The features of Werner syndrome are scleroderma-like skin changes, especially in the extremities, cataract, subcutaneous calcification, premature arteriosclerosis, diabetes mellitus, and a wizened and prematurely aged facies. A particularly instructive pedigree was reported by McKusick (1963). The habitus ... The features of Werner syndrome are scleroderma-like skin changes, especially in the extremities, cataract, subcutaneous calcification, premature arteriosclerosis, diabetes mellitus, and a wizened and prematurely aged facies. A particularly instructive pedigree was reported by McKusick (1963). The habitus is characteristic, with short stature, slender limbs, and stocky trunk. The nose is beaked. Epstein et al. (1966) studied a Japanese patient living in Seattle. Goto et al. (1981) studied 42 Japanese families containing 80 affected persons. Autosomal recessive inheritance was confirmed. Malignancy was frequent in the patients and in the families generally. HLA was not linked. The frequency of Werner syndrome in Japan was estimated to be about 3 per million persons. The origin of the grandparents of the cases would be of interest. Khraishi et al. (1992) described a 47-year-old woman who had been misdiagnosed as having progressive systemic sclerosis with metastatic calcification for 12 years and then developed a painful, distal femoral, osteoblastic cortical juxtaarticular lesion with exuberant soft tissue calcification. This lesion proved to be an osteosarcoma requiring amputation. Ruprecht (1989) reported that in 10 of 18 eyes from 9 patients with Werner syndrome, cataract surgery was complicated by wound dehiscence and its consequences. Additionally, corneal endothelial decompensation occurred in 8 eyes. In view of the reduced growth potential of fibroblasts, he suggested small surgical incisions and other modifications of the usual procedures of cataract surgery, including no local or systemic use of cortisone. Martin (1997) gave a thoughtful review of the question of whether the Werner mutation is a bona fide reflection of mechanisms of 'normal aging.' Mohaghegh and Hickson (2001) reviewed the DNA helicase deficiencies associated with cancer predisposition and premature aging disorders. Goto et al. (1996) found in the literature 124 case reports of neoplasia and Werner syndrome from Japan and 34 case reports from outside Japan, from 1939 to 1995. They found a greater diversity of neoplasia in WRN than was previously known. In Japanese, there were 127 cancers, 14 benign meningiomas, and 5 myeloid disorders, as compared with 30 cancers, 7 benign meningiomas, and 2 myeloid disorders, in non-Japanese. The ratio of epithelial to nonepithelial cancers was about 1:1 for Japanese and for non-Japanese, instead of the usual 10:1. Both series had excesses of soft tissue sarcoma (STS), osteosarcoma, myeloid disorders, and benign meningioma. In addition, the Japanese had an excess of thyroid cancer and melanoma, including 5 intranasal and 13 foot. STS, osteosarcoma, melanoma, and thyroid carcinoma accounted for 57% of all cancer in WRN as compared with an expected 2%, based on the Osaka population between 25 and 64 years of age. Multiple tumors were reported in 19 Japanese and 5 non-Japanese. In Japan, 9 first-degree relatives had WRN and cancer, 6 of whom were concordant as to site and/or cell type.
Yu et al. (1996) identified 4 mutations in in the WRN gene in patients with Werner syndrome. Two of the mutations (604611.0003 and 604611.0004) were splice-junction mutations with the predicted result being the exclusion of exons from the ... Yu et al. (1996) identified 4 mutations in in the WRN gene in patients with Werner syndrome. Two of the mutations (604611.0003 and 604611.0004) were splice-junction mutations with the predicted result being the exclusion of exons from the final messenger RNA. One of these mutations (604611.0004), which resulted in a frameshift and a predicted truncated protein, was found in the homozygous state in 60% of Japanese Werner syndrome patients examined. The other 2 mutations were nonsense mutations (604611.0001 and 604611.0002). The identification of a mutated putative helicase as the gene product of the WRN gene suggested to Yu et al. (1996) that defective DNA metabolism is involved in a complex process of aging in Werner syndrome patients. Oshima et al. (1996) reported 9 new WRN mutations in 10 Werner syndrome patients, including 4 Japanese patients and 6 Caucasian patients. These mutations were located at different sites across the coding region. Oshima et al. (1996) noted that all of the WRN mutations found to date either create a stop codon or cause frameshifts that lead to premature terminations. They noted that the WRN protein is partially homologous to RecQ helicases and that it contains 7 helicase motifs, 2 of which have been found in all ATP-binding proteins. Oshima et al. (1996) briefly reviewed the functions of helicases and reported that DNA helicases have been implicated in a number of molecular processes, including unwinding of DNA during replication, DNA repair, and accurate chromosomal segregation. Goto et al. (1997) studied the helicase gene mutations previously described by Yu et al. (1996) in 89 Japanese Werner syndrome patients. Thirty-five (39.3%) were homozygous for mutation 4 (604611.0004); 1 (1.1%) was homozygous for mutation 1 (604611.0001); 6 (6.7%) were positive for both mutations 1 and 4; 1 was homozygous for a new mutation, which they designated mutation 5 (604611.0005); 13 (14.6%) had a single copy of mutation 4; 3 (3.4%) had a single copy of mutation 1; and the remaining 30 (33.8%) were negative for all 5 mutations. Of the 178 chromosomes in the 89 patients, 89 (50%) carried mutation 4, 11 (6.2%) carried mutation 1, and 2 (1.1%) carried mutation 5. In 76 chromosomes (42.7%), no mutation was identified. Yu et al. (1997) screened Werner syndrome subjects for mutations and identified 5 new ones. Four of these new mutations either partially disrupted the helicase domain region or resulted in predicted protein products lacking the entire helicase region. Their results confirmed that mutations in the WRN gene are responsible for Werner syndrome. In addition, the location of the mutations indicated that the presence or absence of the helicase domain does not influence the Werner syndrome phenotype, suggesting that this syndrome is the result of complete loss of function of the WRN gene product. Moser et al. (1999) reviewed the spectrum of WRN mutations in Werner syndrome, the organization and potential functions of the WRN protein, and the possible mechanisms linking the loss of WRN function with the clinical and cellular phenotypes of Werner syndrome. Monnat (1999) cited results from his own laboratory and from that of the AGENE Research Institute indicating that 80% of the WRN mutations in Japanese Werner syndrome patients led to a lack of detectable mutant protein. Thus many and perhaps all Werner syndrome-associated WRN mutations are likely to be functionally equivalent null alleles. These results contradict the suggestion of Ishikawa et al. (1999) that a different spectrum of mutations in the WRN gene in Japanese may confer a higher risk of thyroid carcinoma of the papillary or follicular type. However, the consistent absence of WRN protein in the cells of patients with Werner syndrome could both favor and partially explain the development of thyroid carcinoma with follicular and anaplastic, as opposed to the more papillary, histology. Using cDNA microanalysis, Kyng et al. (2003) found that fibroblasts from 4 patients with Werner syndrome and fibroblasts from 5 older control individuals (average age 90 years) showed transcription alteration of 435 (6.3%) of 6,192 genes examined compared to cells from young adult controls. Of the 435 genes, 91% of the 249 genes with known function had similar transcription changes in both Werner syndrome patients and normal old age controls. The major functional categories of the similarly transcribed genes of known function included DNA/RNA metabolism, cell growth, and stress response. Kyng et al. (2003) concluded that Werner syndrome may be a good model for normal aging and that both processes are linked to altered transcription.
The following diagnostic criteria have been proposed for Werner syndrome [modified from Nakura et al 1994]:...
DiagnosisClinical DiagnosisThe following diagnostic criteria have been proposed for Werner syndrome [modified from Nakura et al 1994]:Cardinal signs and symptoms (onset after age ten years) Bilateral cataracts Characteristic skin (tight skin, atrophic skin, pigmentary alterations, ulceration, hyperkeratosis, regional subcutaneous atrophy) Characteristic facies that have been described as "bird-like" (i.e., the nasal bridge appears pinched and subcutaneous tissue is diminished) Short stature Premature graying and/or thinning of scalp hair Parental consanguinity (third cousin or closer) or affected sibling Further signs and symptoms Type 2 diabetes mellitus Hypogonadism (secondary sexual underdevelopment, diminished fertility, testicular or ovarian atrophy) Osteoporosis Radiographic evidence of osteosclerosis of distal phalanges of fingers and/or toes [Goto et al 1989]Soft-tissue calcification Evidence of premature atherosclerosis (e.g., history of myocardial infarction) Neoplasms: especially mesenchymal (i.e., sarcomas), rare (e.g., unusual sites of melanomas and osteosarcomas [Goto et al 1996, Ishikawa et al 2000]), or multiple; common carcinomas are also observed Abnormal voice (high-pitched, squeaky, or hoarse [Tsunoda et al 2000]) Flat feet The International Registry of Werner Syndrome uses the above findings to establish a "definite," "probable," or "possible" diagnosis pending molecular genetic confirmation. Any set of diagnostic criteria is imperfect, especially when a diagnosis of Werner syndrome is considered in a young person before many of the symptoms would manifest. Definite diagnosis. All of the cardinal signs and two others Probable diagnosis. The first three cardinal signs and any two others Possible diagnosis. Either cataracts or dermatologic alterations and any four others Exclusion of the diagnosis. Onset of cardinal signs and further symptoms before age ten years, except for short stature Goto [1997] proposed the clinical diagnosis of Werner syndrome if at least four of the following findings are present:Consanguinity Characteristic facial appearance and body habitus Premature senescence Scleroderma-like skin changes Endocrine-metabolic disorders TestingUrinary and serum concentration of hyaluronic acid may be increased in some individuals with Werner syndrome [Tollefsbol & Cohen 1984, Goto 1997, Tanabe & Goto 2001]. Although an increase in urinary hyaluronic acid was used in the past to support the diagnosis of Werner syndrome, this testing is cumbersome and nonspecific, and thus not recommended. Variegated translocation mosaicism. An increase in structural, but not numeric, chromosomal aberrations has been observed in lymphocyte and fibroblast cultures from affected individuals. Chromosomal aberrations (variegated translocation mosaicism) as a result of spontaneous chromosome instability has been observed in cells of individuals with Werner syndrome [Hoehn et al 1975, Grigorova et al 2000], but this finding is not diagnostic. Sensitivity to genotoxic agents. Cells isolated from individuals with Werner syndrome are hypersensitive to the genotoxic agent 4-nitroquinoline oxide. Intermediate sensitivity to the genotoxic agent 4-nitroquinoline oxide is exhibited by cells isolated from individuals heterozygous for WRN mutations [Ogburn et al 1997]. However, these cellular phenotypes are not used for diagnostic purposes. Protein analysis. In the majority of affected individuals, WRN mutations result in the absence of protein on western blot analysis (a truncated protein may be detected in rare cases) or immunoblot analysis [Shimizu et al 2002, Muftuoglu et al 2008]. Protein analysis may be clinically useful in certain circumstances (see Testing Strategy).Molecular Genetic TestingGene. WRN [Yu et al 1996] is the only gene in which mutations are known to cause Werner syndrome. Evidence for locus heterogeneity. No other loci associated with typical forms of Werner syndrome have been identified, but it is theoretically possible that mutations in genes encoding proteins that interact with WRN may produce a similar phenotype. Table 1. Summary of Molecular Genetic Testing Used in Werner Syndrome View in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityWRNSequence analysisSequence variants 2, 3~90% 4, 5Clinical Deletion / duplication analysis 6Exonic and multiexonic deletions and duplications 7Unknown1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. 3. Sequence analysis of genomic DNA is unlikely to detect multiexonic deletions and duplications [Huang et al 2006, Uhrhammer et al 2006, Friedrich et al 2010]. 4. Sequence analysis of the WRN coding region detects mutations in both alleles for approximately 90% of affected individuals. The most common pathologic variant is c.1105C>T, which accounts for 20%-25% of mutations in the European and Japanese populations [Matsumoto et al 1997, Friedrich et al 2010]. Founder mutations have been identified in other populations (see Table 2).5. Deep intronic mutations that affect splicing have been reported; these would not be detected during routine genomic sequencing analysis [Friedrich et al 2010].6. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.7. Reported mutations that require deletion/duplication analysis for detection include deletion and duplication of exon(s) [Friedrich et al 2010, Table A. Genes and Databases (see LSDB and HGMD)]. Mutations that occur in an intron and result in creating a new exon as well as multiexonic deletions and duplications have also been reported [Huang et al 2006, Uhrhammer et al 2006, Friedrich et al 2010].Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing Strategy To confirm/establish the diagnosis in a probandThe diagnosis is primarily established by clinical findings (see Clinical Diagnosis) and may include the following evaluations:Ophthalmologic examination for cataractsTesting for diabetes mellitus (e.g., fasting glucose, hemoglobin A1c, oral glucose tolerance test) Radiographs of the hands and/or feet to evaluate for osteosclerosis of the distal phalanges of the fingers and/or toesEvaluation for hypogonadism (e.g., hormone levels) when fertility evaluation is applicable Molecular testing (sequence analysis followed by deletion/duplication analysis if neither or only one mutation is identified) of WRN may confirm the diagnosis.Protein analysis may be useful in certain instances in combination with sequencing analysis, for example:When only one mutant allele that is known to result in absence of protein is identified by sequencing. If protein analysis failed to detect protein, it would be inferred that the second unidentified allele also either fails to produce or alters the protein, thereby providing strong evidence for a diagnosis of WS.When compound heterozygosity is identified where one allele is known to confer absence of protein but the functional consequences of a second missense variant is unknown. Rarely, protein analysis may reveal that the missense variant confers protein instability, which would define it as a pathologic allele. While protein analysis does not distinguish different types of mutations, it provides important supportive evidence for presence of an alteration. Examples not detected by sequence analysis include intronic mutations, such as: (1) the Sardinian founder mutation, c.2089-3024A>G, which creates a new exon resulting in a protein of altered length; and (2) genomic rearrangements including a large multiple-exon deletion resulting in a protein length alteration in affected individuals of German origin. Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) DisordersWerner syndrome is the only phenotype associated with WRN mutations. Bloom syndrome and Rothmund-Thomson syndrome are caused by mutations in closely related but distinct helicase genes. Atypical Werner syndrome is caused by mutations in LMNA (see Differential Diagnosis).
Werner syndrome is characterized clinically 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. ...
Natural HistoryWerner syndrome is characterized clinically 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 onset of cataracts is approximately 31 years [Epstein et al 1966, Huang et al 2006]. 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. Median age of diagnosis ranges from late 30s to 40s [Epstein et al 1966, Tollefsbol & Cohen 1984, Goto 1997, Huang et al 2006].Male to female ratio. The male:female ratio is believed to be 1:1. In the International Registry of Werner Syndrome, women are slightly over-represented, probably because of ascertainment bias; women are more likely than men to present for medical care and tend to have more concern about a youthful appearance.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 [Huang et al 2006]. Similarly the median life span of Japanese individuals with Werner syndrome is 53 years [Goto & Matsuura 2008]. Malignancy. The spectrum of cancers in individuals with Werner syndrome is unusual in that it includes a large number of sarcomas and very rare types of cancers in typical locations [Goto et al 1996, Yamamoto et al 2003]. 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 [Goto et al 1996]. Common types of carcinomas have also been observed.Osteoporosis. The osteoporosis of individuals with Werner syndrome is unusual in that it especially affects the long bones. In contrast, osteoporosis during normative aging preferentially involves the vertebral bodies, particularly in women. Characteristic osteolytic lesions of the distal joints of the fingers are observed on radiograph. Skin. Deep, chronic ulcers around the ankles (Achilles tendon, medial malleolus, lateral malleolus) are highly characteristic.Neurologic. Controversy exists concerning the degree to which the brain is involved. While individuals with Werner syndrome may have central nervous system complications of arteriosclerosis, they do not appear to be unusually susceptible to Alzheimer disease [Martin et al 1999]. 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 [Epstein et al 1966].
The chronologic order of the onset of signs and symptoms is similar in all individuals with Werner syndrome regardless of the specific WRN mutation [Epstein et al 1966, review by Tollefsbol & Cohen 1984, Goto 1997]. ...
Genotype-Phenotype CorrelationsThe chronologic order of the onset of signs and symptoms is similar in all individuals with Werner syndrome regardless of the specific WRN mutation [Epstein et al 1966, review by Tollefsbol & Cohen 1984, Goto 1997]. The specific cell type in which cancer develops may depend on the type of WRN mutation present. In individuals of Japanese descent, papillary thyroid carcinoma has been associated with an N-terminal mutation, whereas follicular thyroid carcinoma is more frequently observed with a C-terminal mutation [Ishikawa et al 1999]. This finding clearly contradicts the original assumption that all identified WRN mutations result in truncation of the nuclear localization signal of WRN protein and thereby act as null mutations. Further studies may reveal additional genotype-phenotype correlations.
The differential diagnosis depends on the presenting symptoms and age of onset....
Differential DiagnosisThe differential diagnosis depends on the presenting symptoms and age of onset.Atypical Werner syndrome characterizes a small subset of individuals in the Werner Syndrome Registry who have normal WRN protein and some signs and symptoms that sufficiently overlap with the Werner syndrome such that clinicians submit their cases to the International Registry. These individuals typically have comparatively early age of onset (early 20s or earlier) and a faster rate of progression of symptoms than those with typical Werner syndrome. Among this group, four of 26 individuals (15%) had novel heterozygous missense mutations in LMNA [Chen et al 2003]. Mandibulo-acral dysplasia (MAD) is a progeroid syndrome characterized by short stature; type A lipodystrophy with loss of fat in the extremities but accumulation of fat in the neck and trunk; thin, hyperpigmented skin; partial alopecia; prominent eyes; beaked nose; tooth loss; small recessed chin; and short fingers [Cavallazzi et al 1960, Cohen et al 1973]. Mutations in LMNA have been reported by Novelli et al [2002] and Cao & Hegele [2003]. MAD with a generalized loss of subcutaneous fat (termed type B lipodystrophy) and insulin resistance has been attributed to compound heterozygous mutations in the zinc metalloproteinase ZMPSTE24 [Agarwal et al 2003].Hutchinson-Gilford progeria syndrome (HGPS or progeria of childhood), like Werner syndrome, affects multiple organs with presentations characterized as accelerated aging. Newborns with HGPS usually appear normal, but profound failure to thrive occurs during the first year. Characteristic facies, partial alopecia progressing to total alopecia, loss of subcutaneous fat, stiffness of joints, bone changes, and abnormal tightness of the skin over the abdomen and upper thighs usually become apparent during the second to third year. Motor and mental development is normal. Individuals with HGPS develop severe atherosclerosis. Death usually occurs as a result of complications of cardiac or cerebrovascular disease generally between age six and 20 years. Average life span is approximately 13 years. About 90% of individuals with HGPS have the p.Gly608Gly mutation in exon 11 of LMNA. Inheritance is autosomal dominant. All individuals with HGPS have a de novo mutation. Early-onset type 2 diabetes with secondary complications of vascular disease and skin complications could mimic some features of Werner syndrome. Though bilateral ocular cataracts (probably presenting as posterior subcapsular cataracts) are one of the most commonly observed features of Werner syndrome, the age of onset is typically in the second decade when graying of hair and skin findings would likely be present. Isolated juvenile cataracts are therefore not likely to be a feature of Werner syndrome. Myotonic dystrophy type 1 or myotonic dystrophy type 2 could be a consideration with young adult-onset cataracts, and adults may show muscle wasting although other manifestations (such as myotonia or cardiac conduction abnormalities) are quite different and onset is usually in adulthood. Scleroderma, mixed connective tissue disorders, and lipodystrophy may have skin features similar to those of Werner syndrome. Distal atrophy and skin ulcerations in the absence of other manifestations characteristic of Werner syndrome could raise the possibility of Charcot-Marie-Tooth disease or familial leg ulcers of juvenile onset. Other cancer-prone syndromes including Rothmund-Thomson syndrome (RTS) (caused by mutations in RECQL4) and Bloom syndrome (caused by mutations in BLM) may be considered if cancer is the presenting symptom. However, RTS and Bloom syndrome are childhood-onset disorders. Werner syndrome cells do not exhibit the increased sister chromatid exchange typical of Bloom syndrome. Li-Fraumeni syndrome (caused by mutations in TP53) may present with multiple cancers, including non-epithelial cancers similar to those observed in Werner syndrome, but juvenile-onset cataracts and other manifestations of Werner syndrome are not part of Li-Fraumeni syndrome. The following conditions share at least two features of Werner syndrome, but are less likely to be confused with the condition because they are characterized by onset in childhood and additional characteristic features:The Flynn-Aird syndrome includes cataracts combined with skin atrophy and ulceration; neurologic abnormalities are also present [Flynn & Aird 1965]. The branchiooculofacial syndrome is characterized by premature graying in adults. Eye findings typically include strabismus, coloboma, and micropthalmia. Dysmorphic facial features are also present. The SHORT syndrome (short stature, hyperextensibility, hernia, ocular depression, Rieger anomaly, and teething delay) may have progeria-like facies and lipodystrophy. Type 2 diabetes mellitus, as well as cataracts and glaucoma, have been reported in affected individuals [Schwingshandl et al 1993, Sorge et al 1996]. Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease in an individual diagnosed with Werner syndrome, the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with Werner syndrome, the following evaluations are recommended:Screen for type 2 diabetes mellitus by standard clinical assays such as fasting glucose level, hemoglobin A1c or oral glucose tolerance test Lipid profile Physical examination for cancers common in Werner syndrome, (e.g., thyroid nodules, skin tumors) Ophthalmologic examination including slit lamp examinationSkin examination for common findings, especially early ulcerations of the feet, with special attention to nail beds and soles of feet for lentiginous melanomaHead MRI if neurologic symptoms including new onset seizures, focal neurologic signs such as weakness or visual field defect, or symptoms such as diploplia or headache are present. These can be indicative of meningioma, a common neoplasm in Werner syndrome.Assessment of coping and psychological fitness in light of prognosis Genetics consultationInfants with Werner syndrome are unaffected at birth, so there are no special precautions or investigations recommended in the neonatal period.Treatment of ManifestationsThe following are appropriate:Aggressive treatment of skin ulcers with standard or novel techniques [Akiyama et al 2000, Yamamoto et al 2003, Yeong & Yang 2004]. Bosentan has been reported to be effective in the treatment of digital ulcers in individuals with systemic sclerosis, and its use has been recently reported to be beneficial in people with Werner syndrome [Matucci-Cerinic et al 2011, Noda et al 2011]. Control of type 2 diabetes mellitus. Favorable results have been reported with use of pioglitazone [Imano et al 1997, Durbin 2004, Yokote et al 2004]. Use of cholesterol-lowering drugs if lipid profile is abnormal. Muscle atrophy is a potential complication. Surgical treatment of ocular cataracts. Complications are common and specific techniques can optimize outcome [Ruprecht 1989, Shintani et al 1993]. Treatment of malignancies in a standard fashion Prevention of Secondary ComplicationsTo prevent secondary complications:Lifestyle counseling for smoking avoidance, regular exercise, and weight control to reduce atherosclerosis risk Excellent skin care, trauma avoidance, and examination to treat problems early SurveillanceAppropriate surveillance includes the following:Screening for type 2 diabetes mellitus at least annually Annual lipid profile At least annual physical examination for malignancies common in Werner syndrome and other skin manifestations Annual ophthalmologic examination for cataracts Attention to symptoms of angina, or peripheral or cerebrovascular disease Agents/Circumstances to AvoidSmoking and excess weight increase the risk of atherosclerosis. Trauma to the extremities should be avoided.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Pregnancy ManagementIn 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 WS are rare, but in the International Registry of Werner Syndrome, many of the women have had offspring. Preterm delivery has been reported in several cases, and has been attributed to cervical incompetence. Preeclampsia is another reported obstetric complication [Murakami et al 2003]. 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 InvestigationSearch ClinicalTrials.gov 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.OtherAffected individuals may benefit from reproductive advice regarding the rapid decline in fertility. Although topical PDGF-BB has been shown to provide some improvement of granulation, it failed to heal the ulcer in a person with Werner syndrome [Wollina et al 2004].
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Werner Syndrome: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDWRN8p12Werner syndrome ATP-dependent helicaseWerner Syndrome Mutational Database WRN homepage - Mendelian genesWRNData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Werner Syndrome (View All in OMIM) View in own window 277700WERNER SYNDROME; WRN 604611RECQ PROTEIN-LIKE 2; RECQL2Molecular Genetic PathogenesisThe mechanism by which WRN mutations cause the Werner syndrome phenotype is not clear. WRN encodes a multifunctional nuclear protein of 1,432 amino acids [Yu et al 1996] that is a member of the RecQ family of DNA helicases. The N-terminal region of the protein encoded by WRN has exonuclease activity as well. DNA-type helicases are ATP-dependent 3'→ 5' helicases that are necessary to maintain genomic integrity in cells. Other human RecQ helicases are encoded by RECQL, BLM (responsible for the Bloom syndrome), RECQL4 (responsible for the Rothmund-Thomson syndrome) and RecQL5 [reviewed by Bohr 2008]. The WRN helicase preferentially unwinds DNA structures, such as tetraplex DNA, double-strand DNA with mismatch "bubbles" and Holliday junctions. It unwinds DNA-DNA double strands as well as DNA-RNA double strands. WRN exonuclease activity also preferentially digests single strands in complex DNA structures, such as double-stranded DNA with mismatched ends or bubbles. WRN helicase and exonuclease activities are modified by binding to interacting proteins (e.g., Ku complex, p53, replication protein A) and by phosophorylation [Bohr 2008, Rossi et al 2010].Biochemical and cell biologic 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 metabolisms and 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 [Bohr 2008, Rossi et al 2010].Normal allelic variants. WRN consists of 35 exons. The allelic variant of unknown significance c.2500C>T was found in populations of Spanish ancestry with a heterozygote frequency of 0.007. This change abolishes helicase and exonuclease activities in vitro. Homozygous individuals could exhibit some of the phenotypes of WS, but this has not been demonstrated [Kamath-Loeb et al 2004].Pathologic allelic variants. More than 70 different disease-causing WRN mutations have been identified. The majority of mutations are stop codons, insertions, or deletions that result in a frame shift or splice donor or acceptor site mutations that result in exon skipping. Several missense mutations that abolish helicase activity or confer protein instability have been reported. Mutations that occur in an intron and result in creating a new exon as well as multiexonic deletions and duplications have also been reported [Huang et al 2006, Uhrhammer et al 2006, Friedrich et al 2010]. The most common pathologic variant is c.1105C>T, which accounts for 20%-25% of mutations in the European and Japanese populations [Matsumoto et al 1997, Friedrich et al 2010]. Founder mutations have been reported in some populations (Table 2). Cancerous tissues obtained from the normal individuals commonly show alterated methylation status of the WRN promoter resulting in transcriptional silencing of WRN [Agrelo et al 2006]. Epigenetic inactivation of WRN would lead to enhanced chromosomal instability.Table 2. Selected WRN Allelic VariantsView in own windowClass of Variant AlleleDNA Nucleotide ChangeProtein Amino Acid ChangeReference SequencesUnknown significancec.2500C>T 1p.Arg834CysNM_000553.4 NP_000544.2Pathologicc.1105C>Tp.Arg369Xc.2089-3024A>G 2 See footnote 3c.2179dupT 4p.Cys727Leufs*5c.3139-1G>C 5See footnote 6c.3460-2A>C 7See footnote 8c.3590delA 9p.Asn1197Thrfs*2See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).1. See Genotype-Phenotype Correlations.2. A founder mutation in the Sardinian population [Masala et al 2007]3. Creates a new exon between exons 18 and 19 that introduces a stop codon and alters the length of the protein [Masala et al 2007]4. Potential founder mutation in Moroccan population [Friedrich et al 2010]5. Founder mutation in Japanese population accounts for approximately 60% of mutations in affected individuals of this group [Satoh et al 1999].6. Results in exon 26 skipping7. Potential founder mutation in Turkish population [Friedrich et al 2010]8. Results in exon 30 deletion9. Potential founder mutation in Dutch population [Friedrich et al 2010]Normal gene product. The normal gene product has 1,432 amino acids. The central region of the WRN protein contains the consensus domains of RecQ type helicases [Gray et al 1997] and the N-terminal region contains exonuclease domains [Huang et al 1998]. A nuclear localization signal is at the C-terminal end of the protein [Suzuki et al 2001]. A highly acidic transactivation sequence is present between exonuclease and helicase domains [Balajee et al 1999]. There are two consensus domains in the C-terminal region whose functions have not been completely elucidated: a RecQ C-terminal conserved (RCQ) region and a helicase RNaseD C-terminal (HRDC) conserved region. The RCQ region, which contains a zinc finger motif and a winged helix motif (WH) may be involved in the regulation of helicase enzymatic activity by modulating DNA binding as well as protein folding of WRN helicase [Kitano et al 2010]. The HDRC region is speculated to mediate protein-protein interactions. Abnormal gene product. A majority of the mutations result in the truncation of the protein. In addition to the loss of the nuclear localization signal in WRN mutant proteins [Huang et al 2006], the mutant mRNAs and the resulting mutant proteins exhibit shorter half-lives than do the wild-type mRNA and WRN protein [Yamabe et al 1997].