of age, predominantly from cardiovascular disease or malignancy.[1][2][3][4]

The term “progeria” originates from the Greek word for old age, geras. Jonathan Hutchinson first described HGPS in 1886, and Hastings Gilford subsequently detailed its postmortem characteristics. In 2003, mutations in the gene encoding lamin A were identified as the underlying cause.[5] In 1904, Otto Werner reported a family with 2 brothers and 2 sisters, aged 36 to 40 years, exhibiting clinical features of premature aging. In 1934, Oppenheimer and Kugel described 2 similar cases and established the eponym "Werner syndrome." This disorder provides a valuable model for studying aging, offering insights into the mechanisms of senescence and potential therapeutic interventions.[6]

Etiology

HGPS may be inherited in either an autosomal dominant or, less commonly, an autosomal recessive manner. In autosomal dominant cases, a single affected parent can transmit the disorder, with up to a 50% probability of inheritance in offspring. HGPS typically results from a de novo heterozygous mutation in the lamin A gene located on chromosome 1q22. Lamin A forms a structural framework that maintains nuclear integrity. Disruption of this framework leads to cellular instability, which appears to drive the accelerated aging observed in affected individuals.

Werner syndrome is transmitted in an autosomal recessive manner, indicating that children with this condition inherit a defective gene from both parents. Approximately 1 in 4 offspring is expected to manifest the disorder, while the remaining children may be carriers. The condition results from a homozygous or compound heterozygous mutation in the RECQL2 gene, which encodes a helicase protein homologous to the Escherichia coli RecQ DNA helicase, located on chromosome 8p12. Helicase plays a critical role in DNA and RNA replication and repair.

Although genetic instability is a normal feature of aging, individuals with Werner syndrome cannot adequately repair these abnormalities. This inability leads to the accumulation of genetic damage, producing a premature aging phenotype that primarily affects specific tissues. Neurocognitive deficits are generally absent, suggesting that Werner syndrome represents a segmental aging syndrome rather than a global acceleration of the aging process.[7][8]

Epidemiology

Werner syndrome is an uncommon disorder, with an estimated incidence of approximately 1 case per 1 million individuals. The condition is more prevalent in Japan and Sardinia than in other regions.[9] Approximately 1,000 cases have been reported globally, with over 800 occurring in Japan. Among 116 Japanese patients, about 30% were identified as resulting from consanguineous marriages.[10] No racial predilection has been observed, and both sexes are equally affected. Clinical manifestations may appear during midadolescence or be delayed until around 30 years of age. The mean age at diagnosis is 37 years.

HGPS is considerably rarer, with an expected incidence of 1 in 4 to 8 million births, corresponding to an overall prevalence of approximately 1 in 20 million individuals. The male-to-female ratio is approximately 1.2:1, based on reports from multiple ethnicities worldwide.[11]

Pathophysiology

Werner syndrome results from mutations in the WRN gene (RECQL2), which encodes a homolog of the Escherichia coli RecQ DNA helicase. Nearly all identified mutations predict a truncated protein, and more than half of Japanese patients are homozygous for a specific splice-site mutation. The Werner protein possesses exonuclease and helicase functions, which contribute to efficient DNA repair, particularly through base excision, and suppress illegitimate recombination. Consequently, absence of WRN activity results in genomic instability.

The accumulation of senescent cells, characterized by reduced replicative capacity and an increasing number of mutations, is believed to underlie the clinical manifestations of premature aging and the elevated risk of cancer. A minority of patients exhibit atypical Werner syndrome and lack pathogenic WRN alterations. These individuals carry heterozygous missense mutations in LMNA that affect the heptad repeat region, likely disrupting protein-protein interactions. Compared with patients harboring WRN mutations, those with atypical Werner syndrome usually present earlier and display more pronounced age-related features. Atypical Werner syndrome may represent a late-onset variant of HGPS.[12]

A Japanese patient with Werner syndrome exhibited compound heterozygous WRN mutations, including a guanine-to-adenine change at the 1st nucleotide of the intron immediately following coding nucleotide 1720 (c.1720+1G>A) and a guanine-to-cytosine change at the nucleotide immediately preceding coding nucleotide 3139 (c.3139-1G>C) in the Japanese population. No malignancies were observed despite the patient being 43 years old.[13]

Skin fibroblasts from patients demonstrate stress-induced senescence, including decreased growth rates, prolonged cell cycles, and altered morphology, likely mediated by the p38α MAP kinase pathway.[14] A 2010 study reported 18 novel mutations, encompassing 2 genomic rearrangements, a deep intronic mutation generating a novel exon, a splice consensus mutation resulting in the use of an adjacent splice site, and 2 rare missense mutations.[15]

The majority of patients with both classic and atypical forms of HGPS harbor a de novo heterozygous point mutation affecting the splicing of the lamin A gene, LMNA. This gene encodes 2 protein products, lamin A and lamin C, which are essential components of the nuclear lamina and contribute to the structural scaffolding of the nucleus.[16]

Histopathology

Cutaneous histopathology varies according to anatomical location and patient age, and it is typically uninformative for diagnosis.[17] In HGPS, the epidermis appears largely normal, with minimal hyperkeratosis and a slight increase in basal layer melanin. Dermal elastic tissue remains intact, whereas dermal collagen is often thickened and hyalinized. Adnexal structures show normal or reduced density, and arrector pili muscles are typically prominent. Inflammatory infiltrates are usually absent.

In Werner syndrome, the epidermis demonstrates hyperkeratosis and atrophy, with localized hypermelanosis in the basal layer. Appendages are reduced in number and atrophic, and the dermis exhibits fibrosis with variable hyalinization. Adipose tissue is atrophic and frequently replaced by hyalinized connective tissue. Vascular alterations resembling diabetic angiopathy may also be observed.

History and Physical

Patients with Werner syndrome appear unaffected at birth and develop normally until adolescence or the 2nd decade of life, when signs and symptoms of accelerated aging begin to emerge. Clinical features include skin ulcers, cataracts, hair graying or loss, and hypogonadism. Loss of subcutaneous fat and dermal atrophy produces a scleroderma-like appearance. Nailfold capillary abnormalities resembling those observed in scleroderma have also been reported.[18]

Affected individuals often present with a bird-like facial appearance, short stature, a high-pitched voice, dental abnormalities, reduced body weight, and low body mass index. Rapid loss of muscle mass occurs predominantly in the limbs, with relative preservation of the trunk. Decreased grip strength and reduced skeletal muscle index lead to sarcopenia before the age of 40. Mobility is impaired, and osteoporosis affects the distal limb bones more than the vertebral column. Soft tissue calcifications, particularly of tendons, are common, with Achilles tendon calcification proposed as a diagnostic criterion.[19] Foot deformities such as pes planus, hallux valgus, and flexion contractures may develop, potentially resulting in ulceration, osteitis, and osteomyelitis.

Metabolic abnormalities are also observed, including the development of type 2 diabetes mellitus and increased visceral fat accumulation. Cardiovascular complications may occur, such as atherosclerosis, mitral regurgitation, and aortic stenosis. Patients with Werner syndrome have an elevated risk of tumor formation, with up to 10% developing malignancies. The spectrum of tumors differs from that seen in the general aging population. Approximately 50% of reported malignancies are soft tissue sarcomas, including schwannoma, rhabdomyosarcoma, malignant fibrous histiocytoma, leiomyosarcoma, and osteosarcoma of the upper extremities. Other reported neoplasms include meningiomas, malignant melanoma, and thyroid carcinoma.[20]

Although children with HGPS generally appear normal at birth, growth failure and other clinical manifestations typically emerge within the 1st year of life. Linear growth progresses at approximately 1/2 the normal rate and lacks the usual pubertal acceleration. Most patients demonstrate delayed sexual maturation and present with both short stature and low weight relative to height.[21]

Upon the onset of growth failure, patients develop distinctive craniofacial features, including an abnormally large cranium, frontal bossing, a large open anterior fontanelle, prominent scalp veins, and pronounced eyes due to delayed facial bone development. Additional facial characteristics include a slender, beaked nose with defined contours and micrognathia. These features typically become pronounced by 2 to 3 years of age, producing a characteristic "plucked bird" appearance.

Truncal abnormalities include a slender pyriform thorax, thin and shortened clavicles, and marked thoracic kyphosis resulting in a stooped posture. Abdominal prominence relative to the chest and hypoplastic nipples further contribute to the unusual body shape. Cognitive development is generally normal, although patients may exhibit self-consciousness regarding their appearance.

Evaluation

Genetic testing using nuclear sequencing combined with reverse transcription-polymerase chain reaction and western blot protein analysis can confirm a diagnosis of HGPS. Prenatal testing through amniocentesis or chorionic villus sampling is available for families at high risk of having infants with this condition.[22][23][24]

Patients diagnosed with Werner syndrome require regular screening for hyperlipidemia, breast and colorectal cancer, diabetes, and thyroid abnormalities. Given the prevalence of musculoskeletal abnormalities and soft tissue sarcomas in this population, imaging studies such as x-ray, computed tomography, or magnetic resonance imaging should be performed when clinically indicated to evaluate for underlying disorders, infections, or tumors. Dual-energy x-ray absorptiometry scans should also be conducted regularly to assess and monitor osteoporosis.

Treatment / Management

No definitive therapy is available for progeria at this time. Management focuses on symptomatic treatment of associated conditions. Genetic counseling holds critical importance. Radiotherapy is contraindicated in radiosensitive syndromes.[25]

Patients with Werner syndrome require caution with chemotherapy due to increased chemotoxicity from impaired DNA repair mechanisms. Symptomatic management of associated disturbances is the mainstay of care. Atherosclerosis, hypertension, diabetes, and other comorbidities are managed with standard monitoring and conventional medical therapy.

Severe cutaneous ulcers may respond to bosentan, an endothelin receptor antagonist. Orthotics can address complications arising from foot deformities. Cataracts are treated surgically. Sarcopenia may benefit from diets rich in branched-chain amino acids, structured exercise programs, vitamin D supplementation, and hormone therapy, although malignancy risk warrants careful consideration. Etidronate has been reported to alleviate painful soft tissue calcifications.

Management of diabetes mellitus and hyperlipidemia with appropriate diet and pharmacotherapy, including thiazolidinediones, metformin, dipeptidyl peptidase 4 inhibitors, and lipid-lowering agents, may reduce complications such as atherosclerosis. Vitamin C reversed age-related metabolic irregularities and extended longevity in a mouse model of Werner syndrome, suggesting potential human benefit.

Emerging therapies under investigation include mTOR inhibitors and CRISPR/Cas9-mediated gene repair.[26][27] Preliminary research indicated that the application of farnesyltransferase inhibitors (FTIs) restored nuclear morphology in human cells affected by HGPS in vitro. These FTIs also enhanced body weight, bone density, strength, and survival in murine models of progeria.[28] Administration of the FTI lonafarnib, either as monotherapy or in combination with the bisphosphonate zoledronate and pravastatin, has demonstrated modest yet significant improvements in survival among patients with HGPS.[29] MTOR inhibitors, such as sirolimus and everolimus, enhance autophagic degradation of progerin.[30] A clinical investigation examining the combination of everolimus and lonafarnib is currently in progress.

Antisense oligonucleotides that reduce progerin transcript and protein levels have partially ameliorated the cardiovascular phenotype and extended lifespan in a transgenic mouse model of HGPS.[31] Preclinical studies indicate that combination therapies, such as lonafarnib and baricitinib, have synergistic effects, substantially extending lifespan and improving multiple health parameters.[32] Consistent cardiovascular monitoring is advised, and low-dose aspirin may be beneficial. No dietary regimen has been shown to modify disease progression.

Although growth limitation in HGPS is often not associated with growth hormone deficiency, exogenous growth hormone administration can increase weight and, to a lesser extent, height. Joint mobility may be preserved with physical and occupational therapy. Genetic and psychological counseling may benefit patients and their families. Skin ulcers may be resistant to treatment and require prompt, vigorous intervention, potentially including skin grafting.[33]

Recent studies highlight the potential of nicotinamide mononucleotide supplementation to improve HGPS-associated phenotypes by restoring mitochondrial function and enhancing oxidized nicotinamide adenine dinucleotide (NAD+) biosynthesis.[34] Bone marrow-derived mesenchymal stem cell therapy has demonstrated short-term benefits, including increased lean body mass, improved bone density, and reduced arterial stiffness. Cardiovascular deterioration persists, but the safety profile of mesenchymal stem cell therapy is favorable, with no severe adverse effects reported. Long-term efficacy requires further investigation.[35] CRISPR base editing and other gene-editing techniques have shown potential for correcting underlying LMNA mutations in HGPS models, resulting in substantial improvements in vascular health and lifespan.[36][37]

Differential Diagnosis

The differential diagnosis for HGPS includes Werner syndrome, atypical Werner syndrome, Néstor–Guillermo progeria syndrome, metageria, and acrogeria. In contrast to HGPS, patients with Werner syndrome exhibit an increased risk of malignancy, cataracts, and premature canities. Additional disorders that should be distinguished from HGPS include Cockayne syndrome, Rothmund–Thomson syndrome, ataxia–telangiectasia, Kindler syndrome, Wiedemann–Rautenstrauch syndrome (neonatal progeroid syndrome), and forms of Ehlers–Danlos syndrome and cutis laxa with progeroid features. Clinical overlap may also occur with other LMNA-related disorders, including early-onset myopathy with progeroid features, restrictive dermopathy, and mandibuloacral dysplasia.[38]

Werner syndrome must be differentiated from ataxia–telangiectasia and prolidase deficiency, the latter characterized by facial dysmorphism, telangiectasias, recalcitrant leg ulcers, and premature canities. The condition must also be distinguished from conditions associated with plantar keratoderma and scleroderma-like dermal changes, such as Huriez syndrome.

Prognosis

Patients with Werner syndrome typically survive into the 5th decade of life. The average lifespan is approximately 54 years, with mortality most often resulting from cardiovascular and cerebrovascular diseases or malignancies. Some studies suggest that heterozygous carriers may have an increased risk of malignancy and myocardial infarction compared with the general population.[39] In HGPS, premature development of progressive coronary and cerebral atherosclerosis leads to a median life expectancy of approximately 14 years.[40]

Complications

The complications of progeroid syndromes are largely related to age-associated disorders. Alongside dermatological alterations, patients with Werner syndrome frequently exhibit osteoporosis, particularly in the lower extremities, often linked to parathyroid dysfunction. Diabetes mellitus develops in at least 30% of affected individuals, with many others showing impaired glucose tolerance. Rapidly progressive cataracts typically arise between ages 20 and 40. Significant cystoid macular edema may occur following laser treatment for cataracts.[41] Surgical trauma likely acts as a precipitating factor. This edema can be difficult to manage.[42]

Additional endocrine complications include hypopituitarism and hypogonadism or agonadism, as well as early menopause. Soft tissue calcifications are common. Pregnancy complicated by Werner syndrome has been documented.[43] Cardiovascular disease, particularly arteriosclerosis, represents a major cause of mortality due to fatal myocardial infarction. Cancer risk is elevated, with fibrosarcomas affecting approximately 10% of patients. Other malignancies include thyroid carcinoma, various organ cancers, hematological neoplasms, meningiomas, and cutaneous cancers such as squamous cell carcinoma arising from chronic ulcers on the ankle and heel.

Additional complications in HGPS include osteopenia, low-frequency conductive hearing loss, corneal dryness, and hyperopia. Mild insulin resistance is observed in up to 50% of patients, but overt diabetes mellitus is uncommon.

Consultations

Management of patients with Werner syndrome requires an interprofessional approach tailored to the individual's secondary complications. Relevant specialties may include endocrinology, dietetics, cardiology, geriatrics, ophthalmology, infectious disease, oncology, and orthopedic surgery. The development of a malignancy necessitates referral to the appropriate specialist for tumor staging and management.

Deterrence and Patient Education

Clinicians should refer patients and their families to a genetic counselor for detailed information regarding the condition. Participation in support groups, such as the National Organization for Rare Disorders, should be encouraged. Affected families may also be eligible for prenatal diagnostic testing.

Pearls and Other Issues

Werner and other progeroid syndromes are epigenetically distinct conditions.[44] HGPS, caused by an LMNA gene defect that manifests early in life, is also referred to as "progeria." Adult progeria, or Werner syndrome, is typically diagnosed based on distinctive clinical features and associated comorbidities. A key aspect of this condition is normal development during the 1st decade of life. The defining feature of the syndrome is a marked discrepancy between chronological age and physical appearance. Premature aging, characterized by gray hair and sclerodermatous skin changes, typically begins in the 20s to 30s and is associated with cataracts, diabetes mellitus, atherosclerosis, malignancies, and osteoporosis.[45]

Enhancing Healthcare Team Outcomes

Progeria, or HGPS, is an exceedingly rare, fatal genetic disorder that causes rapid aging in children. Patients with this condition appear healthy at birth but typically show signs of accelerated aging within the first 2 years of life. The mean life expectancy for children with HGPS is approximately 14.5 years, with mortality primarily resulting from myocardial infarction or cerebrovascular accident secondary to severe atherosclerosis.

Werner syndrome, or adult progeria, is also an exceedingly rare genetic disorder, making clinical encounters uncommon for most practitioners. The disorder involves systemic premature aging. Consequently, affected individuals require evaluation by an interprofessional team, including a social worker, therapist, cardiologist, dermatologist, endocrinologist, orthopedic surgeon, ophthalmologist, oncologist, and rheumatologist. The primary goal is to optimize quality of life and provide comprehensive supportive care.[46]

An interprofessional approach necessitates that each healthcare provider understands their role and contributes their expertise to the patient’s care plan. Effective interprofessional communication is critical for teamwork and the sharing of clinical information. Care coordination ensures appropriate diagnosis, treatment, and follow-up, reducing errors and improving patient outcomes. By integrating expertise, strategy, ethical practice, and coordinated communication, healthcare professionals can deliver patient-centered care and enhance outcomes for individuals with progeria.

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References

1.

Sarbacher CA, Halper JT. Connective Tissue and Age-Related Diseases. Subcell Biochem. 2019;91:281-310. [PubMed: 30888657]

2.

Isaev NK, Stelmashook EV, Genrikhs EE. Neurogenesis and brain aging. Rev Neurosci. 2019 Jul 26;30(6):573-580. [PubMed: 30763272]

3.

Kuk MU, Kim JW, Lee YS, Cho KA, Park JT, Park SC. Alleviation of Senescence via ATM Inhibition in Accelerated Aging Models. Mol Cells. 2019 Mar 31;42(3):210-217. [PMC free article: PMC6449716] [PubMed: 30726661]

4.

Sargolzaeiaval F, Zhang J, Schleit J, Lessel D, Kubisch C, Precioso DR, Sillence D, Hisama FM, Dorschner M, Martin GM, Oshima J. CTC1 mutations in a Brazilian family with progeroid features and recurrent bone fractures. Mol Genet Genomic Med. 2018 Nov;6(6):1148-1156. [PMC free article: PMC6305643] [PubMed: 30393977]

5.

Merideth MA, Gordon LB, Clauss S, Sachdev V, Smith AC, Perry MB, Brewer CC, Zalewski C, Kim HJ, Solomon B, Brooks BP, Gerber LH, Turner ML, Domingo DL, Hart TC, Graf J, Reynolds JC, Gropman A, Yanovski JA, Gerhard-Herman M, Collins FS, Nabel EG, Cannon RO, Gahl WA, Introne WJ. Phenotype and course of Hutchinson-Gilford progeria syndrome. N Engl J Med. 2008 Feb 07;358(6):592-604. [PMC free article: PMC2940940] [PubMed: 18256394]

6.

Lautrup S, Caponio D, Cheung HH, Piccoli C, Stevnsner T, Chan WY, Fang EF. Studying Werner syndrome to elucidate mechanisms and therapeutics of human aging and age-related diseases. Biogerontology. 2019 Jun;20(3):255-269. [PubMed: 30666569]

7.

Geng L, Liu Z, Zhang W, Li W, Wu Z, Wang W, Ren R, Su Y, Wang P, Sun L, Ju Z, Chan P, Song M, Qu J, Liu GH. Chemical screen identifies a geroprotective role of quercetin in premature aging. Protein Cell. 2019 Jun;10(6):417-435. [PMC free article: PMC6538594] [PubMed: 30069858]

8.

Oshima J, Kato H, Maezawa Y, Yokote K. RECQ helicase disease and related progeroid syndromes: RECQ2018 meeting. Mech Ageing Dev. 2018 Jul;173:80-83. [PMC free article: PMC6217841] [PubMed: 29752965]

9.

Goto M, Ishikawa Y, Sugimoto M, Furuichi Y. Werner syndrome: a changing pattern of clinical manifestations in Japan (1917~2008). Biosci Trends. 2013 Feb;7(1):13-22. [PubMed: 23524889]

10.

Koshizaka M, Maezawa Y, Maeda Y, Shoji M, Kato H, Kaneko H, Ishikawa T, Kinoshita D, Kobayashi K, Kawashima J, Sekiguchi A, Motegi SI, Nakagami H, Yamada Y, Tsukamoto S, Taniguchi A, Sugimoto K, Shoda Y, Hashimoto K, Yoshimura T, Suzuki D, Kuzuya M, Takemoto M, Yokote K. Time gap between the onset and diagnosis in Werner syndrome: a nationwide survey and the 2020 registry in Japan. Aging (Albany NY). 2020 Dec 29;12(24):24940-24956. [PMC free article: PMC7803551] [PubMed: 33373317]

11.

Hennekam RC. Hutchinson-Gilford progeria syndrome: review of the phenotype. Am J Med Genet A. 2006 Dec 01;140(23):2603-24. [PubMed: 16838330]

12.

Chen L, Lee L, Kudlow BA, Dos Santos HG, Sletvold O, Shafeghati Y, Botha EG, Garg A, Hanson NB, Martin GM, Mian IS, Kennedy BK, Oshima J. LMNA mutations in atypical Werner's syndrome. Lancet. 2003 Aug 09;362(9382):440-5. [PubMed: 12927431]

13.

Matsumoto N, Ohta Y, Deguchi K, Kishida M, Sato K, Shang J, Takemoto M, Hishikawa N, Yamashita T, Watanabe A, Yokote K, Takemoto M, Oshima J, Abe K. Characteristic Clinical Features of Werner Syndrome with a Novel Compound Heterozygous WRN Mutation c.1720+1G>A Plus c.3139-1G>C. Intern Med. 2019 Apr 01;58(7):1033-1036. [PMC free article: PMC6478977] [PubMed: 30568144]

14.

Davis T, Brook AJ, Rokicki MJ, Bagley MC, Kipling D. Evaluating the Role of p38 MAPK in the Accelerated Cell Senescence of Werner Syndrome Fibroblasts. Pharmaceuticals (Basel). 2016 Apr 28;9(2) [PMC free article: PMC4932541] [PubMed: 27136566]

15.

Friedrich K, Lee L, Leistritz DF, Nürnberg G, Saha B, Hisama FM, Eyman DK, Lessel D, Nürnberg P, Li C, Garcia-F-Villalta MJ, Kets CM, Schmidtke J, Cruz VT, Van den Akker PC, Boak J, Peter D, Compoginis G, Cefle K, Ozturk S, López N, Wessel T, Poot M, Ippel PF, Groff-Kellermann B, Hoehn H, Martin GM, Kubisch C, Oshima J. WRN mutations in Werner syndrome patients: genomic rearrangements, unusual intronic mutations and ethnic-specific alterations. Hum Genet. 2010 Jul;128(1):103-11. [PMC free article: PMC4686336] [PubMed: 20443122]

16.

Worman HJ, Ostlund C, Wang Y. Diseases of the nuclear envelope. Cold Spring Harb Perspect Biol. 2010 Feb;2(2):a000760. [PMC free article: PMC2828284] [PubMed: 20182615]

17.

GABR M, HASHEM N, HASHEM M, FAHMI A, SAFOUH M. Progeria, a pathologic study. J Pediatr. 1960 Jul;57:70-7. [PubMed: 13825821]

18.

Ingegnoli F, Crotti C. Nailfold scleroderma-like capillary abnormalities in Werner syndrome (adult progeria). Vasc Med. 2017 Jun;22(3):246-247. [PubMed: 28466674]

19.

Taniguchi A, Tanaka Y, Takemoto M, Kubota Y, Taniguchi T, Motegi SI, Nakagami H, Maezawa Y, Koshizaka M, Kato H, Tsukamoto K, Mori S, Kuzuya M, Yokote K. Management guideline for Werner syndrome 2020 8. Calcification in tendons associated with Werner syndrome. Geriatr Gerontol Int. 2021 Feb;21(2):163-165. [PubMed: 33260264]

20.

Lauper JM, Krause A, Vaughan TL, Monnat RJ. Spectrum and risk of neoplasia in Werner syndrome: a systematic review. PLoS One. 2013;8(4):e59709. [PMC free article: PMC3613408] [PubMed: 23573208]

21.

Mazereeuw-Hautier J, Wilson LC, Mohammed S, Smallwood D, Shackleton S, Atherton DJ, Harper JI. Hutchinson-Gilford progeria syndrome: clinical findings in three patients carrying the G608G mutation in LMNA and review of the literature. Br J Dermatol. 2007 Jun;156(6):1308-14. [PubMed: 17459035]

22.

Isaev NK, Genrikhs EE, Oborina MV, Stelmashook EV. Accelerated aging and aging process in the brain. Rev Neurosci. 2018 Mar 28;29(3):233-240. [PubMed: 29150992]

23.

Kusumesh R, Sinha BP, Ambastha A, Thakur SK. Management of cataract in Werner syndrome. Indian J Ophthalmol. 2018 Sep;66(9):1337-1339. [PMC free article: PMC6113835] [PubMed: 30127165]

24.

Compagnucci C, Bertini E. The Potential of iPSCs for the Treatment of Premature Aging Disorders. Int J Mol Sci. 2017 Nov 07;18(11) [PMC free article: PMC5713319] [PubMed: 29112121]

25.

Lohynská R, Pechačová Z, Mazaná E, Čejková J, Nováková-Jirešová A, Hornová J, Langová M. Radiotherapy and radiosensitivity syndromes in DNA repair gene mutations. Klin Onkol. 2022 Spring;35(2):119-127. [PubMed: 35459336]

26.

Massip L, Garand C, Paquet ER, Cogger VC, O'Reilly JN, Tworek L, Hatherell A, Taylor CG, Thorin E, Zahradka P, Le Couteur DG, Lebel M. Vitamin C restores healthy aging in a mouse model for Werner syndrome. FASEB J. 2010 Jan;24(1):158-72. [PMC free article: PMC3712979] [PubMed: 19741171]

27.

Kato H, Maezawa Y, Ouchi Y, Takayama N, Sone M, Sone K, Takada-Watanabe A, Tsujimura K, Koshizaka M, Nagasawa S, Saitoh H, Ohtaka M, Nakanishi M, Tahara H, Shimamoto A, Iwama A, Eto K, Yokote K. Generation of disease-specific and CRISPR/Cas9-mediated gene-corrected iPS cells from a patient with adult progeria Werner syndrome. Stem Cell Res. 2021 May;53:102360. [PubMed: 34087989]

28.

Fong LG, Frost D, Meta M, Qiao X, Yang SH, Coffinier C, Young SG. A protein farnesyltransferase inhibitor ameliorates disease in a mouse model of progeria. Science. 2006 Mar 17;311(5767):1621-3. [PubMed: 16484451]

29.

Gordon LB, Shappell H, Massaro J, D'Agostino RB, Brazier J, Campbell SE, Kleinman ME, Kieran MW. Association of Lonafarnib Treatment vs No Treatment With Mortality Rate in Patients With Hutchinson-Gilford Progeria Syndrome. JAMA. 2018 Apr 24;319(16):1687-1695. [PMC free article: PMC5933395] [PubMed: 29710166]

30.

DuBose AJ, Lichtenstein ST, Petrash NM, Erdos MR, Gordon LB, Collins FS. Everolimus rescues multiple cellular defects in laminopathy-patient fibroblasts. Proc Natl Acad Sci U S A. 2018 Apr 17;115(16):4206-4211. [PMC free article: PMC5910873] [PubMed: 29581305]

31.

Erdos MR, Cabral WA, Tavarez UL, Cao K, Gvozdenovic-Jeremic J, Narisu N, Zerfas PM, Crumley S, Boku Y, Hanson G, Mourich DV, Kole R, Eckhaus MA, Gordon LB, Collins FS. A targeted antisense therapeutic approach for Hutchinson-Gilford progeria syndrome. Nat Med. 2021 Mar;27(3):536-545. [PMC free article: PMC10158310] [PubMed: 33707773]

32.

Krüger P, Schroll M, Fenzl FQ, Hartinger R, Lederer EM, Görlach A, Gordon LB, Cavalcante P, Iacomino N, Rathkolb B, Pimentel JAA, Östereicher M, Spielmann N, Wolf CM, de Angelis MH, Djabali K. Baricitinib and Lonafarnib Synergistically Target Progerin and Inflammation, Improving Lifespan and Health in Progeria Mice. Int J Mol Sci. 2025 May 19;26(10) [PMC free article: PMC12112389] [PubMed: 40429989]

33.

Motegi SI, Takemoto M, Taniguchi T, Kubota Y, Taniguchi A, Nakagami H, Maezawa Y, Koshizaka M, Kato H, Mori S, Tsukamoto K, Kuzuya M, Yokote K. Management guideline for Werner syndrome 2020. 7. Skin ulcer associated with Werner syndrome: Dermatological treatment. Geriatr Gerontol Int. 2021 Feb;21(2):160-162. [PubMed: 33142357]

34.

Xu Y, Wu M, Fan Y, Zhang J, Xue D, Zhang M, Shao R, Cai L, Liao X, Zhang L, Zhang J. Nicotinamide Mononucleotide Alleviates Aging Defects in Hutchinson-Gilford Progeria Syndrome. FASEB J. 2025 Aug 15;39(15):e70875. [PubMed: 40742332]

35.

Joo EY, Park JS, Shin HT, Yoo M, Kim SJ, Lee JE, Choi GS. Mesenchymal Stem Cell Therapy for Hutchinson-Gilford Progeria: Improvements in Arterial Stiffness and Bone Mineral Density in a Single Case. Children (Basel). 2025 Apr 18;12(4) [PMC free article: PMC12025413] [PubMed: 40310235]

36.

Abutaleb NO, Gao XD, Bedapudi A, Choi L, Shores KL, Kennedy C, Duby JE, Cao K, Liu DR, Truskey GA. Adenine base editing rescues pathogenic phenotypes in tissue engineered vascular model of Hutchinson-Gilford progeria syndrome. APL Bioeng. 2025 Mar;9(1):016110. [PMC free article: PMC11871533] [PubMed: 40027545]

37.

Schindeler A, Chu J, Au-Yeung C, Kao HY, Ginn SL, O'Donohue AK. In vivo precision base editing to rescue mouse models of disease. Mol Ther Nucleic Acids. 2025 Sep 09;36(3):102622. [PMC free article: PMC12284509] [PubMed: 40704025]

38.

Greally JM, Boone LY, Lenkey SG, Wenger SL, Steele MW. Acrometageria: a spectrum of "premature aging" syndromes. Am J Med Genet. 1992 Oct 01;44(3):334-9. [PubMed: 1488981]

39.

Lebel M. Werner syndrome: genetic and molecular basis of a premature aging disorder. Cell Mol Life Sci. 2001 Jun;58(7):857-67. [PMC free article: PMC11337369] [PubMed: 11497235]

40.

Gordon LB, Campbell SE, Massaro JM, D'Agostino RB, Kleinman ME, Kieran MW, Moses MA. Survey of plasma proteins in children with progeria pre-therapy and on-therapy with lonafarnib. Pediatr Res. 2018 May;83(5):982-992. [PubMed: 29342131]

41.

Oshitari T, Kitahashi M, Mizuno S, Baba T, Kubota-Taniai M, Takemoto M, Yokote K, Yamamoto S, Roy S. Werner syndrome with refractory cystoid macular edema and immunohistochemical analysis of WRN proteins in human retinas. BMC Ophthalmol. 2014 Mar 12;14:31. [PMC free article: PMC3995689] [PubMed: 24620826]

42.

Lyons C, Gallagher D, McSwiney T, McElnea E, Kinsella F. The ophthalmic diagnosis and management of four siblings with Werner syndrome. Int Ophthalmol. 2019 Jun;39(6):1371-1378. [PubMed: 29705892]

43.

Sołek-Pastuszka J, Zagrodnik-Ułan E, Płonka T, Wylot M, Biernawska J, Bohatyrewicz R, Kos W, Zukowski M, Celewicz Z. Pregnancy complicated by Werner syndrome. Acta Obstet Gynecol Scand. 2011 Feb;90(2):201-2. [PubMed: 21241272]

44.

Martin GM, Poot M, Haaf T. Lessons for aging from Werner syndrome epigenetics. Aging (Albany NY). 2020 Feb 05;12(3):2022-2023. [PMC free article: PMC7041779] [PubMed: 32023552]

45.

Takada-Watanabe A, Yokote K, Takemoto M, Fujimoto M, Irisuna H, Honjo S, Futami K, Furuichi Y, Saito Y. A case of Werner syndrome without metabolic abnormality: implications for the early pathophysiology. Geriatr Gerontol Int. 2012 Jan;12(1):140-6. [PubMed: 22188495]

46.

Domínguez-Gerpe L, Araújo-Vilar D. Prematurely aged children: molecular alterations leading to Hutchinson-Gilford progeria and Werner syndromes. Curr Aging Sci. 2008 Dec;1(3):202-12. [PubMed: 20021393]

Disclosure: Haitham Saleh declares no relevant financial relationships with ineligible companies.

Disclosure: Christine Sickles declares no relevant financial relationships with ineligible companies.

Disclosure: Gary Gross declares no relevant financial relationships with ineligible companies.