Werner Syndrome

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 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. 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 is established in a proband with the following cardinal signs: bilateral ocular cataracts, premature graying and/or thinning of scalp hair, characteristic dermatologic pathology, and short stature. Identification of biallelic WRN pathogenic variants on molecular genetic testing confirms the diagnosis if clinical features are inconclusive.

Management.

Treatment of manifestations: Surgical treatment of ocular cataracts using special techniques; cholesterol-lowering drugs if lipid profile is abnormal with statin treatment for those with low-density lipoprotein cholesterol levels >190 mg/dL; lifestyle counseling including tobacco avoidance, regular exercise, and maintenance of healthy weight; treatment of malignancies in a standard fashion; control of type 2 diabetes mellitus; standard treatment of osteoporosis; aggressive treatment of skin ulcers; skin care with trauma avoidance; fertility preservation treatments as needed.

Surveillance: Annual ophthalmologic examination for cataracts; ten-year atherosclerotic cardiovascular disease risk estimation, annual lipid profile, surveillance for cardiovascular risk factors such as hypertension and diabetes mellitus; physical examination including neurologic assessment with attention to signs and symptoms of malignancies common in Werner syndrome; fasting glucose level, hemoglobin A1c, or oral glucose tolerance test annually; monitoring for osteoporosis, and annual skin examination for ulcers and lentiginous melanoma.

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

Genetic counseling.

Werner syndrome is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being neither affected nor a carrier. Carrier testing for at-risk relatives and prenatal testing for a pregnancy at increased risk are possible if the pathogenic variants in the family have been identified.

Suggestive Findings

The diagnosis of Werner syndrome should be suspected in individuals who have the following cardinal signs [Oshima et al 2017]:

• Bilateral ocular cataracts (present in 99%) *
• Premature graying and/or thinning of scalp hair (100%)
• Characteristic dermatologic pathology (96%)
• Short stature (95%)

Approximately 91% of affected individuals have all four cardinal signs.

The clinical diagnosis may be further supported by the presence of the following additional signs and symptoms:

• Thin limbs (present in 98%)
• Pinched facial features (96%)
• Osteoporosis (91%)
• Voice change (89%)
• Hypogonadism (80%)
• Type 2 diabetes mellitus (71%)
• Soft tissue calcification (67%)
• Neoplasm(s) (44%)
• Skin ulcers, usually of distal legs (40%)
• Atherosclerosis (30%)

* Note: Percent frequencies are derived from individuals with a diagnosis of Werner syndrome confirmed by molecular testing.

Establishing the Diagnosis

The clinical diagnosis of Werner syndrome is established in a proband who has all four cardinal signs and two additional signs (definite) or the first three cardinal signs and two additional signs (probable). Identification of biallelic pathogenic variants in WRN on molecular genetic testing confirms the diagnosis if clinical features are inconclusive (see Table 1).

Similar diagnostic criteria have been proposed by Takemoto et al [2013].

Molecular genetic testing

• Single-gene testing. Sequence analysis of WRN is performed first and followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found.
• A multigene panel that includes WRN and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered if single-gene testing (and/or use of a multigene panel that includes WRN) fails to confirm a diagnosis in an individual with features of Werner syndrome. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene that results in a similar clinical presentation).
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Protein analysis. In certain unusual instances, protein analysis may be useful when both pathogenic WRN alleles cannot be identified by sequence analysis. Because the majority of WRN pathogenic variants are null and do not produce WRN protein (or rarely, produce truncated WRN), variants that are not detected by sequencing may be detectable by western blot or immunoblot analysis. Instances where protein analysis may supplement sequence analysis include the following:

• When sequencing identifies only one pathogenic variant known not to produce WRN. If protein analysis failed to detect any WRN protein, it may be inferred that the second unidentified pathogenic allele produced no or unstable WRN, thereby providing strong evidence for a diagnosis of Werner syndrome.
• When compound heterozygosity is identified, where one pathogenic allele is known to confer WRN absence but a second missense variant is of uncertain clinical significance
• If protein analysis implicates a missense variant of uncertain significance in conferring protein instability, which would suggest that it is a pathogenic allele. Such instances are rare.

Clinical Description

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 symptom, often recognized retrospectively, is the lack of a growth spurt during the early teen years.

Symptoms 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.

Facial features. A characteristic facial appearance, termed "bird-like" because of the pinched appearance at the bridge of the nose, evolves during the third or fourth decade.

Cardiovascular. Affected individuals exhibit several forms of arteriosclerosis; the most serious form, coronary artery atherosclerosis, may lead to myocardial infarction, which, together with cancer, is the most common cause of death. The mean age of death in individuals with Werner syndrome is 54 years [Oshima et al 2017]. Similarly, the median life span of Japanese individuals with Werner syndrome is 53 years [Goto et al 2013].

Malignancy. The spectrum of cancers in individuals with Werner syndrome is unusual in that it includes a large number of sarcomas and very rare cancer types in typical locations [Lauper et al 2013]. The most common cancers in Japanese individuals (for whom the most data exist) are soft-tissue sarcomas, osteosarcomas, melanomas, 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 [Lauper et al 2013]. Common types of carcinomas have also been observed.

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. Characteristic osteolytic lesions of the distal phalanges of the fingers are observed on radiograph.

Skin. Deep, chronic ulcers around the ankles (Achilles tendon, medial malleolus, lateral malleolus) are highly characteristic [Kubota et al 2021].

Neurologic. 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. Diffuse changes observed on brain MRI in some individuals warrant further investigation in research studies [De Stefano et al 2003].

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.

Genotype-Phenotype Correlations

The chronologic order of the onset of signs and symptoms 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 p.Arg834Cys allele is common in Latino populations, and results in reduced helicase and exonuclease activity in vitro, but 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 the 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, which accounts for approximately 20% of pathogenic alleles, the prevalence of Werner syndrome is estimated at 1:380,000-1:1,000,000.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Werner syndrome, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Surveillance

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, 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 a proband/at-risk relatives 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

In one study of individuals with Werner syndrome, signs of hypogonadism were reported in 80%; however, approximately half of those had children and showed signs of hypogonadism after age 30 years [Goto 1997]. 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. Preterm delivery has been reported in several cases, and has been attributed to cervical incompetence [Sołek-Pastuszka et al 2011]. Preeclampsia is another reported obstetric complication.

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

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 obligate heterozygotes (i.e., presumed to be carriers of one WRN pathogenic variant based on family history).
• Molecular genetic testing is recommended for the parents of a 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, the following possibilities should be considered:
  • 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].
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Although systematic clinical studies have not been reported, 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 reported, heterozygotes (carriers) are asymptomatic and do not appear to be at increased risk of developing the disorder.

Offspring of a proband

• The offspring of an individual with Werner syndrome are obligate heterozygotes (carriers) for a pathogenic variant in WRN.
• Due to the very low prevalence in the US population, the risk for Werner syndrome in the offspring of an affected individual is negligible unless the affected individual and his/her reproductive partner are consanguineous.
• In Japan, where heterozygotes may be as common as one in 150, the risk for Werner syndrome in an offspring is still less than 1/500.

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 relatives 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.

DNA banking. Because it is likely that testing methodology and our understanding of genes, allelic variants, 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 genetic alteration/s are unknown).

Prenatal Testing and Preimplantation Genetic Testing

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

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

Molecular Pathogenesis

WRN encodes 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 protein is involved in DNA repair, recombination, replication, and transcription as well as combined functions such as DNA repair during replication. WRN protein 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 protein 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

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 (2002-present)
Junko Oshima, MD, PhD (2002-present)

Revision History

• 13 May 2021 (sw) Comprehensive update posted live
• 29 September 2016 (sw) Comprehensive update posted live
• 27 March 2014 (me) Comprehensive update posted live
• 13 December 2012 (cd) Revision: prenatal testing available clinically
• 1 November 2012 (cd) Revision: deletion/duplication analysis available clinically
• 9 February 2012 (cd) Revision: protein analysis clinically available
• 29 December 2011 (cd) Revision: sequence analysis and carrier testing available clinically
• 17 November 2011 (me) Comprehensive update posted live
• 8 March 2007 (me) Comprehensive update posted live
• 13 January 2005 (me) Comprehensive update posted live
• 16 March 2004 (nh) Revision: Normal allelic variants
• 2 December 2002 (me) Review posted live
• 30 July 2002 (nh) Original submission

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