Werner Syndrome

Adult progeria: classic Werner syndrome (WRN) and atypical Werner syndrome

Literature and regulatory information updated: 29 October 2026.

0. Reference Summary Table

The syndrome belongs both to the class of chromosomal instability and DNA repair disorders and to that of dermatological diseases, with the same entity, the same gene and the same OMIM and Orphanet codes [1, 2].

1. Introduction

1.1. Original description and first series

Werner syndrome is named after Otto Werner, who in 1904 described in his thesis a familial picture of premature ageing with cataracts and skin changes; this attribution reaches current reports through authors who cite the original thesis [11, 12]. During the 20th century the syndrome was recognised mainly in Japan: a literature review covering 1904 to 2008 estimated that about 75% of patients identified worldwide were of Japanese origin, which is why much of the clinical series was published in Japanese journals [13]. The review by Epstein, Martin, Schultz and Motulsky, published in 1966 in Medicine, systematised the symptoms, natural history, pathology, genetics and relationship of the syndrome to physiological ageing, and became the clinical reference for the following decades [14]; the authors studied, among others, a Japanese patient living in Seattle [7]. In 1981, Goto and colleagues gathered 42 Japanese families with 80 affected individuals, confirmed autosomal recessive inheritance and estimated the frequency of the syndrome in Japan at about 3 per million inhabitants [7].

1.2. From the international registry to cloning of the gene

In 1992, a linkage study in 21 Japanese families from 16 prefectures mapped the gene to chromosome 8, and in 1994 homozygosity mapping in 27 families of various origins, 26 of them consanguineous, placed it on 8p with LOD scores above 3 in both Japanese and Caucasian families [7]. The International Registry of Werner Syndrome was established in 1988 at the University of Washington (Seattle) to gather patients with a clinical diagnosis and enable positional cloning of the gene [5]. In 1996, Yu and colleagues identified WRN: the predicted protein had 1432 amino acids and similarity to DNA helicases, and four variants were described in patients, two splicing variants with exon skipping and two nonsense variants; one of the splicing variants, with a frameshift and truncated protein, was homozygous in 60% of the Japanese patients studied [15]. This discovery placed the syndrome among the disorders of the RecQ helicase family, alongside Bloom and Rothmund-Thomson syndromes [1, 16]. In 2006, the international registry described 50 distinct variants in 99 patients and revised the median age at death from 46–48 to 54 years [17]; in 2017, the joint update of the Seattle registry and the Japanese Werner Consortium (Chiba) compiled 83 pathogenic variants [5].

1.3. Atypical Werner syndrome

In 2003, Chen and colleagues found that 26 of 129 probands (20%) referred to the registry on clinical suspicion had a normal WRN coding region and classified them operationally as atypical Werner syndrome; in 4 of these 26 (15%) they found novel heterozygous LMNA missense variants (A57P, R133L in two patients and L140R), with abnormal nuclear morphology in fibroblasts and a more severe phenotype than the classic form, concluding that some cases of Werner syndrome are laminopathies [6]. Investigation of cases without WRN variants later identified progeroid syndromes caused by POLD1, SPRTN and SAMHD1; in 2017, the Seattle registry had 155 patients with WRN variants, 12 with LMNA variants, 8 with POLD1 variants and 60 with segmental progeroid phenotypes still without a cause [5].

1.4. Nomenclature and definition of entities

The term “adult progeria” has been kept as a synonym to distinguish Werner syndrome from Hutchinson-Gilford progeria, called “progeria of childhood” [1]. Orphanet defines Werner syndrome (ORPHA:902) as a rare inherited disorder of premature ageing with onset in the third decade and cardinal signs of bilateral cataracts, short stature, greying and thinning of hair, characteristic skin changes and early onset of other age-related diseases [2]. Atypical Werner syndrome (ORPHA:79474) is defined as a heterogeneous group of cases with a clinical diagnosis of Werner syndrome without WRN variants, with an aged appearance and age-related diseases at younger ages than in the general population [3]. Werner syndrome is considered the prototype of the “segmental” progerias, because it reproduces only some of the features of physiological ageing [18].

2. Molecular Genetics and Pathophysiology

2.1. The WRN gene and protein

WRN maps to 8p12 and encodes the “bifunctional 3'-5' exonuclease/ATP-dependent helicase WRN”, a nuclear protein of the RecQ family of DNA helicases [1, 19]. The MANE Select transcript is NM_000553.6, which encodes the protein NP_000544.2 [4]. The gene has 35 exons, with the coding sequence starting in the second, and the region most homologous to RecQ helicases lies in exons 14 to 21; the protein has 1432 amino acids and is organised, from N- to C-terminus, into a nuclease domain, a helicase domain, an RQC (RecQ C-terminal) domain, an HRDC (helicase and RNaseD C-terminal) domain and a nuclear localisation signal [20]. Point variants in the exonuclease domain abolish this activity without affecting the helicase, and the K577M variant abolishes the helicase without affecting the exonuclease, which demonstrated that the two activities are independent [20]. The protein combines an ATP-dependent 3'→5' helicase activity, common to the whole RecQ family, with a 3'→5' exonuclease activity in the N-terminal region, which is unique to WRN among the human RecQ helicases; it also has the RQC and HRDC domains and a C-terminal nuclear localisation signal [1, 18, 19]. It binds preferentially to alternative DNA structures, such as replication forks and Holliday junctions, unwinds G-quadruplexes, dissolves joint molecules formed during recombination or at stalled forks, relieves polymerase stalling at lesions and participates in double-strand break repair; replication protein A enhances strand displacement [19].

2.2. Disease mechanism

The mechanism is loss of function [1]. WRN is involved in DNA repair, recombination, replication and transcription, as well as replication-coupled repair; it unwinds or digests aberrant structures formed during DNA metabolism and regulates recombination intermediates [1]. It also participates in telomere maintenance, a function that may explain part of the phenotype [1, 18]. In WRN-deficient fibroblasts, replication-associated telomere loss on individual sister chromatids triggers chromosome fusions and breakage-fusion cycles, which telomerase reduces; forced expression of telomerase extends the replicative lifespan of these cells, which in culture reach about 20 population doublings, compared with about 60 in normal fibroblasts [7]. The cells are sensitive to the genotoxic agent 4-nitroquinoline 1-oxide (4NQO), but not to gamma radiation or hydrogen peroxide, and lymphoblastoid lines from heterozygous carriers, with about 50% of helicase activity, have intermediate sensitivity [7]. The truncated protein loses the nuclear localisation signal and is not imported into the nucleus, which helps to explain the similarity of phenotypes with different variants; about 80% of Japanese variants produce no detectable protein [7]. Patient fibroblasts share with those of individuals aged about 90 years transcriptional changes in 91% of the genes of known function with altered expression, a finding that supports the use of the syndrome as a model of ageing [7]. Mice with deletion of the helicase C-terminal domain do not age prematurely and have no increased susceptibility to genotoxic agents, but combined WRN and p53 deficiency increases mortality, which shows that the mouse model reproduces the human disease poorly [7]. The cellular deficiency manifests as chromosome breaks and genomic instability [19]; patient fibroblasts show variegated translocation mosaicism (karyotypic instability) and enter replicative senescence early [5, 21]. Werner syndrome cells do not show the increase in sister chromatid exchanges that characterises Bloom syndrome [1]. In the myeloid neoplasms associated with the syndrome, exome sequencing of 4 patients with myelodysplastic syndrome or acute myeloid leukaemia found somatic TP53 mutations in all, present at low allele frequencies more than a year before transformation, complex karyotypes involving TP53 and no prior chemotherapy, suggesting a tendency towards p53 insufficiency [22]. In patient cells, reduced nicotinamide adenine dinucleotide (NAD+), mitochondrial changes and increased basal autophagy, normalised in culture by rapamycin, have been described; these observations underpinned the trials of NAD+ precursors (section 7) [5, 23].

2.3. Inheritance, penetrance and carriers

Classic Werner syndrome has exclusively autosomal recessive inheritance and penetrance is considered complete [5]. The chronological order of manifestations is similar regardless of the variants [1]. Heterozygotes are asymptomatic and do not appear to be at increased risk of developing the disease, although there are no systematic clinical studies [1]; cultured cells from carriers show vulnerability to some genotoxic agents, with no epidemiological correlate studied [5]; the authors of that work, given a carrier prevalence that can reach 1/150 to 1/200 in some populations, raised the question of its public health relevance [7]. The atypical form associated with LMNA results from heterozygous variants (autosomal dominant), so two inheritance patterns, each linked to a different gene, coexist within the same clinical entity [3, 6].

2.4. Variant spectrum

More than 90 different pathogenic variants have been described [1]. In the 2017 update, the 83 known variants comprised 29 small insertions/deletions, 23 splicing variants, 23 nonsense variants, 3 genomic rearrangements and 5 missense variants [5]. Most alleles are null and produce no protein or produce a truncated protein without the nuclear localisation signal; some missense variants abolish helicase activity or destabilise the protein; there are deep intronic variants that create a new exon and multi-exon deletions/duplications [1, 17]. The following table presents the reference variants normalised in VariantValidator (GRCh38) and their ClinVar classification.

Sources: GeneReviews [1], 2017 update [5], VariantValidator [4], ClinVar [24] and the p.Arg834Cys study [25].

In a study of 89 Japanese patients published in 1997, 39.3% were homozygous for “mutation 4” (c.3139-1G>C) and 50% of the 178 chromosomes carried it [7]. In the Japanese series, three variant types (1, 4 and 6) account for 85.7% of alleles, and in the Japanese nicotinamide riboside trial 88.9% of participants had the type 4 variant [23]. Japanese nomenclature by mutation numbers (“Mut4”, “Mut25”) persists in recent publications and must be converted to Human Genome Variation Society (HGVS) nomenclature in the clinical report [26]. The 2017 update documented cases with confirmed variants on virtually every continent and mapped Japan and Sardinia as regions with founder variants with heterozygote frequencies close to 1/150 [5].

2.5. Genotype–phenotype correlations

The phenotype is indistinguishable between variant types and between geographical regions [5]. The exception described concerns thyroid carcinoma in Japanese patients: papillary carcinoma was associated with an N-terminal variant (c.1105C>T) and follicular carcinoma with a C-terminal variant (c.3139-1G>C), which contradicts the idea that all variants act as nulls by truncating the nuclear localisation signal [1, 5]. In a study of sex differences, abnormal voice was less frequent in homozygotes for c.3139-1G>C [27]. No other Mendelian phenotypes associated with germline WRN variants are known [1, 5]; a patient with microcephaly, developmental delay and diabetes, homozygous for p.Arg369Ter, was considered an isolated case probably explained by another cause [5].

2.6. WRN as a therapeutic target in oncology

Outside the context of the syndrome, WRN dependency in tumours with microsatellite instability (MSI) or mismatch repair deficiency (dMMR) has made it a synthetic lethality target: RO7589831 (VVD-133214), a covalent WRN inhibitor, was administered to 88 patients with advanced MSI/dMMR solid tumours in a phase 1 trial, with no maximum tolerated dose identified and with nausea (54.5%), diarrhoea (43.2%), fatigue (39.8%) and anaemia (37.5%) as the most frequent adverse effects [28]. These drugs inhibit the protein that patients with Werner syndrome already lack and have no therapeutic application in the syndrome.

3. Clinical Spectrum and Manifestations by System

3.1. Chronology and frequency of manifestations

Development is normal until the end of the first decade; the first sign, almost always recognised retrospectively, is the absence of the adolescent growth spurt [1]. From age 20, greying and loss of hair, hoarseness and scleroderma-like skin changes appear, and in the fourth decade bilateral cataracts, type 2 diabetes, hypogonadism, skin ulcers and osteoporosis appear; the median age at diagnosis lies between the end of the fourth and the fifth decade [1]. The Oxford Desk Reference gives a mean age at diagnosis of 39 years (standard deviation 7.7) and a mean age at first symptoms of 13 years [16]. The natural history is similar across ethnic groups: the median age at cataracts was 31 years and at diagnosis 37 years in both Japanese and non-Japanese patients [5].

The following table presents the frequency of signs in molecularly confirmed patients in the international registry (basis: Huang et al., 2006), according to GeneReviews.

Source: GeneReviews [1], based on Huang et al. [17].

In the 2020 Japanese registry (40 patients from 32 institutions, mean age at enrolment 50.1 ± 7.5 years), symptom onset occurred at 26.1 ± 9.5 years and diagnosis at 42.5 ± 8.6 years, an interval of about 16 years; almost all had hair changes and cataracts, about 90% had “bird-like” facies and a high-pitched voice, 67.5% impaired glucose tolerance or diabetes, 65.0% dyslipidaemia, 52.5% fatty liver, 15.0% peripheral arterial occlusive disease, 15.0% limb amputation, 20.0% malignant neoplasm and about 30% consanguineous parents [29]. Between the 2009 and 2017 surveys, intractable ulcers (87.5% to 67.5%), angina or infarction (14.8% to 2.5%) and neoplasms (42.4% to 20.0%) decreased, and recording of soft tissue calcification increased (76.7% to 87.5%), a change the authors relate to the inclusion of calcification among the main signs of the 2012 criteria [29]. These figures describe Japanese patients followed in hospitals and already treated, not the natural history without intervention.

3.2. Differences by sex and age

In a Japanese series assessed with the six cardinal signs of the national criteria, 54.2% of men and 21.2% of women had all the signs at diagnosis; at 40 years, 57.1% of men and no women had them all, and the high-pitched, hoarse voice was less frequent in women [27]. In 30 published patients diagnosed between 10 and 30 years of age, hair changes and cataracts occurred in 93.1%, short stature or low weight in 92.9%, abnormalities of glucose or lipid metabolism in 88.9% and skin changes in 84.6%, whereas soft tissue calcification (13.3%), bird-like facies (79.2%) and abnormal voice (73.9%) were less frequent than in the Japanese registry of patients with a mean age of 51 years (93.9%, 92.2% and 82.4%, respectively) [30].

3.3. Eyes

Cataracts are universal, bilateral and rapidly progressive, more often posterior subcapsular than nuclear, with a median onset close to 31 years [1]. Surgery has frequent complications: wound dehiscence, peripheral anterior synechiae, epiretinal membranes and cystoid macular oedema [1]. In a series of 18 eyes of 9 patients, cataract surgery was complicated by wound dehiscence in 10 and corneal endothelial decompensation in 8, and the author proposed small incisions and avoiding topical and systemic corticosteroids [7]. Optical coherence tomography shows thinning of the retina and choroid, and diabetes adds the risk of retinopathy [1]. A recent case with juvenile cataracts as the first sign also had plateau iris and pachychoroid features, and the authors advocate including the syndrome in the work-up of early bilateral cataracts [26]. Isolated congenital, infantile or juvenile cataracts are not typical: the age at onset is usually when greying and skin changes are already present [1]. The 2012 Japanese guideline records a prevalence of 100% in Japanese patients, with a mean age at onset of 31.2 ± 8.5 years, compared with a prevalence below 10% at around 50 years in the general Japanese population; because progression is rapid, the nucleus hardens and phacoemulsification becomes technically more difficult [31]. The same guideline recommends investigating non-age-related causes of cataract (uveitis, trauma, corticosteroids, radiation, atopic dermatitis, tetany, myotonic dystrophy, diabetes, rubella and drugs such as chlorpromazine, busulfan or penicillamine) and considering Werner syndrome in the presence of bilateral nuclear cataracts in a young adult [31].

3.4. Hair, face, voice and teeth

Scalp hair greys and thins from age 20 [1]. The face is characterised by a narrow nasal bridge and tip, hypoplastic alae nasi, loss of subcutaneous fat, thin vermilion of the lips, micrognathia and retrognathia, the appearance described as “bird-like” facies; the permanent dentition is lost early in the third or fourth decade [1, 29]. The voice becomes high-pitched, weak or hoarse [16]; in one reported case, the dysphonia corresponded to paralysis of the right vocal cord and partial paralysis of the left [11].

3.5. Skin, soft tissues and ulcers

Scleroderma-like changes begin in the decade following puberty, first on the face and extremities, with tight, shiny skin due to atrophy of the epidermis, adipose tissue and muscle; ulcers and calcification of soft tissues and of the Achilles or elbow tendons follow at the end of the third and in the fourth decade [1]. Deep, chronic ulcers around the ankles (Achilles tendon, medial and lateral malleoli) are characteristic and one of the main causes of morbidity [1]. In Japanese reports published between January 1996 and October 2016, ulcers were documented in 27 of 63 patients described in Japanese (43%) and in 22 of 56 patients described in English by Japanese authors (40%), mainly on the distal third of the leg, often associated with plantar calluses; the two series may share patients [32, 33]. By site, the Japanese- and English-language reports recorded ulcers on the elbow (11 and 1), heel (6 and 4), Achilles tendon (4 and 5), malleoli (2 and 6), sole (4 and 3), toes (4 and 3), leg (2 and 4) and knee (1 and 2); abnormal glucose metabolism accompanied 43% and 39% of patients, whereas hypertension (5% and 2%) and lower limb ischaemia (2% and 4%) were rare, which distinguishes these ulcers from diabetic and ischaemic foot ulcers [33]. Sclerosis and poikiloderma are most marked on the distal third of the leg and the foot, with inelastic, shiny skin, ankle stiffness, flat foot and toe deformities that can progress quickly; squamous cell carcinoma, acral lentiginous melanoma of the sole and an osteosarcoma of the calcaneus under a heel ulcer have been described as causes of ulceration [33]. Contributors to chronicity include thinning and sclerosis of the skin, fat loss, reduced blood flow, calcification and excess pressure from osteoarticular deformities, and many ulcers arise from hyperkeratotic lesions at pressure points [34]. In the Japanese registry, 66.7% of 51 patients (mean age 48.8 years) had ulcers, and age and systolic blood pressure were independent risk factors [35]. Plain radiography showed Achilles tendon calcification in 70 of 92 patients (76.1%) in the 2010 national survey, compared with 19 of 2151 feet (0.88%) of orthopaedic patients without the syndrome, with one to four masses of 9.7 to 63.2 mm [36]. In an Irish Traveller family with four affected siblings, the “Werner foot” combined painful peripheral neuropathy, chronic ulceration, osteomyelitis and acral melanoma, with a course different from that of the diabetic foot [37].

3.6. Metabolism: diabetes, dyslipidaemia, liver and lipodystrophy

Type 2 diabetes increases from the fourth decade and contributes to atherosclerosis, retinopathy and ankle ulcers [1]. The Japanese consensus classifies it as diabetes associated with genetic syndromes, characterised by visceral fat accumulation and marked insulin resistance despite a low body mass index [38]. Hyperlipidaemia occurs in up to 85% of patients [1]. The systematic review of the 2020 Japanese guideline (119 patients in 98 reports from 1996–2016, of whom 44 had lipid or steatosis data, mean age 45.6 years) found dyslipidaemia in 35 of 41 patients with information (85.4%); among the 25 with laboratory values, there was hypertriglyceridaemia in 76%, raised LDL or non-HDL cholesterol in 68% and low HDL cholesterol in 32% [33, 39]. Of the 33 dyslipidaemic patients with blood glucose information, 31 (93.9%) had diabetes, and the mean body mass index of patients with hypertriglyceridaemia was 18.2 kg/m², i.e. dyslipidaemia occurs without obesity [33]. Hepatic steatosis follows the same pattern: in the 12 reports with steatosis, the mean body mass index was 18.8 kg/m² (maximum 22.6); in the Chiba series, 4 of 9 patients without neoplasia (44%) had a liver/spleen attenuation ratio below 1.0, all lean, and this ratio correlated with HDL cholesterol (positively) and with triglycerides (negatively), but not with aminotransferases [33]. One of the 44 patients in the review had hepatocellular carcinoma at 40 years, with negative hepatitis B and C serology and autoimmune markers, which leaves the role of steatosis open [33]. In the 2010 national survey (196 patients), diabetes was present in 55.7% and impaired glucose tolerance in 6.5%, values similar to those of the 1984 survey, in which 50 of 90 patients undergoing an oral glucose tolerance test (55.6%) had diabetes; fasting hyperinsulinaemia and an excessive insulin response in the test were common and insufficient insulin secretion was rare [31, 33]. The mean age at onset of diabetes in Japanese reports rose from 33.7 years (1966) to 39.3 years (2008) [33]. In a series of 9 patients, the 4 with diabetes had more visceral fat (142.6 ± 40.1 versus 56.1 ± 43.6 cm²) and a higher body mass index (18.7 ± 1.3 versus 16.2 ± 1.2 kg/m²) than the 5 without diabetes, with no difference in muscle mass [33]. Limb lipodystrophy with preserved visceral fat is common, and some patients are initially diagnosed with partial lipodystrophy or type 2 diabetes [12, 40]. In the comparison of 48 patients from the Japanese registry with 101 patients with insulin-resistant type 2 diabetes, hepatic steatosis and fibrosis indices were lower in Werner syndrome, and the liver/spleen attenuation ratio on computed tomography was below 0.9 (criterion for steatosis) in 5 of 20 patients (25%) [41].

3.7. Muscle, bone and sarcopenia

Osteoporosis preferentially affects the long bones, unlike normal ageing, in which vertebral fractures predominate, and acro-osteolysis of the distal phalanges is common [1]. Japanese reports predating densitometry described osteoporosis in 41% of 153 patients and in almost all patients over 40 years of age in a series of 24 [33, 42]. In 10 Chiba patients with a molecular diagnosis (40–60 years), femoral neck bone mineral density was in the osteoporotic range (T-score ≤ −2.5 or ≤70% of the young adult mean) in 6, whereas lumbar spine density was so in only 1 and spinal radiographs of 6 patients showed no fragility fractures [33]. Iliac crest biopsy of a 43-year-old woman with multiple vertebral fractures showed scant osteoid and absent osteoblasts, with low insulin-like growth factor 1 (IGF-1) and normal growth hormone, suggesting reduced bone formation with preserved resorption; joint contracture and foot ulcers, which limit weight-bearing, contribute to greater severity in the lower limbs [33]. Reduced muscle mass is almost constant: in the Japanese registry, the skeletal muscle mass index (4.5 ± 0.9 kg/m² in men and 4.1 ± 0.6 kg/m² in women), grip strength and gait speed (0.8 ± 0.6 m/s) met the Asian criteria for sarcopenia [29]; in a series of 7 patients, only one man who kept up resistance exercise had normal appendicular muscle mass [43]. In the series of 9 patients (39–60 years) analysed by the 2020 guideline using the Asian Working Group for Sarcopenia criteria (appendicular muscle mass index by DXA <7.0 kg/m² in men and <5.4 kg/m² in women; grip <26 kg and <18 kg), all had a muscle index below the threshold, 2 of the 4 men had grip strength above the threshold, and muscle loss preceded visceral fat accumulation [33, 43]. The guideline notes that plantar ulcers and hand deformities often prevent measurement of gait speed and grip strength, which makes the usual sarcopenia criteria difficult to apply [33].

3.8. Gonads and fertility

Fertility declines soon after sexual maturation, with testicular atrophy and probably accelerated loss of ovarian follicles; early menopause and multiple miscarriages are common, but there are successful pregnancies and men who have fathered children, usually at younger ages than average [1].

3.9. Cardiovascular system

Coronary, cerebral and peripheral atherosclerosis is a major cause of morbidity and mortality, and peripheral vascular disease contributes to the ulcers; early-onset hypertension is not typical [1]. In the most recent Japanese series, none of the 14 deaths that occurred between 2011 and 2020 was attributed to atherosclerotic disease, which the authors relate to the treatment of diabetes and dyslipidaemia [44, 45]. Aortic valve sclerosis and a sigmoid septum have been described in a 34-year-old woman [11].

3.10. Kidney

In the Japanese registry followed for three years (51 patients), the creatinine-based estimated glomerular filtration rate fell from 74.8 to 63.4 mL/min/1.73 m² between the first and fourth year, and in the first year the creatinine-based estimate (98.3) was higher than the cystatin C-based estimate (83.2 mL/min/1.73 m²), a divergence consistent with the low muscle mass [46].

3.11. Nervous system

Cerebral involvement is controversial: stroke due to cerebrovascular disease can occur, but there is no particular susceptibility to Alzheimer's disease and cognitive decline is not typical; in a 70-year-old patient with dementia, MRI and autopsy showed no atrophy or Alzheimer pathology, but an occipital meningioma [1].

3.12. Neoplasms

Cancer risk is increased and age at diagnosis is lower than in the general population, with a predominance of non-epithelial cancers [1]. A 1996 review of 124 Japanese and 34 non-Japanese reports (1939–1995) found, among the Japanese, 127 cancers, 14 benign meningiomas and 5 myeloid disorders and, among the non-Japanese, 30 cancers, 7 meningiomas and 2 myeloid disorders; the ratio of epithelial to non-epithelial cancers was about 1:1 in both groups, compared with the usual 10:1, with an excess of soft tissue sarcomas, osteosarcomas, myeloid disorders and meningiomas [7]. A 47-year-old woman misdiagnosed with systemic sclerosis with metastatic calcification for 12 years developed a juxta-articular osteosarcoma of the distal femur that required amputation [7]. A systematic review of 189 patients with 248 neoplasms showed that two-thirds were thyroid tumours, melanoma, meningioma, soft tissue sarcomas, leukaemia and preleukaemic states, and primary bone tumours; in patients living in Japan, the standardised incidence ratio ranged from 53.5 (95% confidence interval [95% CI] 24.5–101.6) for cutaneous melanoma to 8.9 (95% CI 4.9–15.0) for thyroid tumours, and was significant for the six most frequent neoplasms except leukaemia [47]. The 2024 Japanese recommendations give the following median ages at diagnosis: meningioma 39 years (22–67), thyroid 40 (20–57), soft tissue sarcoma 43 (26–58), melanoma 44 (34–59), leukaemia 45 (28–62) and osteosarcoma 49 (20–57); the ratio of epithelial to non-epithelial tumours is 1:1.5, compared with 10:1 in the general population, and multiple primary tumours are more frequent [45]. Melanoma is mainly acral lentiginous or mucosal (nasal mucosa, palms and soles) [1, 45]. The mean age at cancer onset rose from 36.9 years in 1966 to 49.7 years in 2023, and epithelial cancers of the thyroid, lung and breast have increased (epithelial:non-epithelial ratio of 1.6:1 in recent series), in step with increased survival [45, 46].

3.13. Life expectancy and causes of death

Myocardial infarction and cancer have historically been the most frequent causes of death, with a mean age at death of 54 years and a median of 53 years in Japanese patients [1]. In a 2020 Japanese survey (123 living patients), the 14 deaths that occurred between 2011 and 2020 took place at a mean age of 59.0 ± 8.9 years, and the most frequent cause was non-epithelial tumours (8 of the 14) [44].

3.14. Atypical Werner syndrome

Patients with LMNA variants have a more severe phenotype and earlier onset than patients with WRN variants [6]. In the original series, a Portuguese woman with the p.Arg133Leu variant presented at 9 years with short stature, sclerodermatous skin and greying and thinning of hair, developed type 2 diabetes at 23 years and had hypogonadism, osteoporosis and voice change; an African American woman with the same variant was diagnosed at 18 years; a Norwegian man with p.Leu140Arg had onset at 14 years with cataracts, sclerodermatous skin, grey hair, hypogonadism, osteoporosis, soft tissue calcification, premature atherosclerosis and aortic stenosis and regurgitation, and died at 36 years; an Iranian woman with de novo p.Ala57Pro had onset in early adolescence and dilated cardiomyopathy [8]. Hegele proposed that the patients with p.Ala57Pro and p.Leu140Arg rather had late-onset Hutchinson-Gilford progeria, which illustrates the blurred boundary between these laminopathies [8]. Fat distribution in the two women with p.Arg133Leu differed: distal lipodystrophy with preserved truncal fat in one and generalised loss of subcutaneous and intra-abdominal fat in the other [8]. A 19-year-old Chinese woman with the LMNA variant p.Leu140Gln (c.419T>A), inherited from her father, had progeroid facies, greying and thinning of hair, thin skin on the hands and feet, limb lipoatrophy, short stature, incomplete breast development, severe insulin-resistant diabetes, hyperlipidaemia, fatty liver and polycystic ovarian morphology [9].

4. Clinical Recognition and Red Flags

4.1. When to suspect

The syndrome should be considered in an adolescent or young adult who had no pubertal growth spurt and who, from the third decade, develops greying and thinning of hair, bilateral cataracts, scleroderma-like skin changes of the extremities and short stature, particularly if there are affected siblings or parental consanguinity; the absence of a family history does not exclude the diagnosis [1]. The specialties that see these patients first vary: in the Japanese survey, dermatology and plastic surgery reported the highest proportion of patients per department (7.9% and 7.7%), because of foot and ankle ulcers, whereas ophthalmologists, who operate on the cataracts in the third or fourth decade, rarely raised the possibility [29]. Common settings for suspicion are the following:

Women have fewer cardinal signs, and later, than men, so clinical suspicion in women should lead to genetic testing earlier [27]. Below 30 years of age, soft tissue calcification, bird-like facies and abnormal voice are insensitive; the Japanese group proposes testing WRN in patients under 30 years with bilateral cataracts and progeroid hair changes and at least one of three findings: short stature or low weight, abnormal glucose or lipid metabolism, or atrophy or hardening of the skin [30].

4.2. Red flags in diagnosed patients

In a patient already diagnosed, the following warrant rapid assessment: new-onset seizures, focal deficits, visual field changes, diplopia or headache (meningioma); thyroid nodule; new pigmented lesion on the soles, nail beds or nasal mucosa (acral or mucosal melanoma); soft tissue mass or bone pain (sarcoma, osteosarcoma); blood count abnormalities (myelodysplastic syndrome, leukaemia); sudden deterioration in glycaemic control (pancreatic cancer); an ulcer with an atypical course, which should be assessed for associated neoplasia; and angina or claudication [1, 45]. An ulcer with exudate, necrosis or cellulitis requires debridement and infection control, because it can progress to osteomyelitis and amputation; 15% of patients in the Japanese registry had a limb amputation [29, 34, 37].

4.3. Newborn screening

There is no newborn screening, nor any justification for it, because the disease does not manifest in childhood and there is no presymptomatic intervention of proven benefit [1].

5. Diagnosis: Criteria, Testing, and Algorithms

5.1. Clinical criteria of the international registry

The criteria used by the international registry and by GeneReviews rest on four cardinal signs and ten further signs [1]:

The molecular diagnosis is established by biallelic pathogenic or likely pathogenic WRN variants; two variants of uncertain significance, or one pathogenic variant and one of uncertain significance, neither confirm nor exclude the diagnosis [1].

5.2. The 2012 Japanese criteria

The criteria revised by the Japanese group on the basis of the 2009–2011 national survey regarded as cardinal the signs with an incidence above 90%, added genetic testing and Achilles tendon calcification, and dropped demanding requirements such as measurement of urinary hyaluronic acid [31, 48]. The survey sent 6921 questionnaires to departments of hospitals with 200 or more beds, identified 396 patients and obtained clinical data on 196; in these, greying or baldness was present in 98.2%, cataracts in 100% (bilateral in 96%), skin atrophy in 97.5%, ulcers in 87.6%, calluses in 92.4%, flat foot in 90.6%, “bird-like” facies in 95.5%, voice change in 87.5%, abnormal glucose metabolism in 62.2%, dyslipidaemia in 47.0%, malignant neoplasms in 29.7%, consanguinity in 43.0% and Achilles tendon calcification in 76% of the 92 patients radiographed [31]. The criteria were adopted by the Japanese Ministry of Health, Labour and Welfare for designated intractable disease No. 191, whose revised version (due to apply from April 2027) keeps the same categories and adds bilateral “flame-like” Achilles tendon calcification as an imaging finding, the differential diagnosis with Hutchinson-Gilford progeria, Rothmund-Thomson syndrome and Bloom syndrome, and the requirement for a pathogenic WRN variant on genetic testing [49]. They are the only criteria whose accuracy has been validated by genetic testing, with positive and negative predictive values of 100% in men and women in a Japanese series [27, 30]. Their structure is as follows:

Sources: Takemoto et al. [48], Japanese version of the criteria in the 2012 guideline [31], ministerial document for designated intractable disease No. 191 [49] and Sato et al. [30].

The 2012 Japanese guideline explains the changes from the 1984 guide: the old cardinal signs (progeroid appearance, cataracts and skin changes) were subjective and poorly specific, urinary hyaluronic acid had no reference value (it had been measured in only 14 of the 196 patients) and reduced fibroblast proliferative capacity is not feasible in clinical practice [31]. The authors acknowledge that the survey only measured the frequency of signs in patients, without a comparison group, so the sensitivity and specificity of each sign could not be calculated and the categories resulted from group consensus; they recommend soft tissue radiography of the Achilles tendon in all suspected cases, with the caveat that calcification may be absent or subtle in young patients [31]. The practical differences from the international criteria are the inclusion of soft tissue calcification, facies and voice among the cardinal signs and the move of short stature to the secondary signs [1, 48]. The same ministerial document defines a five-grade severity classification, used for financial support (grade 3 or higher): grade 1, skin sclerosis or atrophy in one limb with minimal impact; grade 2, mild limitation without relevant gait impairment; grade 3, independence preserved but restricted by pain from calcifications or ulcers; grade 4, walking only with assistance and partial dependence, including amputation for an intractable ulcer; grade 5, bedridden or wheelchair-bound, or with a malignant neoplasm [49]. The number of patients with a support certificate was 102 in fiscal year 2021 [49].

5.3. Molecular testing

GeneReviews proposes two routes: targeted testing (WRN sequencing or a multigene panel including the differential-diagnosis genes), followed by deletion/duplication analysis (copy number variants, CNV) when sequencing identifies zero or one variant; or, when the phenotype is atypical and the syndrome has not been considered, exome or genome sequencing [1].

Sources: GeneReviews [1], international registry [50].

The proportion of variants detectable by each method is not equivalent to the clinical sensitivity of the test: in the international registry, 179 of 188 patients with classic Werner syndrome (95.2%) had biallelic variants identified by conventional methods, and in the remaining 9 the second variant only emerged with long-read sequencing or RNA studies [50]. In a patient with one variant and a typical picture, a negative test for the second allele does not exclude the diagnosis [1, 50]. The report should state the gene, the versioned transcript (NM_000553.6), the HGVS nomenclature of each variant, the zygosity, the phase when known and the ACMG/AMP (American College of Medical Genetics and Genomics/Association for Molecular Pathology) class [1, 4]. Apparent homozygosity requires testing of both parents, because it may correspond to a deletion of the other allele or to uniparental isodisomy [1]. Novel homozygous missense variants, such as p.(Ala616Pro) in the Chinese case or p.(Leu619Arg) described in a young woman with CIDEC-related partial lipodystrophy, call for caution until functional or protein studies are available [12, 51]. The large number of WRN variants of uncertain significance in ClinVar reflects its inclusion in hereditary cancer panels and not the frequency of the disease [19]. The p.(Arg834Cys) variant, frequent in Latin American populations, is benign for the syndrome [24, 25].

5.4. Ancillary investigations in the diagnostic evaluation

Ankle radiography is a simple supporting investigation: Achilles tendon calcification, present in 76.1% of patients and in 0.88% of feet of orthopaedic controls, has been proposed as a diagnostic criterion [36]. The 2020 guideline defines three radiographic patterns that, on their own, should raise suspicion of the calcification characteristic of the syndrome: a single segmental calcification of 2 cm or more without continuity with the calcaneus; two or more segmental calcifications smaller than 2 cm without continuity with the calcaneus; and an extensive “flame-like” calcification in the body of the tendon [33, 36]. The spur at the tendon insertion on the calcaneus, which results from endochondral ossification, and the intratendinous calcifications of tendinopathy or after rupture are different and should not be confused with this finding [33]. Ophthalmological assessment with slit lamp and optical coherence tomography, densitometry, assessment of glucose and lipid metabolism and gonadal assessment complete the characterisation (section 11) [1]. Renal function should also be estimated using cystatin C, because creatinine overestimates glomerular filtration in patients with sarcopenia [46]. In atypical Werner syndrome, the investigation includes sequencing of LMNA, POLD1 and other progeroid genes by panel or exome [1, 5].

5.5. Practical algorithm

5.6. Prenatal and preimplantation diagnosis

Once the pathogenic variants have been identified in the family, prenatal diagnosis and preimplantation genetic testing are technically possible; their use in an adult-onset disease is a personal decision that should be discussed before pregnancy [1].

6. Differential Diagnosis

The differential diagnosis depends on the manifestation that brings the patient to the clinic and on the age at onset [1]. The following table brings together the entities from GeneReviews and the dysmorphology sources consulted.

Sources: GeneReviews [1], OMIM [52, 53], Smith's [54, 55], Oxford Desk Reference [16], MDPL [56], atypical Werner syndrome [5, 6].

6.1. Atypical Werner syndrome and laminopathies

The atypical form comprises patients with a clinical diagnosis of Werner syndrome without WRN variants; heterozygous LMNA variants were found in about 15% of this registry subgroup [1, 6]. The practical distinction rests on earlier onset, faster progression, normal WRN protein and the molecular result [1]. The Oxford Desk Reference lists atypical Werner syndrome among the LMNA allelic disorders, alongside autosomal dominant Emery-Dreifuss muscular dystrophy, dilated cardiomyopathy 1A, limb-girdle dystrophy 1B, familial partial lipodystrophy, Charcot-Marie-Tooth disease type 2, mandibuloacral dysplasia and Hutchinson-Gilford progeria, with overlapping phenotypes, and notes that in patients with laminopathy-related muscle disease the risk of cardiac conduction disturbances and sudden death is high [57]. The spectrum of laminopathies, including Hutchinson-Gilford progeria, mandibuloacral dysplasia and familial partial lipodystrophy type 2, enters the differential diagnosis.

6.2. Hutchinson-Gilford progeria and other childhood progerias

In Hutchinson-Gilford progeria, growth failure begins between 6 and 18 months, with alopecia and fat loss in childhood, and senescence progresses faster; in Werner syndrome, the sclerodermatous changes, cataracts and subcutaneous calcifications only appear after puberty [1, 54]. Mandibuloacral dysplasia begins between 3 and 14 years and is distinguished by mandibular hypoplasia, osteolysis of the clavicles and distal phalanges, and type A lipodystrophy [55]. MDPL syndrome shares lipodystrophy, atrophic skin, plantar calluses and, in one recent case, soft tissue calcification with a refractory ulcer, but differs by sensorineural deafness, absence of cataracts, preserved hair and the absence of a known cancer predisposition [1, 56].

6.3. RecQ family genomic instability syndromes and others

Bloom and Rothmund-Thomson syndromes, also caused by RecQ helicases, enter the differential diagnosis when the presentation is oncological, but they begin in childhood; Werner syndrome cells do not have the increase in sister chromatid exchanges that characterises Bloom syndrome [1]. Bloom syndrome, the Cockayne spectrum and Rothmund-Thomson syndrome, with the other RECQL4 disorders, enter the differential diagnosis. Li-Fraumeni syndrome can produce sarcomas and other non-epithelial cancers at a similar age, but does not cause juvenile cataracts or premature ageing [1].

6.4. Disorders mimicking the diabetes and scleroderma of Werner syndrome

The diabetes of Werner syndrome is often classified as type 1 or type 2: in the Chinese case described in section 10, 11 years passed between the diagnosis of type 2 diabetes and the genetic diagnosis, and the lipoatrophy first led to a diagnosis of diabetes associated with familial partial lipodystrophy [12]. The coexistence of CIDEC-related partial lipodystrophy with a novel homozygous WRN missense variant and papillary thyroid carcinoma at 17 years shows how difficult the interpretation of WRN can be outside the classic picture [51]. Sclerodermatous skin changes can raise suspicion of systemic sclerosis, but the association with cataracts, grey hair and short stature and the absence of the findings specific to systemic sclerosis point towards Werner syndrome [1].

7. Treatment and Risk Management Strategies

7.1. Evidence base and reference documents

There are no evidence-based guidelines for Werner syndrome and no guidelines from European or North American scientific societies [1, 19]. There are three reference documents: GeneReviews (March 2026 update), which covers initial evaluation, treatment, surveillance and agents to avoid [1]; the Japanese consensus “Management guideline for Werner syndrome 2020”, published in 2021 in eight parts (dyslipidaemia and fatty liver, sarcopenia, diabetes, osteoporosis, infection, ulcers with surgical and non-surgical treatment, dermatological treatment of ulcers, and tendon calcification), based on reviews of Japanese reports and institutional series, with a Japanese-language version published by the same group and organised as clinical questions [10, 32–34, 36, 38, 39, 42, 43, 58]; and the 2024 Japanese cancer screening recommendations [45]. The 2020 guideline updates the 2012 Japanese guideline, which contained the diagnostic criteria and chapters on cataracts, atherosclerosis, ulcer pain, neoplasms and genetic counselling that the 2020 edition did not revise [31, 33]. The answers in the 2020 guideline are based on case reports (systematic review of the Japanese and English literature from 1996–2016) and on series of 9 to 12 Chiba patients; there are no trials or formal grades of recommendation [33]. There is no approved therapy that cures the disease [1]. Management is multidisciplinary and by manifestation, and GeneReviews recommends shared decision-making that takes into account risk factors and personal and family history [1].

7.2. Initial evaluation after diagnosis

7.3. Treatment by manifestation

7.4. Skin ulcers: prevention and treatment

Ulcers are the manifestation that most impairs quality of life and the main reason for amputation [29, 32]. The Japanese consensus regards the callus as a therapeutic target for ulcer prevention and recommends careful assessment of weight-bearing ulcers and calluses before any surgery, because they determine pain and gait [32]. Dermatological treatment follows the principles for chronic ulcers: topical keratolytic for the hyperkeratosis surrounding the ulcer; cleansing with saline, warm water or antiseptic and surgical debridement, with scalpel or scissors, of necrotic or infected tissue; topical agents that soften necrotic tissue with moisture control; granulation-promoting agents once necrosis without infection has been removed; dressings that maintain a moist environment; and surgery when conservative treatment fails [34]. Current wound-healing techniques make it possible to close, with minimally invasive surgery, ulcers that previously required extensive interventions [32]. In the Japanese registry, patients without ulcers more often received metformin and pioglitazone, and pioglitazone was associated with a lower frequency of ulcers; this is a cross-sectional analysis of 51 patients, which does not prove a preventive effect [35]. Apart from bosentan, none of the following measures is targeted therapy for the disease; they are adaptations of the general principles of chronic wound management described by the 2020 Japanese guideline [33].

Assessment of each ulcer records site, depth, exudate, size, inflammation or infection, granulation tissue, necrosis and pocketing, according to the items of the DESIGN-R® scale of the Japanese Society of Pressure Ulcers; in Werner syndrome the ulcer easily reaches bone and joint, so cortical penetration suggests osteomyelitis and opening of the capsule suggests septic arthritis [33]. Plain radiography and computed tomography document the shape of the foot and the state of each bone and are repeated because the deformities progress quickly; magnetic resonance imaging is indicated when osteomyelitis is suspected; and vascular assessment is mandatory, because lower limb ischaemia may require revascularisation [33]. An ulcer that does not progress as expected should raise suspicion of neoplasia (squamous cell carcinoma, acral melanoma, osteosarcoma) and prompt referral to dermatology [33, 34].

Dermatological treatment separates two situations [33, 34]. With infection or necrosis: cleansing with saline or warm water, surgical debridement with scalpel or scissors, antiseptics (povidone-iodine, chlorhexidine, benzalkonium chloride) when infection sets in, chemical debridement (cadexomer iodine, povidone-iodine gel, bromelain) when surgical debridement is not possible, silver sulfadiazine for dry wounds and absorbent agents (cadexomer iodine, sugar with povidone-iodine) for exudative ones; occlusive dressings should be avoided at this stage because they worsen infection. Without infection or necrosis: promoters of granulation and epithelialisation (alprostadil and bucladesine ointments, among others available in Japan), moist-environment dressings chosen according to exudate (hydrocolloid if scant; alginate, chitin, hydrofibre, hydropolymer or polyurethane foam if abundant) and keratolytics (salicylic petroleum jelly, urea) for peri-ulcer hyperkeratosis and for corns and calluses [33]. Basic fibroblast growth factor (bFGF, trafermin spray, marketed in Japan) is effective for granulation, but the guideline urges caution because of the frequency of neoplasms in these ulcers [33]. Hyperbaric oxygen and negative pressure may promote healing; skin grafts alone often fail and artificial dermis or flaps are generally more useful, bearing in mind that debridement can enlarge the ulcer because of the low proliferative capacity of fibroblasts [33].

Wound bed preparation precedes surgery and determines its outcome [32, 33]. Frequent debridement and curettage remove the yellowish-white tissue that may contain biofilm in critical colonisation, recognised by the NERDS signs (non-healing wound, exudate in abundance, red and bleeding granulation, debris, smell), and allow samples to be taken for culture, including intramedullary pus when osteomyelitis is found [33]. Pain is the main obstacle: unlike the diabetic ulcer, sensation is generally preserved, local infiltration is painful and diffuses poorly in sclerosed tissue, and the guideline proposes anaesthetic block at a site of softer skin, such as the mid-leg (for example, sural nerve block) [33]. Cleansing is useful and showering the foot should not be prohibited merely because an ulcer is present, observing standard precautions because hospital taps, showers and baths may be contaminated with multidrug-resistant bacteria [33]. Negative pressure therapy is not applied to infected wounds and requires foam cut to size, because thin skin and the proximity of bone facilitate pressure injuries; in joint infection it may be combined with continuous irrigation [33].

The callus is treated as the precursor stage of the ulcer: a Chiba patient with an untreated heel callus, off-the-shelf footwear and intense activity progressed to cortical breach and calcaneal osteomyelitis [32, 33]. Prevention rests on insoles and orthopaedic footwear custom-made by orthotists, for outdoor and indoor use, which reduce pain but have to be remade frequently because the toe deformities progress; active treatment includes paring the callus with a blade and salicylic acid dressings, maintained as long as excess pressure persists; moisturising the dry skin of the legs and feet may reduce calluses and ulcers [33].

Ulcer infection was addressed in a separate part of the guideline, which likens it to the diabetic foot: the organisms are the same, but poorer healing makes infection longer and chronic, favours resistant bacteria and increases the need for surgical excision, so identification of the organism and collaboration with plastic surgery and orthopaedics are central [33, 58]. Severity is classified using the Infectious Diseases Society of America (IDSA) diabetic foot scale (no infection; mild, with erythema of 0.5–2 cm limited to the skin and subcutaneous tissue; moderate, with erythema >2 cm, deeper involvement, abscess, osteomyelitis, septic arthritis or fasciitis; severe, with two or more systemic inflammatory response criteria) [33]. Samples should be of deep tissue obtained by biopsy or curettage after cleaning and debriding the wound, of aspirated pus, or of bone biopsy if osteomyelitis is suspected; superficial swabs of wounds without signs of infection or not debrided isolate colonisers and lead to excessively broad-spectrum antibiotics; in an infected deep ulcer, a positive probe-to-bone test suggests osteomyelitis and indicates bone biopsy for culture [33]. Empirical antibiotic therapy targets streptococci and Staphylococcus aureus and is broadened after four questions: risk of meticillin-resistant S. aureus (MRSA), antibiotic in the last month (cover Gram-negatives), risk of Pseudomonas, and severity [33]. The guideline's examples are, for mild or chronic infection, oral antibiotics such as cefalexin, co-amoxiclav, co-trimoxazole, minocycline, clindamycin or levofloxacin; for moderate to severe infection, ampicillin with sulbactam as first choice in the absence of resistance, piperacillin with tazobactam, cefepime with metronidazole, or meropenem, with vancomycin or daptomycin for MRSA, always with renal adjustment [33]. Duration follows that for the diabetic foot and is adjusted to improvement of local signs, because skin tissue recovers poorly [33]:

Source: 2020 Japanese guideline, part 5 (infection), which adapts the IDSA diabetic foot guideline [33, 58].

7.5. Bosentan

Bosentan is an endothelin receptor antagonist that GeneReviews classifies as targeted therapy for lower limb ulcers, because it reduces vasoconstriction, on the basis of a report in Werner syndrome and the RAPIDS-2 trial in digital ulcers of systemic sclerosis [1, 59, 60]. In Werner syndrome its use is off-label in all jurisdictions.

Sources: GeneReviews [1], Tracleer® EPAR [61], FDA label [62].

The GeneReviews maintenance dose allows 125 mg once daily, below the dose in the European label for digital ulcers (125 mg twice daily), and the 20-week duration lies within the controlled experience of the label, which is limited to 6 months [1, 61]. The European label states that the drug reduces new ulcers but does not accelerate healing of existing ones, which contrasts with the GeneReviews indication, supported by case observations and not by a trial in the syndrome [1, 19, 61]. In Werner syndrome, hepatotoxicity warrants particular attention because of the frequent hepatic steatosis, and the interaction with glibenclamide is relevant in diabetic patients [41, 62]. In Portugal, Tracleer® (Janssen-Cilag International) and generic bosentan (Accord, Aurobindo/Generis, Mylan/Viatris) are authorised and marketed as 62.5 mg and 125 mg tablets and 32 mg dispersible tablets [63]. In Brazil, the Tracleer® registration is inactive and generic bosentan and the similar product Bospulmo® (registered in 2025) are active [64].

7.6. Diabetes and metabolism: recent experience

The diabetes of Werner syndrome responds better to drugs that reduce insulin resistance than to insulin alone [12, 38]. In the Chinese case described in section 10, 86 U/day of insulin did not control blood glucose, and adding metformin (0.5 g four times daily), pioglitazone (45 mg daily), dapagliflozin (10 mg daily), fenofibrate, acipimox and atorvastatin to basal-bolus insulin reduced insulin requirements [12]. The authors point out that thiazolidinediones have adverse bone effects and a possible association with some neoplasms, which calls for weighing their long-term use in a disease with osteoporosis and cancer predisposition [12]. In a 48-year-old Japanese man not controlled with pioglitazone and metformin, dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, improved insulin resistance and glycaemic control without adverse effects [65]. Metreleptin has been used in 3 patients with Werner syndrome and partial lipodystrophy; in the most recent case, a 38-year-old woman went from an HbA1c of 8.6% to 7.4% in 26 weeks, with reduced hepatic steatosis, stiffness and volume [40]. As early as 1997, troglitazone (400 mg/day for 4 weeks) reduced in 5 patients the area under the glucose and insulin curves in the oral tolerance test by 26% and 43%, one of the first data in favour of insulin sensitisers [7]. These observations are case reports or very small series and do not demonstrate benefit in controlled series.

7.7. Agents and circumstances to avoid

Smoking and obesity increase the risk of atherosclerosis, and smoking and alcohol increase the risk of osteoporosis and cataracts [1]. Falls are prevented with grab rails in the bathroom, removal of slippery surfaces and obstacles, and adequate lighting [1]. Trauma to the extremities and prolonged pressure on the elbows, feet and ankles should be avoided, as should excessive sun exposure, with sunscreen, clothing and glasses with an ultraviolet filter [1]. The Japanese recommendations advise weighing the use of X-rays in screening examinations, because the cells of the syndrome are susceptible to radiation-induced chromosomal aberrations, although without clinical evidence of harm, and prefer ultrasound and magnetic resonance imaging, by analogy with Bloom syndrome [45]. Declining renal function requires attention to the type and dose of drugs [46].

7.8. Regulatory status

Sources: labels and registries [61, 62, 66], nicotinamide riboside trial [23] and GeneGuidance [19].

7.9. Clinical trials

Sources: [23, 66, 67].

None of these studies is large enough to demonstrate clinical efficacy. The nicotinamide riboside trial was powered for safety, the efficacy results are secondary outcomes without published confidence intervals for the between-arm difference, the absence of a washout period limits interpretation of the crossover, and there were withdrawals during the placebo phase because of aspiration pneumonia or neoplasia [23]. The SR-0379 study had no placebo control group in Werner syndrome [67]. No published trials with negative results, suspensions or withdrawals were found in the sources consulted; the absence of records does not demonstrate that none exist.

7.10. Developments in the past 12 months

7.11. Pregnancy, lactation, perioperative care and transition

Pregnancies are rare, but several women in the international registry have had children; possible complications include cardiac events during delivery, difficult venous access because of the scleroderma, preterm birth and pre-eclampsia, and referral to maternal-fetal medicine may be warranted [1]. In vitro fertilisation and oocyte donation have not been described in women with the syndrome [1]. In a 34-year-old Irish pregnant woman with dysphonia due to vocal cord paralysis, anaesthetic assessment at 24 weeks showed an ejection fraction of 55% and mild aortic valve sclerosis; caesarean section at 34 weeks, for abnormal liver function tests and rising blood pressure, was performed under spinal anaesthesia to avoid intubation, with an uncomplicated course [11]. Bosentan is contraindicated in pregnancy [61, 62]. Perioperatively, the airway, coronary and valvular disease, poor wound healing, skin fragility at pressure points and renal function should be considered [1, 11, 46]. Because the disease manifests in adulthood, paediatric transition does not arise; diagnosis in young people under 30 years is increasingly frequent and allows surveillance to start earlier [30].

7.12. Divergences between sources

Sources: [1, 2, 5, 24, 27, 30, 33, 48, 61].

8. Reproductive Options and Family Counselling

8.1. Recurrence risks

Classic Werner syndrome is autosomal recessive [1]. The parents of an affected individual are presumed heterozygous and should be tested after molecular diagnosis of the proband, to confirm heterozygosity and allow a reliable risk calculation [1]. If only one parent is a carrier, with paternity and maternity confirmed, one of the variants may have arisen de novo in the proband or through post-zygotic germline mosaicism in a parent; when the proband appears homozygous, a deletion of one or more exons on the other allele, not detected by sequencing, and uniparental isodisomy must be excluded [1]. Each sibling of an affected individual has, at conception, a 25% chance of being affected, 50% of being an asymptomatic carrier and 25% of being neither affected nor a carrier [1]. The children of an affected individual are obligate heterozygotes, unless the other parent is a carrier or affected, and each sibling of the proband's parents has a 50% chance of being a carrier [1].

8.2. Cascade testing and evaluation of siblings

GeneReviews recommends evaluating the older and younger siblings of an affected individual, even if asymptomatic, to start treatment and prevention early: by molecular testing when the familial variants are known, or by clinical examination with assessment of growth, skin and slit-lamp ophthalmology when they are not [1]. European family series, such as the four Irish Traveller siblings with diabetes and complex foot disease, show that the diagnosis in one sibling allows surveillance of the others to be brought forward [37].

8.3. Carriers and partner testing

Heterozygotes are asymptomatic and do not appear to have an increased risk of disease, although there are no systematic clinical studies [1]. Carrier testing of the partner should be considered, particularly in consanguineous couples or those of the same ancestry; in Japan, the carrier frequency of the founder variant c.3139-1G>C is 1/167, and in Sardinia the heterozygote frequency of the c.2089-3024A>G variant is about 1/120 [1, 5]. In the Lithuanian case described in section 10, the parents came from the same region and the variant was found in the heterozygous state in 2 of 1000 individuals in the local database [21].

8.4. Prenatal and preimplantation diagnosis and DNA banking

Prenatal diagnosis and preimplantation genetic testing are possible once the familial variants have been identified, and the ideal time to discuss them is before pregnancy; genetic counselling should be offered to young adults who are affected, carriers or at risk [1]. In a patient without a molecular diagnosis, DNA banking should be offered [1]. Fertility preservation (oocytes, sperm or embryos) should be discussed early, given the early decline in fertility [1].

8.5. Testing of minors

Because the disease manifests after puberty and early detection allows surveillance and prevention to begin, GeneReviews includes younger siblings in targeted evaluation, by molecular testing or clinical examination [1]. The sources consulted do not specifically discuss carrier testing in minors.

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and what each estimate measures

The different estimates are not directly comparable: the Orphanet prevalence for the USA and Europe is two to five times higher than the GeneReviews genetic estimate, and heterozygote frequencies describe founder populations, not whole countries [1, 19]. Prevalence varies with consanguinity [1]. In Japan, parental consanguinity affected about 30% of registry patients, and the distribution of patients across the country no longer shows regional clusters, which the authors attribute to the decline in consanguineous marriages and to population mobility [29].

9.2. Founder populations and geographical distribution

Japan and Sardinia have founder variants with heterozygote frequencies close to 1/150; Morocco (c.2179dup), Turkey (c.3460-2A>C/G), the Netherlands (c.3590del) and India/Pakistan (c.561A>G) have possible founder variants, defined by three or more independent families with the same variant; there are isolated cases on virtually every continent [1, 5]. Outside Japan, the most frequent variant is c.1105C>T [5]. Recent European data include an Irish Traveller family (an endogamous population with frequent consanguinity) with four affected siblings, an Irish pregnant woman homozygous for c.3961C>T (p.Arg1321Ter) and a Lithuanian man homozygous for c.1578del [11, 21, 37]. The p.(Arg834Cys) variant, frequent in Latin American populations, does not cause the syndrome [25]. Regarding Portugal, the only reference found is the Portuguese patient with atypical Werner syndrome due to the LMNA variant p.Arg133Leu included in the 2003 international registry series [8]; the main sources present no epidemiological data from Portugal or Brazil, and their absence from these sources does not demonstrate that there are no patients in these countries. The high prevalence in Sardinia was documented as early as 1982, with the description of six patients and an estimate of the gene frequency [7].

9.3. Differences by sex and age

The phenotype is less complete in women, and 86.7% of women, compared with 64% of men, required genetic testing for diagnosis in a Japanese series [27]. In patients under 30 years, the late signs (calcification, facies, voice) are insensitive [30].

9.4. Reference networks and associations

The International Registry of Werner Syndrome (University of Washington, Seattle; wernersyndrome@uw.edu) performs molecular diagnosis for patients from around the world and studies atypical cases, and the Japanese Werner Consortium (Chiba University) has maintained the Japanese registry since 2016 [1, 5, 35]. GeneReviews lists MedlinePlus, the National Organization for Rare Disorders (NORD) and NCBI Genes and Disease as patient resources [1]. In the sources consulted, no European Reference Network expressly includes the syndrome within its scope; ERN-Skin and ERN GENTURIS have related scopes (rare skin diseases and tumour predisposition syndromes), and Orphanet (ORPHA:902) is the starting point for identifying specialised centres in each country [2].

10. Illustrative Clinical Case

10.1. Lithuanian man diagnosed at 45 years

Druta and colleagues described, in 2024, a 45-year-old Lithuanian man admitted to a neurology department with painful muscle spasms, myalgia and weakness [21]. The spasms had begun at 10 years and there had been an episode of diplopia in childhood; over the years painful tenderness of the feet with walking difficulty, contractures of the plantar tendons and atrophy of the adipose tissue of the extremities appeared [21]. An arthrodesis of the right foot was complicated by postoperative infection, with necrosis and amputation of the third and fourth toes [21]. He had previous diagnoses of hypopituitarism, hyperprolactinaemia, hypogonadism, gout and hypertension, and at 45 years non-toxic multinodular goitre and hypothyroidism were diagnosed; his hair had begun to turn grey at 30 years [21]. Examination showed a height of 178 cm and weight of 78 kg, micrognathia, a beaked nose, sclerodermatous skin on the face and extremities, thin limbs with subcutaneous atrophy, abdominal obesity, foot deformity and toe contractures; there was percussion myotonia in the palms and forearms, plantar hyperaesthesia and allodynia, but electromyography showed no myopathy or myotonia, and the initial diagnosis was secondary small-fibre sensory polyneuropathy with myotonia [21]. Exome sequencing, analysed for progeroid and neuromuscular genes, identified the variant NM_000553.6:c.1578del, p.(Leu528CysfsTer29), in the homozygous state, classified as pathogenic or likely pathogenic in ClinVar and with no homozygotes in gnomAD v4 (allele frequency 0.000023) [4, 21, 24]. The parents came from the same region (northern Samogitia), which suggests a common ancestral allele, but could not be tested [21]. In culture, 56.72% of the patient's fibroblasts were senescent (senescence-associated β-galactosidase activity), compared with 0.43% and 0.53% in controls; Figure 1 of the article shows the protein domains with the position of the variant, the X-gal-stained cultures and the percentages of senescent cells (https://pmc.ncbi.nlm.nih.gov/articles/PMC11887839/figure/F1/) [21]. The authors recommend treating osteoporosis according to general guidelines, caring for the skin lesions of the extremities and controlling dyslipidaemia with a statin [21].

The case illustrates three points: presentation with neuromuscular and foot complaints, which delayed diagnosis until the fifth decade; the usefulness of the exome when the syndrome has not been considered, as provided for by the second GeneReviews route; and the risk of foot surgery in a disease with poor wound healing, also emphasised by the Japanese consensus [1, 21, 32]. No cataracts were described in the report, which shows that not all cardinal signs are present or recorded at the time of diagnosis [21].

10.2. Diabetes as the presentation: a case from Xinjiang

Yusufu and colleagues reported a 50-year-old man, the son of consanguineous parents, with diabetes diagnosed in 2013 (blood glucose 19.5 mmol/L and triglycerides 19.53 mmol/L), treated for 11 years as type 2 diabetes and then as diabetes associated with familial partial lipodystrophy [12]. He had had no pubertal growth spurt (final height 170 cm), and developed greying and alopecia in 2018, limb lipoatrophy in 2019, diabetic retinopathy and neuropathy, high-frequency sensorineural hearing loss and cataracts, diagnosed in 2024 [12]. On examination, he had a high-pitched, hoarse voice, bird-like facies, thin limbs and atrophy of the gluteal fat and muscles (Figure 1 of the article: https://pmc.ncbi.nlm.nih.gov/articles/PMC13508835/figure/f1-amjcaserep-27-e952718/) [12]. The exome showed homozygosity for the missense variant NM_000553.6:c.1846G>C, p.(Ala616Pro), with his daughter, son and a brother heterozygous (Figure 2: https://pmc.ncbi.nlm.nih.gov/articles/PMC13508835/figure/f2-amjcaserep-27-e952718/) [4, 12]. With 86 U/day of insulin, control was inadequate; adding metformin, pioglitazone and dapagliflozin reduced insulin requirements [12]. The variant had not been described before and was not studied functionally, so its pathogenicity rests on the phenotype and segregation; the treatment regimen is that of an individual case and not a recommendation [12].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

The mean age at death has increased over recent decades and stands at 54 years in the international registry series and a median of 53 years in Japanese patients, with myocardial infarction and cancer as the main causes [1, 17]. The 2011–2020 Japanese series shows a mean age at death of 59.0 years, no deaths from atherosclerotic disease and non-epithelial tumours as the main cause (8 of 14 deaths) [44]. The 2024 Japanese recommendations attribute this trend to better treatment of diabetes and dyslipidaemia and estimate current life expectancy at 59 years [45]. In the Japanese registry followed for three years, about 30% of patients developed a malignant neoplasm and estimated glomerular filtration fell by a mean of 11.4 mL/min/1.73 m² between the first and fourth year [46]. The absence of deaths from atherosclerosis in a series of 14 deaths does not mean that cardiovascular risk has disappeared.

11.2. Surveillance table

GeneReviews proposes annual surveillance for all systems [1]. The 2024 Japanese cancer recommendations, the first specific ones, classify the thyroid, meningioma, sarcomas, melanoma and haematological neoplasms as high-frequency and the lung, breast, pancreas and gastrointestinal tract as lower-frequency; the intervals derive from Japanese screening programmes and from recommendations for other progeroid syndromes, and efficacy, starting age, intervals and cost-effectiveness have not been evaluated [45]. The preference for ultrasound and magnetic resonance imaging over X-rays and computed tomography applies to screening, not to the investigation of symptoms [45].

12. Summary and Concluding Remarks

Werner syndrome is an autosomal recessive segmental progeria caused by biallelic loss-of-function variants in WRN, which encodes a RecQ family helicase and exonuclease involved in replication, repair and telomere maintenance [1, 5]. Development is normal until puberty, the absence of the growth spurt is the first sign and, from the third decade, greying, bilateral cataracts, sclerodermatous skin, short stature, insulin-resistant diabetes, dyslipidaemia, hypogonadism, osteoporosis of the long bones, sarcopenia, tendon calcification, ankle ulcers, atherosclerosis and mainly non-epithelial cancers accumulate [1, 29, 45]. Diagnosis rests on clinical criteria (international or Japanese) and molecular genetics; sequencing identifies biallelic variants in the great majority of patients, but a missing second allele may require CNV analysis, RNA studies or long-read sequencing, and the absence of WRN variants leads to atypical Werner syndrome, partly caused by LMNA variants [1, 6, 50]. The mean delay of about 16 years between first symptoms and diagnosis, longer in women, justifies the Japanese proposal to test young patients with bilateral cataracts and hair changes associated with short stature, metabolic or skin changes [27, 29, 30]. Management is multidisciplinary and rests on GeneReviews, the 2020 Japanese consensus and the 2024 cancer recommendations: insulin-sensitising drugs and statins, prevention and active treatment of calluses and ulcers, densitometry, adapted cataract surgery and screening of the thyroid, skin, meningioma, sarcomas and haematological neoplasms [1, 32, 38, 45]. Bosentan is used off-label for ulcers, with monthly liver monitoring, and mechanism-targeted therapies (NAD+ precursors, progerinin, antisense oligonucleotides for the Japanese founder variant) are at the stage of small trials or preclinical work [1, 23, 61, 66, 68]. Life expectancy has risen to about 59 years, and non-epithelial tumours are now the main cause of death in Japanese series [44, 45]. Almost all cohort data come from Japan; European data are limited to reports of families and isolated cases, and the sources consulted include no data from Portugal or Brazil [5, 21, 37].

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