Clinical characteristics.

Werner syndrome is characterized by the premature appearance of features associated with normal aging and cancer predisposition. Individuals with Werner syndrome develop normally until the end of the first decade. The first sign is the lack of a growth spurt during the early teen years. Early findings (usually observed in the 20s) include premature graying and/or thinning of scalp hair, hoarseness, and scleroderma-like skin changes, followed by bilateral ocular cataracts, type 2 diabetes mellitus, hypogonadism, skin ulcers, and osteoporosis in the 30s. Myocardial infarction and cancer are the most common causes of death; the mean age of death in individuals with Werner syndrome is 54 years.

Diagnosis/testing.

The diagnosis of Werner syndrome can be established in a proband with clinical diagnostic criteria (presence of all four cardinal signs: bilateral ocular cataracts, premature graying and/or thinning of scalp hair, characteristic dermatologic pathology, and short stature; and two additional characteristic signs) or biallelic WRN pathogenic variants identified by molecular genetic testing.

Management.

Targeted therapy: Bosentan reduces vasoconstriction to improve healing of lower-extremity ulcers.

Supportive care: UV-blocking sunglasses may reduce risk of cataracts; surgical treatment of ocular cataracts; treatment of diabetic retinopathy per ophthalmologist; standard treatment of osteoporosis; fertility preservation treatments as needed; medications to manage type 2 diabetes mellitus; treatment of malignancies in a standard fashion; lifestyle counseling including tobacco avoidance, regular exercise, and maintenance of healthy weight; preventative skin care to avoid ulcers; aggressive treatment of skin ulcers; cholesterol-lowering drugs if lipid profile is abnormal with statin treatment for those with total cholesterol levels >200 mg/dL.

Surveillance: Annual surveillance includes ophthalmologic examination for cataracts; dual-energy x-ray absorptiometry to assess bone density; assessment for signs/symptoms of hypogonadism; fasting glucose level, hemoglobin A1c, or oral glucose tolerance test; physical examination including neurologic assessment with attention to signs and symptoms of malignancies common in Werner syndrome; skin examination for ulcers and lentiginous melanoma; ten-year atherosclerotic cardiovascular disease risk estimation, lipid profile, blood pressure, lifestyle counseling, and assessment for cardiovascular risk factors.

Agents/circumstances to avoid: Avoid smoking and obesity, which increase the risk for atherosclerosis. Avoid smoking and alcohol, which increase the risk of osteoporosis and cataracts. Avoid falls, trauma to the extremities, and excessive sun exposure.

Evaluation of relatives at risk: Evaluate apparently asymptomatic older and younger sibs of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures.

Genetic counseling.

Werner syndrome is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a WRN pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the WRN pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.

Suggestive Findings

Werner syndrome should be suspected in individuals who have the following cardinal signs, additional characteristic signs, and family history.

Cardinal signs (91% of individuals have all four cardinal signs)

• Bilateral ocular cataracts
• Premature graying and/or thinning of scalp hair
• Characteristic dermatologic pathology
• Short stature

Additional characteristic signs

• Thin limbs
• Pinched facial features
• Osteoporosis
• Voice change
• Hypogonadism
• Type 2 diabetes mellitus
• Soft tissue calcification
• Neoplasm(s)
• Skin ulcers, usually of distal legs
• Atherosclerosis

Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

Clinical Description

Werner syndrome is characterized by the premature appearance of features associated with normal aging and cancer predisposition. Early findings include premature graying and/or thinning of scalp hair, hoarseness, and scleroderma-like skin changes, followed by bilateral ocular cataracts, type 2 diabetes mellitus, hypogonadism, skin ulcers, and osteoporosis. To date, more than 300 individuals have been identified with biallelic pathogenic variants in WRN [Yokote et al 2017]. The following description of the phenotypic features associated with this condition is based on these reports.

Onset. Individuals with Werner syndrome develop normally until the end of the first decade. The first symptom, often recognized retrospectively, is the lack of a growth spurt during the early teen years. Additional clinical manifestations typically start in the 20s. Initial findings include loss and graying of hair, hoarseness, and scleroderma-like skin changes, followed by bilateral ocular cataracts, type 2 diabetes mellitus, hypogonadism, skin ulcers, and osteoporosis in the 30s. Median age of diagnosis ranges from late 30s to 40s [Oshima et al 2017, Takemoto et al 2013].

Cataracts. Median age of onset of cataracts is approximately 31 years [Oshima et al 2017]. Bilateral cataracts are universal and progress rapidly in individuals with Werner syndrome. Complications from surgical treatment are common and include (among others) wound dehiscence, peripheral anterior synechiae, epiretinal membrane formation, and cystoid macular edema [Lyons et al 2019]. Specific intraoperative and postoperative techniques (phacoemulsification, small incision size, use of viscoelastic to protect corneal endothelium, use of a weak topical steroid to avoid suppression of fibroblast proliferation) have been reviewed [Lyons et al 2019] in order to optimize outcome. Retinal and choroidal thinning has been observed in individuals with Werner syndrome by optical coherence tomography [Nagai et al 2022]. Individuals with Werner syndrome and diabetes are also at risk for diabetic retinopathy.

Characteristic facial features include a narrow nasal ridge, narrow nasal tip, hypoplastic alae, loss of subcutaneous fat in the face, thin vermilion of the upper and lower lips, micrognathia, and retrognathia. Premature loss of the secondary dentition evolves during the third or fourth decade.

Osteoporosis. The osteoporosis of individuals with Werner syndrome is unusual in that it preferentially affects the long bones [Mori et al 2021]. In contrast, osteoporosis during normative aging preferentially involves the vertebral bodies, particularly in women. Other skeletal abnormalities in individuals with Werner syndrome include characteristic osteolytic lesions of the distal phalanges of the fingers (acroosteolysis).

Reduced fertility. Fertility appears to decline soon after sexual maturity. This decline in fertility is associated with testicular atrophy and probable accelerated rate of loss of primordial follicles in the ovaries, although data are sparse. Early menopause is common in women, as are multiple miscarriages, but successful pregnancies have also been reported. Men have fathered children, usually at younger ages than in the general population.

Diabetes. The risk of type 2 diabetes mellitus increases beginning in the fourth decade and is a source of multisystem complications including atherosclerosis, retinopathy, and deep ankle ulcers. Therefore, optimal management includes regular screening for type 2 diabetes mellitus by fasting glucose, hemoglobin A1c, or oral glucose tolerance testing. Treatment with oral medications such as thiazolidinediones and metformin have been effective, along with surveillance and treatment for the known complications associated with type 2 diabetes mellitus [Takemoto et al 2021].

Malignancy. The risk of cancer in individuals with Werner syndrome is increased and the age at diagnosis is younger than in the general population. Non-epithelial cancers are more common in individuals with Werner syndrome and include sarcomas and very rare cancer types in typical locations [Aono et al 2024b]. The most common cancers in Japanese individuals (for whom the most data exist) are soft-tissue sarcomas, osteosarcomas, malignant melanomas, meningiomas, hematologic malignancies, and thyroid carcinomas. Acral lentiginous melanomas (most often observed on the feet and nasal mucosa) are particularly prevalent compared to levels observed in the general population. There has been a shift toward older age at cancer diagnosis and an increase in epithelial cancers including breast, thyroid, and lung in individuals with Werner syndrome, likely reflecting improvements in early detection and increased life expectancy.

Skin. Scleroderma-like changes in the skin appear in the decade after puberty, with onset first in the face and extremities. A taut and shiny appearance is the result of atrophy of epidermis, adipose, and muscle tissue. This is followed by development of skin ulcers and calcification of soft tissues and the Achilles tendon or elbow tendons in the late 20s and 30s [Ogata et al 2021].

Deep, chronic ulcers around the ankles (Achilles tendon, medial malleolus, lateral malleolus) are highly characteristic and a major contributor to morbidity associated with the disease [Kubota et al 2021].

Cardiovascular disease. Affected individuals exhibit several forms of arteriosclerosis, which are a major cause of morbidity and mortality; coronary artery atherosclerosis may lead to myocardial infarction and peripheral vascular disease may contribute to chronic ulcers. Hyperlipidemia is seen in up to 85% of individuals with Werner syndrome and is reported to respond to treatment with statin-type medications [Tsukamoto et al. 2021]. Early-onset hypertension is not a typical feature of Werner syndrome.

Neurologic manifestations. Controversy exists concerning the degree to which the brain is involved. While individuals with Werner syndrome may have cerebrovascular disease resulting in stroke, they do not appear to be unusually susceptible to Alzheimer disease. Cognitive changes are not typically observed. Recent brain MRI and postmortem studies of an individual in his 70s with molecularly confirmed Werner syndrome and dementia were negative for cerebral atrophy or pathologic diagnosis of Alzheimer disease, although a left occipital meningioma was present [Kuzuya et al 2021].

Prognosis. Myocardial infarction and cancer are the most common causes of death in individuals with Werner syndrome. The mean age of death in individuals with Werner syndrome has increased significantly over the past several decades and is currently 54 years [Oshima et al 2017]. Similarly, the median life span of Japanese individuals with Werner syndrome is 53 years [Goto et al 2013].

Genotype-Phenotype Correlations

The chronologic order of the onset of manifestations is similar in all individuals with Werner syndrome regardless of the specific WRN pathogenic variants.

The specific cell type in which cancer develops may depend on the type of WRN pathogenic variant present. In individuals of Japanese descent, papillary thyroid carcinoma has been associated with an N-terminal variant, whereas follicular thyroid carcinoma is more frequently observed with a C-terminal variant [Ishikawa et al 1999]. This finding clearly contradicts the original assumption that all identified WRN pathogenic variants result in truncation of the nuclear localization signal of WRN protein and thereby act as null variants.

The c.2500C>T (p.Arg834Cys) allele is common in Latino populations and results in reduced helicase and exonuclease activity in vitro, but homozygosity for this allele does not appear to cause Werner syndrome, as multiple Mexican individuals homozygous for the allele have been reported to have no clinical features of Werner syndrome [Kamath-Loeb et al 2017].

Nomenclature

An older term for Werner syndrome was "progeria of the adult" (to distinguish it from Hutchinson-Gilford progeria syndrome, which was often referred to as progeria of childhood).

Prevalence

The prevalence of Werner syndrome varies with the level of consanguinity in populations.

Apparent WRN founder variants contribute to higher prevalence in some populations. In the Japanese, the frequency ranges from about 1:20,000 to 1:40,000, based on the frequencies of detectable heterozygous pathogenic variants [Yokote et al 2017]. This is most likely the result of a founder variant in the Japanese population. Similarly, in the Sardinian population, the frequency is estimated at 1:50,000 [Yokote et al 2017].

Based on the population allele frequency of the most common pathogenic variant, c.1105C>T (p.Arg369Ter), which accounts for approximately 20% of pathogenic alleles, the prevalence of Werner syndrome is estimated at 1:380,000-1,000,000.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Werner syndrome, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

To date, there is no approved therapy that provides a cure for Werner syndrome (see Therapies Under Investigation).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 7 are recommended.

Agents/Circumstances to Avoid

Smoking and obesity increase the risk of atherosclerosis.

Smoking and alcohol ingestion increase the risk of osteoporosis and cataracts.

Falls resulting in fracture can be prevented or reduced by adding grab bars in the bathroom, eliminating slippery surfaces and tripping hazards, and providing adequate lighting.

Avoid trauma to the extremities and prolonged pressure to the elbows, feet, and ankles, where ulcers commonly form.

Avoidance of excessive sun exposure and use of sunscreen, protective clothing, and UV-blocking sunglasses may reduce the risk of skin cancer (including melanoma) and cataracts.

Evaluation of Relatives at Risk

It is appropriate to evaluate apparently asymptomatic older and younger sibs of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures. Evaluations can include:

• Molecular genetic testing if the pathogenic variants in the family are known;
• Clinical examination including growth assessment, skin examination, and ophthalmology evaluation including slit lamp examination if the pathogenic variants in the family are not known.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Reports in the medical literature of pregnancy in individuals with Werner syndrome are rare; however, many of the women in the International Registry of Werner Syndrome have had offspring [J Oshima, personal observation]. Potential pregnancy-related complications include cardiac events during delivery, difficulty with intravenous access due to scleroderma, preterm delivery, and preeclampsia [Fallon et al 2024]. Referral to a maternal-fetal medicine specialist in high-risk pregnancies may be appropriate.

The use of assisted reproductive technologies such as in vitro fertilization and egg donation has not been reported in women with Werner syndrome.

Therapies Under Investigation

The Japanese Werner Consortium (PI K Yokote, Chiba University, Japan) conducted the first ever double-blind, randomized, crossover placebo-controlled clinical trial with the NAD⁺ precursor nicotinamide riboside with favorable results [Shoji et al 2025].

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

Werner syndrome is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected individual are presumed to be heterozygous for a WRN pathogenic variant.
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a WRN pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Although systematic clinical studies have not been published, heterozygotes (carriers) are asymptomatic and do not appear to be at increased risk of developing the disorder.

Sibs of a proband

• If both parents are known to be heterozygous for a WRN pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Although systematic clinical studies have not been published, heterozygotes (carriers) are asymptomatic and do not appear to be at increased risk of developing the disorder.

Offspring of a proband. Unless an affected individual's reproductive partner also has Werner syndrome or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in WRN.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a WRN pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the WRN pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk sibs for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• Carrier testing should be considered for the reproductive partners of individuals affected with Werner syndrome and individuals known to be carriers of a WRN pathogenic variant, particularly if consanguinity is likely and/or if both partners are of the same ancestry (see Prevalence). Founder variants have been identified in several populations (see Table 8). In Japan, the carrier frequency of the WRN founder variant, c.3139-1G>C, is 1:167 [Yokote et al 2017].

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Once the WRN pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

WRN encodes bifunctional 3'-5' exonuclease/ATP-dependent helicase WRN (WRN), a multifunctional nuclear protein that is a member of the RecQ family of DNA helicases [Yu et al 1996]. DNA-type helicases are ATP-dependent 3' → 5' helicases that are necessary to maintain genomic integrity in cells. The N-terminal region of the protein encoded by WRN has exonuclease activity as well.

Studies suggest that WRN is involved in DNA repair, recombination, replication, and transcription as well as combined functions such as DNA repair during replication. WRN can potentially unwind or digest aberrant DNA structures accidentally generated during various DNA metabolic processes and can also regulate DNA recombination and repair processes by unwinding or digesting intermediate DNA structures. WRN is also involved in the maintenance of telomeres. These findings are consistent with the notion that WRN plays a role in maintenance of genomic stability [Croteau et al 2014].

More than 90 different WRN pathogenic variants have been identified. The majority of pathogenic variants are stop codons, insertions, or deletions that result in a frameshift, or a splice donor or acceptor site variant that results in exon skipping. Several missense variants that abolish helicase activity or confer protein instability have been reported. Pathogenic variants that occur in an intron and result in creation of a new exon as well as multiexon deletions and duplications have also been reported [Yokote et al 2017].

Mechanism of disease causation. Loss of function

Author Notes

International Registry of Werner Syndrome
Phone: 206-543-5088
Fax: 206-685-6356

Dr Oshima (ude.wu@dracip) and Dr Hisama (ude.icu.sh@amasihf) are actively involved in clinical research regarding individuals with Werner syndrome. They would be happy to communicate with persons who have any questions regarding diagnosis of Werner syndrome or other considerations.

Dr Oshima and Dr Hisama are also interested in hearing from clinicians treating families affected by atypical progeroid disorders in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders.

Contact Dr Oshima to inquire about review of WRN variants of uncertain significance.

Acknowledgments

Research Support from NIH National Cancer Institute R01CA210916 (PI J Oshima)

In memory of Dr George M Martin's pioneering contributions to the understanding of the molecular and cellular causes of aging and Alzheimer disease, and his lifelong dedication to the understanding of Werner syndrome.

Austad SN. George M. Martin: tribute and personal remembrance. Geroscience. 2023;45:2085-2086. [PMC free article] [PubMed]

Author History

Nancy Hanson, MS, CGC; University of Washington (2002-2011)
Fuki M Hisama, MD (2011-present)
Dru F Leistritz, MS, CGC; University of Washington (2002-2011)
George M Martin, MD; University of Washington (2002-2026)
Junko Oshima, MD, PhD (2002-present)

Revision History

• 25 March 2026 (sw) Comprehensive update posted live
• 13 May 2021 (sw) Comprehensive update posted live
• 29 September 2016 (sw) Comprehensive update posted live
• 27 March 2014 (me) Comprehensive update posted live
• 17 November 2011 (me) Comprehensive update posted live
• 8 March 2007 (me) Comprehensive update posted live
• 13 January 2005 (me) Comprehensive update posted live
• 2 December 2002 (me) Review posted live
• 30 July 2002 (nh) Original submission

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